1 4

KEY CONCEPTS
Disorders of consciousness include disorders in

which the level of consciousness (arousal or wakefulness) is impaired, such as acute confusional
states and coma, and those in which the level of
consciousness is normal but the content of consciousness is altered, such as dementia and amnestic disorders.
Certain causes of acute confusional state must be

identied urgently because they may lead rapidly
to severe structural brain damage or death, and
prompt treatment can prevent these complications: hypoglycemia, bacterial meningitis, subarachnoid hemorrhage, and traumatic intracranial hemorrhage.
An acute confusional state can be most readily

distinguished from dementia by the time course
of the impairment: acute confusional states are
acute or subacute in onset, typically developing
over hours to days, whereas dementia is a chronic
disorder that evolves over months or years.
The most common causes of dementia are

Alzheimer disease, dementia with Lewy bodies,
and vascular dementia; reversible causes of
dementia are rare, but are important to diagnose.
Consciousness is awareness of the internal or

ushing), hallucinations, and motor abnormalities
external
(tremor, asterixis, or myoclonus).
world, and disorders of consciousness can affect
either the
Disturbances of the Content
level
ofAbnormalities
consciousness
or
the
content
of
Disturbances
of theof
Level
of
the
level
of consciousness
areConsciousness
consciousness.
of Consciousness
characterized by impaired arousal or wakefulMany pathologic conditions can impair the
ness, and they result from acute lesions of the
content of consciousness without altering the
ascending reticular activating system (Figure 11) or
level of consciousness. Examples include isoboth cerebral hemispheres. The most severe degree
lated disorders of language or memory due to focal
of
brain lesions and widespread deterioration of mental
depressed consciousness is coma, in which the
function (dementia) from more diffuse, chronic pathopatient
logic processes. Dementia differs from acute confuis unresponsive and unarousable. Less severe
sional states in several respects (Table 11), and
depression
distinof consciousness results in an acute confusional state
guishing between these two syndromes is the pivotal
or
step in evaluating a patient with altered
delirium, in which the patient responds to at least
consciousness.
some
The time course of the disorderacute or substimuli in a purposeful manner but is sleepy, disoriacute in acute confusional states and chronic in
ented, and inattentive. In some acute confusional
dementiais the single most helpful differenstates, agitation predominates or alternates with
tiating feature.
drowsiConfusional states, dementia, and circumscribed
ness, and may be accompanied by autonomic
changes
(fever, tachycardia, hypertension, sweating, pallor, or
DISORDERS OF COGNITIVE FUNCTION / 3

sional states are acute to subacute in onset, whereas
deThalamus
mentias are chronic disorders. In an acute confusional
state, the observations of others may be the only
historical information available. When dementia is
suspected,
it is useful to have access to a relative or close
acquaintance who can furnish details about the patients
previous level of functioning; the time when dysfunction
became
evident; History
and the nature of any changes in
Prior Medical
personality, behavior, mood, intellect, judgment,
A.
CARDIOVASCULAR SYSTEM
memA
history
of stroke,
hypertension,
vasculitis,
or
ory,
or facility
with language.
Associated
problems
cardiac
such
Brainstem reticular
disease
may suggest
a vascularand
cause
of a
as gait disorders,
incontinence,
headaches
also
activating system
confusional
should be explored.
B.
DIABETES
state
or multiinfarct dementia.
Cognitive disturbance in diabetic patients may result
from a hyperosmolar nonketotic state or insulin-inFigure 11. Brainstem reticular activating system and duced hypoglycemia.
Cerebral hemisphere
its ascending projections to the thalamus and cerebral

hemispheres.
C. SEIZURE DISORDER
A history of epilepsy suggests ongoing seizures, a

memory disorders are discussed in this chapter. postictal state, or head trauma in a confused patient.
Coma
D. HEAD TRAUMA
is discussed in Chapter 10.
Recent head trauma suggests intracranial
hemorrhage.
I. APPROACH TO DIAGNOSIS
Remote head trauma may produce amnestic
syndrome
LCOHOLISM
orofA
chronic
subdural hematoma with dementia.
Evaluation of the patient with a suspected disorderE.
consciousness is aimed rst at characterizing the Alcoholism predisposes patients to acute confusional
states from intoxication, withdrawal, postictal state,
nature
of the disorder (eg, acute confusional state, coma,head trauma, hepatic encephalopathy, and Wernicke
encephalopathy. Chronic memory disturbance in an
dealmentia, amnestic syndrome) and second at
coholic is likely due to Korsakoff syndrome.
determining
HISTORY
the cause.
approach
used is outlined below. F. DRUG HISTORY
History
of The
Present
Illness
A confusional state can result from overdose with inThe history should establish the time course of thesulin, sedative-hypnotics, opioids, antidepressants,
andisorder and provide clues to its nature and cause. tipsychotic agents, or hallucinogens, or from sedative
ConfuTable 11. Differences between acute confusional states and dementia.
Acute Confusional State
Dementia
Level of consciousness
Impaired
Course
Acute to subacute; uctuating
Not impaired, except occasionally late in

course
Chronic; steadily progressive
Autonomic hyperactivity
Often present
Absent
Prognosis
Usually reversible
Usually irreversible
4 / CHAPTER 1
drug withdrawal. Elderly patients may be more sensiFamily History
tive to the cognitive side effects of drugs that are well
The family history can point to a heredodegenerative
tolerated by younger patients.
disorder, such as Huntington disease, as the cause of
dementia.
G. PSYCHIATRIC HISTORY
A history of psychiatric illness may suggest overdose
with psychotherapeutic drugs such as
GENERAL PHYSICAL EXAMINATION
benzodiazepines,
A general physical examination helps to classify the
antidepressants, or antipsychotic agents; a previously
disundiagnosed medical disorder capable of producing
order as either an acute confusional state or
organic psychosis (hypothyroidism, vitamin B12 de- dementia
ciency); or a functional disorder masquerading as and
an may suggest a systemic disease as its cause
(Tables
Vital
Signs & General Appearance
acute
confusional state or dementia.
H.
OTHER
12
and
13).
Individuals who engage in unprotected sexual interFever, tachycardia, hypertension, and sweating occur
course, intravenous drug users, recipients of contamiin
nated blood or clotting factor transfusions, the sexual
many confusional states, but meningitis or sepsis
partners of all these persons, and infants of infected
must
mothers are at particular risk for developing acquired
receive early consideration in the febrile patient. Hyimmunodeciency syndrome (AIDS).
pertension should raise the possibility of hypertensive
encephalopathy, intracranial hemorrhage, renal
disease,
or diagnosis
Cushing syndrome.
Hypothermia
occurs with expoTable 12. Clinical features helpful in the differential
of acute confusional
states.
Feature
Headache
Vital signs
Fever
Hypothermia
Hypertension
Tachycardia
Bradycardia
Most Suggestive of
Feature
Head trauma, meningitis, subarachnoidTetany

hemorrhage
Cranial nerves
Papilledema
Infectious meningitis, anticholinergic
intoxication, withdrawal from ethanol
Dilated pupils
or sedative drugs, sepsis
Intoxication with ethanol or sedative
drugs, hepatic encephalopathy, hypoConstricted
glycemia, hypothyroidism, sepsis
pupils
Anticholinergic intoxication,withdrawal
Nystagmus/
from ethanol or sedative drugs,hypertensive encephalopathy,subarachnoid hem- ophthalmoorrhage,sympathomimetic intoxication plegia
Motor
Anticholinergic intoxication, withdrawal
Tremor
from ethanol or sedative drugs, thyrotoxicosis, sepsis
Hypothyroidism
Asterixis
HyperventilationHepatic encephalopathy, hyperglycemia,
Hemiparesis
sepsis
Hypoventilation Intoxication with ethanol or sedative
drugs, opioid intoxication, pulmonary Other
Seizures
encephalopathy
General examination
MeningismusMeningitis, subarachnoid hemorrhage
Skin rash
Meningococcal meningitis
Ataxia
Most Suggestive of
Hypocalcemia
Hypertensive encephalopathy, intracranial mass
Head trauma, anticholinergic intoxication, withdrawal from ethanol or sedative
drugs, sympathomimetic intoxication
Opioid intoxication
Intoxication with ethanol, sedative
drugs, or phencyclidine, vertebrobasilar
ischemia,Wernicke encephalopathy
Withdrawal from ethanol or sedative
drugs, sympathomimetic intoxication,
thyrotoxicosis
Metabolic encephalopathy
Cerebral infarction, head trauma, hyperglycemia, hypoglycemia
Withdrawal from ethanol or sedative
drugs, head trauma, hyperglycemia,
hypoglycemia
Intoxication with ethanol or sedative
drugs,Wernicke encephalopathy

Table 13. Clinical features helpful in the differential diagnosis of dementia.
Feature
Most Suggestive of
History
Unprotected sexual
AIDS dementia complex
intercourse, intravenous
drug abuse, hemophilia,
or blood transfusions
Family history
Headache
Vital signs
Hypothermia
Huntington disease,Wilson
disease
Hypothyroidism
Multiinfarct dementia
Hypotension
Hypothyroidism
Bradycardia
Hypothyroidism
Acquired hepatocerebral
degeneration
Kayser-Fleischer rings
Wilson disease
Cranial nerves
Papilledema
Ophthalmoplegia
Progressive supranuclear palsy
Pseudobulbar
palsy
Multiinfarct dementia, progressive supranuclear palsy

Dementia with Lewy bodies, corticobasal ganglionic degeneration,
acquired hepatocerebral degeneration,
Wilson disease, AIDS dementia complex
Asterixis
Acquired hepatocerebral degeneration
Myoclonus
Creutzfeldt-Jakob disease, AIDS dementia complex
Rigidity
Dementia with Lewy bodies, corticobasal ganglionic degeneration,

acquired hepatocerebral degeneration,
Creutzfeldt-Jakob disease, progressive
supranuclear palsy,Wilson disease
Chorea
Huntington disease,Wilson disease
Chronic meningitis
Jaundice
Most Suggestive of
Argyll Robertson Neurosyphilis

pupils
Motor
Tremor
Brain tumor, chronic subdural
hematoma
Hypertension
General examination
Meningismus
Feature
Other
Gait apraxia
Normal pressure hydrocephalus

Brain tumor, chronic subdural Polyneuropathy Neurosyphilis, vitamin B12 deciency,
hematoma
with hypoAIDS dementia complex
reexia
sure to cold, ethanol or sedative drug intoxication,Head & Neck

hypoglycemia, hepatic encephalopathy, Wernicke en-Examination of the head may reveal signs of trauma,
such as scalp lacerations or contusions, postauricular
cephalopathy, hypothyroidism, or shock. In most dementias, the patient does not appear acutely ill hematoma (Battle sign), periorbital hematoma
(raccoon
unless a suggests hepatic disease, and lemon-yellow
Jaundice
eyes), hemotympanum, or cerebrospinal uid (CSF)
systemic
coloration
disorder
of the Membranes
skin
is also
maypresent.
occur in vitamin B12 deSkin & Mucous
otorrhea or rhinorrhea. Percussion of the skull over a
ciency. Coarse dry skin, dry brittle hair, and subcutaneous edema are characteristic of hypothyroidism.subdural hematoma may cause pain. Meningeal
signs,
Pesuch as neck stiffness on passive exion, thigh exion
techiae are seen in meningococcemia, and petechiae
upon exion of the neck (Brudzinski sign), or resistor
ecchymoses may reect coagulopathy caused by ance to passive extension of the knee with the hip
exed (Kernig sign), are seen in meningitis and subliver
arachnoid hemorrhage.
disease, disseminated intravascular coagulation, or
Chest & Abdomen
thrombotic thrombocytopenia purpura. Hot, dry skin
is characteristic of intoxication with anticholinergicCardiac murmurs may be associated with infective
drugs. Cushing syndrome may be associated with endocarditis and its neurologic sequelae. Abdominal exacne.
Hyperpigmentation of the skin may be evidence ofamination may reveal a source of systemic infection
or
Adsuggest liver disease. Rectal examination may
dison disease. Needle tracks associated with
provide
intravenous
drug use suggest drug overdose, AIDS, or infectiveevidence of gastrointestinal bleeding, which often
preencipitates hepatic encephalopathy.
docarditis.
6 / CHAPTER 1
NEUROLOGIC EXAMINATIONS
Mental Status Examination
Table 15. Minimental status examination.

Item
Points1
Evaluation of mental status (Table 14) helps to

Orientation
classify
Time (1 point each for year, season, month,
a disorder as a confusional state, dementia, a circumdate, and day of the week)
5
scribed cognitive disturbance (aphasia, amnesia), or
a
Place (1 point each for state, county, city,
psychiatric illness. The mental status examination is building, and oor or room)
5
most useful if performed in a standardized fashion,
Registration
and
Repeat names of three objects (1 point per object)
3
complex functions can be adequately evaluated only
when the basic processes upon which they dependAttention and calculation
Serial 7s or spell world backward (1 point
are
5
preserved. Thus, memory, language, calculation, or per subtraction or letter)
abRecall
straction cannot be assessed reliably in a patient who
Recall names of three objects repeated
is
previously (1 point per object)
3
poorly arousable or inattentive. The Minimental
Language
Status
Name pencil and watch (1 point each)
2
Examination
(Table 15) is mental
often used
as a rapid bedTable
14. Comprehensive
status
side screening test for dementia.
examination.
Repeat no ifs, ands, or buts
1
In performing the mental status examination, the
3
level of consciousness and attention are evaluated Follow three-step command (1 point per step)
Level of consciousness
rst.
Attention and concentration
Read and follow:close your eyes
1
If
these are
impaired,
Language
and
speech an acute confusional state
Write a complete sentence
1
exists,
Comprehension
Repetition
Fluency
Naming
Reading
Writing
Calculation
Speech
Mood and behavior
Content of thought
Hallucinations
Delusions
Abstraction
Judgment
Memory
Immediate recall
Recent memory
Remote memory
Integrative sensory function
Astereognosis
Agraphesthesia
Two-point discrimination
Allesthesia
Extinction
Unilateral neglect and anosognosia
Disorders of spatial thought
Integrative motor function
Apraxia
Construction
Copy two intersecting pentagons
Total
30
1Atotal score of should generally lead to more detailed

investigation of the possibility of dementia, although norms
vary to some extent with age and education.
AdaptedfromGreenbergDA:Dementia.In:Geri
arc.LonerganET(editor),Appleton&Lange,tis
and it may be difcult or impossible to conduct the

remainder of the mental status examination. If the level
of consciousness and attention are adequate, more
complex
functions are examined next to
A.
LEVEL OFcortical
CONSCIOUSNESS
deterThe
level of consciousness is described in terms of
mine
the whether there is global cortical dysfunction,
which
indicates
dementia.
patients
apparent
state of wakefulness and response
to
stimuli. Impairment of the level of consciousness
should always be documented by a written
description
of the patients responses to specic stimuli rather
than
by the use of nonspecic and imprecise terms such
as
lethargy, stupor, or semicoma.
1. NormalThe patient with a normal level of
consciousness appears awake and alert, with eyes
open
at rest. Unless there is deafness or a language
disorder,

verbal stimulation results in appropriate verbal re-guage, is mediated by the lower cranial nerves and
sponses.
their
2. ImpairedMild impairment of consciousness supranuclear connections. Dysarthria, a disorder of
may be manifested by sleepiness from which the arpatient is easily aroused when spoken to. As con- ticulation, is sometimes difcult to distinguish from
sciousness is further impaired, the intensity of stimuaphasia, but it always spares oral and written
lation required for arousal increases, the duration of
language
arousal declines, and the responses elicited become
comprehension and written expression.
less purposeful.
Aphasia may be a feature of diffuse cortical
disease,
B. ATTENTION
as it is in certain dementias, but language
Attention is the ability to focus on a particular
impairment
sensory
with otherwise normal cognitive function should sugstimulus to the exclusion of others; concentration gest
is
a focal lesion in the dominant hemisphere. A dissustained attention. These processes are grossly imorder of comprehension (receptive, or Wernicke,
paired in acute confusional states, usually less
aphaimpaired
sia) commonly leads to a false impression of a
in dementia, and unaffected by focal brain lesions.confusional
Atstate or psychiatric disturbance.
tention can be tested by asking the patient to repeatThere are a variety of aphasic syndromes, each
a
charseries of digits or to indicate when a given letter acterized by a particular pattern of language impairappears
ment; several have fairly precise pathoanatomic
in a
randomAND
series.
A normal person can repeat ve
C.
LANGUAGE
SPEECH
correlato essential elements of language are
The
tions. In addition to the most classic syndromes,
seven digits correctly and identify a letter in a series
comprehension,
described in Figure 12, variations are sometimes obwithout
error.
repetition,
uency, naming, reading, and writing, all
served. For example, global aphasia refers to a synof
drome that incorporates elements of both expressive
which should be tested when a language disorder and receptive aphasia; however, it does not imply
(aphasia) is suspected. Calculation disorders
that
(acalculia)
aphasia is complete, and some degree of comprehenare probably closely related to aphasia. Speech, the
sion and of uency may be preserved. Transcortical
moaphasias are conditions in which Wernicke area, the
Arcuate fasciculus
tor activity that is the nal step in the expression of
arlancuate fasciculus, and Broca area are themselves preserved, but their connections to other parts of the
brain
are interrupted. These disconnection syndromes may
be distinguished clinically by the fact that, since the
circuit comprising Wernicke area, the arcuate fasciculus,
and Broca area is intact, repetition is preserved.
Broca area
Wernicke area
Language Functions Preserved
Pathologic Site
Wernicke area
Arcuate fasciculus
Broca area
Type of
Aphasia
Receptive
Conductive
Expressive
Comprehension
+
+
Figure 12. Anatomic basis and clinical features of aphasias.
Repetition
Fluency
+
+
8 / CHAPTER 1
D. MOOD AND BEHAVIOR
terograde or posttraumatic amnesia, impairment of
Demented patients may be apathetic, inappropriately
memory in the period following the insult.
elated, or depressed, and their moods can uctuate. 3. Testing of memoryMemory is assessed cliniIf
cally by testing immediate recall, recent memory,
the examination is otherwise normal, early dementia
and
easily can be confused with depression. Delirious paremote memory, which correspond roughly to
tients are agitated, noisy, and easily provoked to registraE. CONTENT OF THOUGHT
anger.
tion, storage, and retrieval, respectively.
Abnormalities of thought content can help to distin- a. Immediate recallTests of immediate recall are
guish organic from psychiatric disease. Visual hallucisimilar to tests of attention and include having the
nations are common in acute confusional states, pawhereas auditory hallucinations and xed delusions
tient repeat a random series of numbers or other
are most common with psychiatric disorders. ImpairinforF. MEMORY
ment of abstraction may be revealed by the patients
mation that has not been learned previously. The
1. Functional components of memoryMemory is
concrete (literal) interpretation of proverbs or inability
ability
the ability to register, store, and ultimately retrieve
to recognize conceptual differences and similarities.
to repeat implies that the material has been
inJudgment is commonly tested by asking what the paregistered.
formation. Storage and retrieval of memories can be
tient would do in a hypothetic situation, such as ndimpaired by either diffuse cortical disease or focal Most normal adults can repeat a series of seven
ing a stamped, addressed letter on the sidewalk. numbers
bilatforward and ve backward without difculty.
eral dysfunction of the medial temporal lobes or their
b. Recent memoryTests of recent memory assess
connections.
the
a. RegistrationThe ability to receive information ability to learn new material. Typically, the patient
through the various sensory modalities is largely ais given three or four items to remember and asked
to
funcrecall them 3 minutes later. Nonverbal tests, in which
tion of attention.
b. StorageThe process whereby selected new an
in- object previously shown to the patient is selected
from
formation is learned, or memorized, may be mediated a group of objects, may be useful, especially for
by limbic structures, including the hippocampus. patients with expressive aphasia. Orientation to place
and time, which requires newly learned information,
Stored memories are reinforced by repetition and by
is
emotional signicance; they are thought to be
another important test of recent memory.
diffusely
c. Remote memoryThe practical distinction bedistributed in association areas of the cerebral cortex.
G.
INTEGRATIVE
ENSORY FUNCTION
tween
recent Sand
remote memory is that only recent
c. RetrievalRetrieval is the ability to access previSensory
integration
disorders
from parietal
memory
requires
an
ongoing ability
to learnlobe
new
ously learned information.
lesions
infor2. AmnesiaMemory disorder (amnesia) may be
are
manifested
misperception
inattention
mation.
Remoteby
memory
is testedofbyorasking
the to
an isolated decit or one feature of global cognitive
sensory
stimuli
on
the
contralateral
side
of
the
body,
dysfunction. In acute confusional states, attention patient
is
when
the
primary
sensory
modalities
are
intact.
recall material that someone of comparable
impaired, resulting in defective registration and antoinPatients with parietal lesions may exhibit the
cultural
ability to learn new material. In dementia, attention
is
followeducational background can be assumed to
typically normal and problems with recent andtoand
a
ing
signs:
know.
lesser extentremote memory usually predominate.1. AstereognosisThe patient cannot identify, by
Common examples are personal, historical, or
In psychogenic amnesia, subjective and
touch,
an object placed in the hand.
geographic
emotionally
2.
AgraphesthesiaThe
patient
is unable
to idendata, but the questions selected
must
be appropriate
charged memories are affected more than retention
tify
a
number
written
on
the
hand.
for
of
3.patient,
Absence
of personal
two-pointitems
discriminationThis
is
and
must be veriable.
objective facts and events; in organic amnesia, thethe
an inability to differentiate between a single stimulus
reand two simultaneously applied adjacent, but sepaverse is true. Isolated loss of memory for personalrated, stimuli that can be distinguished by a normal
idenperson.
tity (the inability to remember ones own name) in an4. AllesthesiaThis is misplaced localization of a
awake and alert patient is virtually pathognomonictactile
of
stimulus.
a
5. ExtinctionA visual or tactile stimulus is perpsychogenic disorder.
ceived when applied alone to the side contralateral to
Additional terms sometimes used to denote
the lesion but not when stimuli are applied bilaterally.
aspects
6. Unilateral neglect and anosognosiaBody imof acute-onset amnesia (eg, following head trauma)
age disorders caused by parietal lobe lesions take the
inform of unilateral neglect. The patient tends not to
clude retrograde amnesia, loss of memory for events
use
immediately prior to the onset of the disorder, and
an-

the contralateral limbs, may deny that there is
C. MULTIPLE CRANIAL NEUROPATHIES
anything
These can accompany infectious or noninfectious
wrong with them (anosognosia), and may even failmeningitis
to
or AIDS dementia complex.
recognize them.
7. Disorders of spatial thoughtThese include conMotor Findings
structional apraxia, right/left disorientation, and neglect of external space on the side opposite the
A. ACUTE CONFUSIONAL STATE
affected
In the acutely confused patient, a variety of motor
parietal lobe. Tests for constructional apraxia include
abhaving the patient ll in the numbers on a clock face,
normalities may suggest the cause.
H.
INTEGRATIVE
MOTOR
FUNCTION
copy
geometric
gures,
or build gures with blocks. 1. Hemiparesis is most apt to be due to an intracraApraxia is the inability to perform previously learned
nial structural lesion, although focal neurologic signs
tasks, such as nger snapping or clapping the hands
may be present in metabolic disorders such as hypotoglycemia and nonketotic hyperglycemia.
gether, despite intact motor and sensory function. 2. Tremor is common in sedative drug or ethanol
Uniwithdrawal and other states accompanied by
lateral apraxias are commonly caused by
autonomic
contralateral
hyperactivity.
premotor frontal cortex lesions. Bilateral apraxias, 3. Asterixis, a apping tremor of the outstretched
such
hands or feet, is seen in hepatic, renal, and
Gait
& Station
as gait apraxia, may be seen with bifrontal or diffuse
pulmonary
cerebral
lesions.
It
is useful
to observe the patient standing and
encephalopathy and in drug intoxication.
walking
4. Myoclonus, which consists of rapid shocklike
early in the neurologic examination, since these muscle contractions, can occur with uremia, cerebral
activihypoxia, or hyperosmolar nonketotic states.
ties may reveal additional neurologic abnormalities 5. Cerebellar signs such as broad-based ataxic gait
asCranial Nerves
and, often, dysmetria on heel-knee-shin maneuver
sociated with disturbed cognitive function.
B. DEMENTIA
In patients with impaired cognitive function, abnor-acMotor
signs
are useful
in the differential
company
Wernicke
encephalopathy
and diagnosis
sedative of
malities associated with cranial nerves may suggest
dementia.
drug
the
1. ChoreaHuntington disease, Wilson disease.
intoxication.
underlying cause.
2. Tremor, rigidity, or bradykinesiaWilson disA. LESIONS OF THE EYES AND EARS
ease,
acquired hepatocerebral degeneration.
1. Papilledema suggests an intracranial mass,
3.
MyoclonusCreutzfeldt-Jakob
disease, AIDS
hyperdementia
complex.
tensive encephalopathy, or other process that
4. AtaxiaSpinocerebellar degenerations, Wilson
increases
disease, paraneoplastic syndromes, Creutzfeldt-Jakob
intracranial pressure.
2. In the confused patient, pupillary constrictiondisease, AIDS dementia complex.
5. ParaparesisVitamin B12 deciency, hydrosuggests opiate ingestion; dilated pupils are
cephalus, AIDS dementia complex.
characteristic of anticholinergic intoxication but may also be a
manifestation of generalized sympathetic
Abnormalities of Sensation
hyperactivity.
& Tendon Reexes
Small, irregular pupils that react poorly to lightbut
Dementias associated with prominent sensory abnorbetter to accommodationcan be seen in neumalities and loss of tendon reexes include vitamin
rosyphilis.
3. Sedative drugs and Wernicke encephalopathyB12
neurosyphilis, and AIDS dementia
B.
PSEUDOBULBAR
PALSYor ophthalmoplegia. Selectivedeciency,
produce
nystagmus
imcomplex.
This
syndrome
is
characterized
by
dysarthria,
pairment of vertical gaze (especially downward) Primitive Reexes
dysphaoccurs
A number of reexes that are present in infancy and
gia,
jaw supranuclear
jerk and gag reexes,
and
earlyhyperactive
in progressive
palsy.
subsequently disappear may be released by frontal
uncontrollable laughing or crying unrelated to emotionallobe
dysfunction in later life. It is presumed that such
state (pseudobulbar affect). It results from bilateral
release
interruption of the corticobulbar and corticospinal results from loss of cortical inhibition of these
primitive
tracts.
(frontal release signs), which include palmar
Dementing processes that produce this syndrome reexes
inand
plantar
grasps as well as palmomental, suck,
clude progressive supranuclear palsy and multiinfarct
snout,
dementia.
10 / CHAPTER 1
rooting, and glabellar reexes. Although these
contraction of ipsilateral chin (mentalis) and perioral
responses
(orbicularis oris) muscles.
are often seen in both acute confusional states and 4. The suck reex consists of involuntary sucking
demovements following the stimulation of the lips.
mentia, many can also occur in normal elderly adults.
5. The snout reex is elicited by gently tapping the
Their presence alone does not constitute evidencelips
of and results in their protrusion.
cognitive dysfunction.
6. In the rooting reex, stimulation of the lips
1. The palmar grasp reex is elicited by strokingcauses them to deviate toward the stimulus.
the
7. The glabellar reex is elicited by repetitive tapskin of the patients palm with the examiners ngers.
ping on the forehead. Normal subjects blink only in
If
rethe reex is present, the patients ngers close
sponse to the rst several taps; persistent blinking is
around
an
those of the examiner. The force of the patients abnormal
response
(Myerson sign).
LABORATORY
INVESTIGATIONS
grasp
Laboratory studies are critical in diagnosing disorders
may increase when the examiner attempts to
of
withdraw
cognitive function. Useful investigations are listed in
the ngers, and the patient may be unable to
Tavoluntarily
release
the grasp. studies in acute confusional states.
Table
16. Laboratory
2. The plantar grasp reex consists of exion and
adduction
of the toes Most
in response
to stimulation of
Test
Useful in Diagnosis of
Test
Most Useful in Diagnosis of
the
sole
Bloodof the foot.
ECG
Anticholinergic intoxication, vascuWBC
3. The palmomental
reex is
elicited bysepsis
scratching
lar disorders
Meningitis,
encephalitis,
along the length of the palm of the hand and results
Cerebrospinal uid
Hepatic encephalopathy
in PT and PTT
Arterial blood gas Hepatic encephalopathy, pulmonary encephalopathy, uremia,
sepsis
WBC, RBC
Meningitis, encephalitis, subarachnoid hemorrhage
Grams stain
Bacterial meningitis
Sodium
Hyponatremia
AFB stain
Tuberculous meningitis
Serum urea
nitrogen and
creatinine
Uremia
India ink stain
Cryptococcal meningitis
Cultures
Infectious meningitis
Glucose
Hyperglycemia, hypoglycemia
Cytology
Leptomeningeal metastases
Osmolality
Alcohol intoxication, hyperglycemia Glutamine

VDRL
Hepatic encephalopathy, Reye
Liver function
tests, ammonia syndrome
Thyroid function
tests
Hyperthyroidism, hypothyroidism
Calcium
Hypercalcemia, hypocalcemia
Drug screen
Drug intoxications
Cultures
Meningitis, sepsis
FTA or MHA-TP
Syphilitic meningitis
HIV antibody titer AIDS and related disorders

Urine, gastric aspirate
Drug screenDrug intoxication
Stool
Guaiac
Cryptococcal
antigen
Polymerase chain Bacterial meningitis, tuberculous

reaction
meningitis, syphilitic meningitis,
Lyme disease, viral meningitis and
encephalitis, AIDS, leptomeningeal
metastases
CT brain scan or MRI Cerebral infarction, intracranial
hemorrhage, head trauma, toxoplasmosis, herpes simplex
encephalitis, subarachnoid hemorrhage
EEG
Complex partial seizures, herpes

simplex encephalitis, nonconvulsive
seizures

bles 16 and 17; those most likely to establish or Table 18. Arterial blood gases in acute
supconfusional states.
port a diagnosis in acute confusional states are
complete
Pattern
Differential Diagnosis
blood count, arterial blood gases and pH, serum
sodium, serum glucose, serum urea nitrogen and Metabolic acidosis (with Diabetic ketoacidosis, lactic
creatiincreased anion gap) acidosis (postictal, shock, sepsis),
toxins (methanol, ethylene glynine, liver function tests, drug screens, blood
col, salicylates,1 paraldehyde),
cultures,
uremia
stool test for occult blood, lumbar puncture, brain
comRespiratory alkalosis
Hepatic encephalopathy, pulputed tomography (CT) scan or magnetic resonance
monary insufciency,
imaging (MRI), and electroencephalogram (EEG).
salicylates,1 sepsis
Some of these studies can yield a specic
Respiratory acidosis
Pulmonary insufciency, sedadiagnosis.
tive drug overdose
Abnormal arterial blood gas or cerebrospinal uid
(CSF) proles, for example, narrow the differential 1diSepsis and salicylates produce a combined acid-base disagnosis to one or a few possibilities (Tables 18 and
order.
19).
Reversible dementia may be diagnosed on the
basis
II.
ACUTE CONFUSIONAL
STATES
of laboratory
studies (see Table 17).
The most comDRUGS
mon reversible dementias are those due to
Many drugs can cause acute confusional states, espeintracranial
Common causes of acute confusional states are listed
cially when taken in greater than customary doses, in
masses,
normal pressure hydrocephalus, thyroid dysin
combination with other drugs, by patients with
function,
and vitamin B12 deciency.
Table 110.
altered
drug metabolism from hepatic or renal failure, by the
elderly, or in the setting of preexisting cognitive
Table 17. Laboratory studies in dementia.
impairTest
Most Useful in Diagnosis of ment. A partial list of drugs that can produce acute
confusional
states is provided in Table 111.
ETHANOL
INTOXICATION
Ethanol intoxication
produces a confusional state with
Blood
nystagmus,
dysarthria,
and limb and gait ataxia. In
Hematocrit, mean
Vitamin B12 deciency
noncorpuscular volume
(MCV), peripheral
alcoholics, signs correlate roughly with blood ethanol
blood smear, vitamin
levels, but chronic alcoholics, who have developed
B12 level
tolerance to ethanol, may have very high levels without
Thyroid function tests Hypothyroidism
appearing intoxicated. Laboratory studies useful in conLiver function tests
Acquired hepatocerebral
degeneration,Wilson disease rming the diagnosis include blood alcohol levels and
serum osmolality. In alcohol intoxication, serum
Ceruloplasmin, copper Wilson disease
osmolality determined by direct measurement exceeds the
FTA or MHA-TP
Neurosyphilis
calHIV antibody titer
AIDS dementia complex
culated osmolality (2 serum sodium + 120 serum gluCerebrospinal uid
cose + 13 serum urea nitrogen) by 22 mosm/L for
VDRL
Neurosyphilis
every
100 mg/dL of ethanol present. Intoxicated patients
Cytology
are
CT scan or MRI
Brain tumor, chronic subdural at high risk for head trauma. Alcohol ingestion may
hematoma, multiinfarct demencause
life-threatening
hypoglycemia, and chronic
ETHANOL
WITHDRAWAL
tia, normal pressure hydroalcocephalus
Three
are recognized
holismcommon
increaseswithdrawal
the risk ofsyndromes
bacterial meningitis.
(Figure
13). Because of the associated risk of
TreatEEG
Creutzfeldt-Jakob disease
Wernicke
ment is not required unless a withdrawal syndrome
encephalopathy
(discussed later), patients presenting
ensues, but alcoholic patients should receive thiamine
to
prevent Wernicke encephalopathy (see below).
12 / CHAPTER 1
Table 19. Cerebrospinal uid proles in acute confusional states.
Opening Red Blood

Appearance PressureCells
White
Blood
Cells
Glucose
Protein Glutamine Smears Cultures
Normal
Clear,
colorless
70200 0/L
mm H2O
mono-
nuclear/ mg/dL
1
mg/dL
Bacterial
meningitis
Cloudy
Normal
(PMN)2
Tuberculous
meningitis
Normal or
cloudy
Normal
(MN)3,5
Fungal
meningitis
Normal or Normal
cloudy
or
Normal
(MN)
Viral meningitis/
encephalitis
Normal
Normal4 (MN)5
Normal
or
Normal
Gram
stain
Normal
AFB stain
Normal
India ink
prep
(Cryptococcus)
Normal6 Normal
or
Normal
Parasitic meningitis/
Normal or Normal
encephalitis
cloudy
or
Normal
(MN,E)7 Normal
Normal
or
Normal
Amebas
may be
seen on
wet
mount
Leptomeningeal
metastases
Normal or Normal
cloudy
or
Normal
Normal
or (MN)
Normal
or
Normal
Cytology
Subarachnoid
hemorrhage
Pink-red
(supernatant
yellow)
Normal
or
(PMN)8
Normal
or 8
Normal
Normal
Normal
Normal
Normal
Normal
Hepatic
Normal
encephalopathy
1
Lumbar cerebrospinal uid.

PMN, polymorphonuclear predominance.
3 MN, mononuclear (lymphocytic or monocytic) predominance.
4 Red blood cell count may be elevated in herpes simplex encephalitis.
5 PMN predominance may be seen early in course.
6 Glucose may be decreased in herpes or mumps infections.
7 E, eosinophils often present.
8 Pleocytosis and low glucose, sometimes seen several days after hemorrhage, reect chemical meningitis caused by
subarachnoid blood.
positive; negative; can be positive or negative.
2
with these syndromes should be given thiamine, 100

ness, agitation, anorexia, nausea, insomnia,
mg/d, intravenously or intramuscularly, until a normal
tachycardia,
diet can be ensured.
and hypertension. Confusion, if present, is mild. Illusions and hallucinations, usually visual, occur in
1. TREMULOUSNESS & HALLUCINATIONS
about
This self-limited condition occurs within 2 days after
25% of patients. Treatment with diazepam, 520 mg,
cessation of drinking and is characterized by
or chlordiazepoxide, 2550 mg, orally every 4 hours,
tremulouswill terminate the syndrome and prevent more
serious
consequences of withdrawal.

Table 110. Common causes of acute confusional states.
Metabolic Disorders
Drugs1
Ethanol intoxication
Ethanol withdrawal
Sedative drug intoxication
Sedative drug withdrawal
Opioids
Anticholinergics
Phencyclidine
Endocrine disorders
Hypothyroidism
Hyperthyroidism
Hypoglycemia
Hyperglycemia
Electrolyte disorders
Hyponatremia
Hypocalcemia
Hypercalcemia
Nutritional disorders
Wernicke encephalopathy
Organ system failure
Reye syndrome
Uremia
Dialysis disequilibrium
Pulmonary encephalopathy
Organ transplantation
1 See
Infectious and Noninfectious Meningitis/Encephalitis

Bacterial meningitis
Viral meningoencephalitis
Herpes simplex virus encephalitis
AIDS
Fungal meningitis
Parasitic infections
Vascular Disorders
Hypertensive encephalopathy
Subarachnoid hemorrhage
Vertebrobasilar ischemia
Right (nondominant) hemisphere infarction
Systemic lupus erythematosus
Disseminated intravascular coagulation
Thrombotic thrombocytopenic purpura
Head Trauma
Concussion
Intracranial hemorrhage
Seizures
Postictal state
Complex partial seizure
also Table 111.
2. SEIZURES
lasts for up to 72 hours. It is characterized by confuEthanol withdrawal seizures occur within 48 hours sion,
of agitation, fever, sweating, tachycardia,
abstinence, and within 724 hours in about two-thirds
hypertenof cases. Roughly 40% of patients who experiencesion, and hallucinations. Death may result from conseizures have a single seizure; more than 90% have
comitant infection, pancreatitis, cardiovascular
becollapse,
tween one and six seizures. In 85% of the cases, the
or trauma. Treatment consists of diazepam, 1020 mg
inintravenously, repeated every 5 minutes as needed
terval between the rst and last seizures is 6 hoursuntil
or
less. Anticonvulsants are usually not required, as the patient is calm, and correction of uid and elecseizures cease spontaneously in most cases. Unusual
trolyte abnormalities and hypoglycemia. The total refeaquirement for diazepam may exceed 100 mg/h. Contures such as focal seizures, prolonged duration ofcomitant receptor blockade with
SEDATIVE DRUG INTOXICATION
seizures (>612 hours), more than six seizures, atenolol,
status
The
classic
signs
ofhas
sedative
drug overdose are
50100
mg/d,
also
been recommended.
epilepticus, or a prolonged postictal state should confuprompt a search for other causes or complicating facsional state or coma, respiratory depression, hypotentors, such as head trauma or infection. The patientsion, hypothermia, reactive pupils, nystagmus or abshould be observed for 612 hours to make certainsence of ocular movements, ataxia, dysarthria, and
that
hyporeexia. The most commonly used sedative-hyp3.
DELIRIUM
TREMENSare not present. Because patientsnotic drugs are benzodiazepines and barbiturates.
atypical
features
This
with most serious ethanol withdrawal syndrome typiGlutethimide or very high doses of barbiturates may
cally
beginsseizures
35 daysmay
after
cessation
of drinking
and
withdrawal
develop
delirium
tremens,
produce large, xed pupils. Decerebrate and
didecorticate
azepam or chlordiazepoxide is sometimes given posturing can occur in coma that is caused by
prophysedative
lactically.
14 / CHAPTER 1
Table 111. Some therapeutic drugs associated
with acute confusional states.
Acyclovir
Disulram
Amantadine
Ergot alkaloids
Aminocaproic acid
Ethanol
Amphetamines
Ganciclovir
Anticholinergics
Hallucinogens
Anticonvulsants
Isoniazid
Antidepressants
Ketamine
Antihistamines (H1 and H2) Levodopa
Antipsychotics
Lidocaine
L-Asparaginase
Methylphenidate
Baclofen
Methylxanthines
Barbiturates
Nonsteroidal antiinammaBenzodiazepines
tory drugs
Opioids
receptor antagPenicillin
onists
Phenylpropanolamine
Cephalosporins
Quinacrine
Chloroquine
Quinidine
Clonidine
Quinine
Cocaine
Salicylates
Corticosteroids
Selegiline
Cycloserine
Thyroid hormones
Cyclosporine
Digitalis glycosides
monia and pulmonary edema caused by uid

overload.
Barring the development of infections or
cardiovascular
complications, patients who arrive at the hospital
with
adequate cardiopulmonary function should survive
SEDATIVE
DRUG WITHDRAWAL
without sequelae.
Clinical Findings
Like ethanol, sedative drugs can produce confusional

states or seizures when intake is stopped abruptly.
The
frequency and severity of withdrawal syndromes depend upon the duration of drug intake and the dose
and half-life of the drug. They occur most often in patients taking large doses for at least several weeks.
Intermediate- or short-acting agents are those most likely
to
produce withdrawal symptoms when discontinued.
Withdrawal syndromes commonly develop 13
days
after cessation of short-acting agents but may not appear until a week or more after longer-acting drugs
are
discontinued. Symptoms are identical to those of
drug overdose. The diagnosis can be conrmed byethanol withdrawal and are similarly self-limited. Myoclonus and seizures may appear after 38 days,
toxicologic analysis of blood, urine, or gastric aspirate,however, and may require treatment. Seizures usually
but
occur
blood levels of short-acting sedatives do not correlate
only when the average daily drug intake is several
with clinical severity.
times
Management is directed at supporting the patients
respiratory and circulatory function while the drugthe
is usual therapeutic dose. A syndrome indistinguishable
being cleared. Complications include aspiration pneu- from delirium tremens may also occur, and also
tends to be restricted to patients taking several times
60
Tremulousness and hallucinations
Percentage
the drugs daily sedative dose.
onset in each
Sedative drug withdrawal syndrome can be congroup50
Seizures
rmed by evaluating the patient about 1 hour after
ad40
ministering pentobarbital, 200 mg orally or intramus30
cularly. The absence of signs of sedative drug
Delirium tremens
intoxication (sedation, nystagmus, dysarthria, or
OPIOIDS
20
ataxia)
establishes
the patient
is tolerant
to sedative
Opioids can that
produce
analgesia,
mood changes,
confu10
drugs
sional states, coma, respiratory depression,
and
makes sedative drug withdrawal a likely
pulmonary
0
0
1
2
3
4
5
6
7
14
diagnosis,
edema, nausea and vomiting, pupillary constriction,
although
other
causesretention,
must be and
excluded.
Sedative
hypotension,
urinary
reduced
gastroinDays after cessation of drinking
drug
testinal motility. Their chronic use is associated with
is treated
a long-acting barbiturate
Figure 13. Ethanol withdrawal syndromes in relation withdrawal
tolerance and
physicalwith
dependence.
such
as
phenobarbital,
administered
orally
to the time since cessation of drinking. (Datafrom
Examination may reveal needle tracks
orto
the
maintain
VictorM,AdamsRD:Theeffectofalcoholon abovethenervoussystem.ResPublAssocRes
a calm statesigns,
without
of intoxication,
mentioned
butsigns
the cardinal
featuresand
of opioid
NervMentDis1952;32:526573.)
tapered are pinpoint pupilswhich usually constrict
overdose
over
about
2 weeks.respiratory depression. These feain bright
lightand
tures can also result from pontine hemorrhage, but
opi-

oid overdose can be distinguished by the patientsbances
reinclude at affect, psychomotor retardation,
sponse to the opioid antagonist naloxone. After agiadmintation, and psychosis. The neurologic examination
istration of naloxone, pupillary dilation and full recovmay
ery of consciousness occur promptly. When large show dysarthria, deafness, or ataxia, but the most
doses
charof opioids or multiple drug ingestions are involved,acteristic abnormality is delayed relaxation of the
however, slight dilation of the pupils may be the only
tenobservable effect.
don reexes. Untreated, the condition can progress to
Treatment involves intravenous administration of
seizures and coma.
naloxone, 0.40.8 mg, and sometimes ventilatory
Laboratory abnormalities include low thyroid horsupmone [triiodothyronine(T3) and tetraiodothyronine
port. Because naloxones action may be as short as
(T1
4)] levels and elevated thyroid-stimulating hormone
hourand many opioids are longer-actingit should
(TSH) and serum cholesterol. Hypoglycemia and hybe readministered as the patients condition dictates.
ponatremia may occur, and arterial blood gases may
With
appropriate
treatment,
patients
should
recover
reANTICHOLINERGIC DRUGS
uneventfully.
veal respiratory acidosis. CSF protein is typically eleMuscarinic anticholinergic drugs are used to treat vated; CSF pressure is occasionally increased.
gasTreatment is of the underlying thyroid disorder and, in
trointestinal disturbances, parkinsonism, motion sickHYPERTHYROIDISM
severe myxedema madness or coma, rapid thyroid
ness, and insomnia. Antipsychotic drugs, tricyclic reAcute exacerbation of hyperthyroidism (thyrotoxic criantiplacement
with alevothyroxine
together
with
may cause
confusional state,
coma,
or death. In
depressants, and many antihistamines also exhibitsis)
hydrocortiyounger
patients,
agitation,
hallucinations,
and psyprominent anticholinergic activity. Overdose with any
sone
for
the
possible(activated
coexistent
adrenal
insufciency.
chosis
are
common
crisis),
whereas
those
of these agents can produce a confusional state with
over age 50 tend to be apathetic and depressed (apaagthetic crisis). Seizures may occur. Neurologic
itation, hallucinations, xed and dilated pupils,
examinablurred
vision, dry skin and mucous membranes, ushing,tion shows an exaggerated physiologic (action)
fever, urinary retention, and tachycardia. In some tremor
and hyperreexia; ankle clonus and extensor plantar
cases,
rethe diagnosis can be conrmed by toxicologic
sponses are rare. The diagnosis is conrmed by
analysis
assaying
of blood or urine. Symptoms usually resolve spontahormones (T3 and T4) in the blood. Treatment
neously, but treatment may be required, especiallythyroid
if
includes
correction of hyperthermia, uid and eleclife-threatening
cardiac arrhythmias occur. In such
PHENCYCLIDINE
trolyte
disorders,
cardiac arrhythmias, and congestive
cases, the cholinesterase inhibitor physostigmine can
heart
failure,
and
administration of antithyroid drugs
Phencyclidine
(PCP) can produce drowsiness,
re(propylthiouracil
or
methimazole), iodide, propranolol,
agitation,
verse the abnormality by interfering with the breakHYPOGLYCEMIA
and
hydrocortisone.
The underlying disorder that predisorientation,
amnesia,
hallucinations,
paranoia,may
and
down of acetylcholine.
However,
physostigmine
cipitated
thyrotoxic
crisis
also be sought.
viproduce bradycardia and seizures, so it is rarely used. Prompt treatment ofshould
hypoglycemia
is essential
olent behavior. Neurologic examination may show
because hypoglycemic encephalopathy may
large
progress rapidly from a reversible to an irreor small pupils, horizontal and vertical nystagmus,versible stage, and denitive therapy can be quickly
ataxia,
and
hypertonicity, hyperreexia, and myoclonus. Thereeasily administered.
may
The most common cause is insulin overdose in dibe analgesia to a surprising degree. In severe cases,
abetic patients, but oral hypoglycemic drugs, alcocomholism, malnutrition, hepatic failure, insulinoma,
plications include hypertension, malignant
and non-insulin-secreting bromas, sarcomas, or hyperthermia,
brosarcomas may also be responsible. Neurologic
ENDOCRINE
status epilepticus,DISTURBANCES
coma, and death. Benzodiazepines
symptoms usually develop over minutes to hours. Almay
though no strict correlation between blood glucose
HYPOTHYROIDISM
be useful for sedation and treating muscle spasms,levels and the severity of neurologic dysfunction can
and
beademonstrated, prolonged hypoglycemia at levels
Profound hypothyroidism (myxedema) may produce
antihypertensives,
anticonvulsants,
and
dantrolene
of
confusional state, coma,
or dementia.
Cognitive
(for
30 mg/dL or lower invariably leads to irreversible
disturmalignant hyperthermia) may be required. Symptoms
brain damage.
and signs usually resolve within 24 hours.
16 / CHAPTER 1
Clinical Findings
Table 112. Features of hyperglycemic

encephalopathies.
Early signs of hypoglycemia include tachycardia,

sweatHyperosmolar
ing, and pupillary dilation, which may be followed by
Nonketotic
Diabetic
a
State
Ketoacidosis
confusional state with somnolence or agitation.
NeuroPatient age
Young
Middle-aged to
logic dysfunction progresses in a rostral-caudal
elderly
fashion
(see Chapter 10), and may mimic a mass lesion Type of diabetes Juvenile-onset or Adult-onset
insulincausing
dependent
transtentorial herniation. Coma ensues, with
spasticity,
Blood glucose
extensor plantar responses, and decorticate or
(mg/dL)
300600
decerebrate posturing. Signs of brain stem dysfunction Serum osmolality
(mosm/L)
subsequently appear, including abnormal ocular
Treatment
Ketosis
movements
The
is conrmed
by Respiratory
measuring blood
Metabolic acidosis
and diagnosis
loss of pupillary
reexes.
depression,
glucose
bradycardia, hypotonia, and hyporeexia ultimately
Uncommon
Common
levels,
but treatment with glucose50 mL of 50% Coma
sudextrose
be begun
neurologic
pervene, intravenouslyshould
at which point irreversible
brain damage Focal
is
immediately,
signs
imbefore
the
blood
glucose
level
is
known.
minent.
Seizures
Improvement
Hypoglycemic coma is often associated with focal
in
the levelsigns
of consciousness
evident within
neurologic
and focal or is
generalized
seizures.present; absent.
minutes
after glucose administration in patients with
reversible
hypoglycemic encephalopathy. The consequences of
Treatment & Prognosis
HYPERGLYCEMIA
inadvertently
worsening
what later
provesketoacidosis
to be hyperTreatment of diabetic ketoacidosis includes insulin,
Two
hyperglycemic
syndromes,
diabetic
glycemic
encephalopathy
are hyperglycemia,
never as seriouscan
as prouid and electrolyte (especially potassium and phosand
hyperosmolar
nonketotic
thoseencephalopathy
of
duce
or coma. Either syndrome, phate) replacement, and antibiotics for concomitant
a failure to treat hypoglycemia.
indistinfections. Blood glucose levels should be allowed to reguished by a variety of clinical and laboratory
main at 200300 mg/dL for 24 hours to reduce the
features
(Table 112), may be the presenting manifestationrisk
of of brain edema. Deaths are usually related to
sepsis,
diabetes. Impaired cerebral metabolism, intravascular
coagulation from hyperviscosity, and brain edemacardiovascular or cerebrovascular complications, or
refrom
rapid correction of hyperglycemia contribute to nal failure. In hyperosmolar nonketotic
hyperglycemia,
pathogenesis. Findings
Whereas the severity of hyperosmolarity uid replacement is most important; 0.5 N saline is
Clinical
adcorreSymptoms
include
blurred
vision,
dry
skin,
anorexia,
except to patients with circulatory
lates well with depression of consciousness, the ministered
HYPOADRENALISM
polyuria,
and
polydipsia.
Physical
examination
may
collapse,
degree
show
hypotension
and
other
insufciency
produces
fatigue,
weakwho should receive
normal saline.
Insulin
is also
reof systemic
acidosis
does
not.signs of dehydration, Adrenocortical
espeness,
weight
loss,
anorexia,
hyperpigmentation
quired. Death is usually due to misdiagnosis or of the
cially in hyperosmolar nonketotic hyperglycemia. skin,
hypotension, nausea and vomiting, abdominal
coexistDeep, rapid (Kussmaul) respiration characterizes diapain,
and diarrhea or constipation. Neurologic
ing disease.
betic ketoacidosis. Impairment of consciousness manifesvaries
tations include confusional states, seizures, or coma.
from mild confusion to coma. Focal neurologic signs
Treatment is administration of hydrocortisone and
and generalized or focal seizures are common in corhyperrection of hypovolemia, hypoglycemia, electrolyte
osmolar nonketotic hyperglycemia. Laboratory
disndings
turbances, and precipitating illnesses.
are summarized in Table 112.

includes water restriction or, for severe symptoms,
infuHyperadrenalism (Cushing syndrome) usually results
sion of hypertonic saline with or without intravenous
from the administration of exogenous glucocorticoids.
furosemide. Excessively rapid correction of hyponaClinical features include truncal obesity, facial
tremia may cause central pontine myelinolysis, a
ushing,
disorhirsutism, menstrual irregularities, hypertension, der of white matter that can produce a confusional
weakstate, paraparesis or quadriparesis, dysarthria,
ness, cutaneous striae, acne, and ecchymoses.
dysphaNeuropsygia, hyper- or hyporeexia, and extensor plantar rechiatric disturbances are common and include
sponses. Severe cases can result in the locked-in syndepression
drome (see Chapter 10), coma, or death. MRI may
or euphoria, anxiety, irritability, memory impairment,
show pontine and extrapontine white matter lesions.
psychosis, delusions, and hallucinations; fully
There is no treatment, so prevention is essential, and
developed
may best be achieved by restricting water intake and
acute confusional states are rare. The diagnosis is usconing small amounts of hypertonic saline to raise the
ELECTROLYTE
DISORDERS
rmed by elevated 24-hour
urine-free cortisol levelHYPERCALCEMIA
or
serum
sodium concentration to 125130 mmol/L, at a
a
rate
Symptoms
not
exceeding
include thirst,
8 mmol/L/d.
polyuria, constipation, nauHYPONATREMIA
defective response to a low-dose dexamethasone sea and vomiting, abdominal pain, anorexia, and
suppresClinical Findings
ank
sion test. When a pituitary tumor is the cause, thepain from nephrolithiasis. Neurologic symptoms are
Hyponatremia,
particularly when acute, causes brain
usual
alswelling
due
to
hypoosmolality
of extracellular uid.
treatment is transsphenoidal
hypophysectomy.
ways present with serum calcium levels higher than
Symptoms include headache, lethargy, confusion,
17
weakmg/dL (8.5 meq/L) and include headache, weakness,
ness, muscle cramps, nausea, and vomiting.
and lethargy.
Neurologic
Physical examination may show dehydration, absigns include confusional state or coma, papilledema,
dominal
distention, focal neurologic signs, myopathic
tremor, asterixis, rigidity, extensor plantar responses,
weakness, and a confusional state that can progress
and
to
focal or generalized seizures. Hyponatremia may also
coma. Seizures are rare. The myopathy spares bulbar
produce focal signs by unmasking preexisting
muscles and tendon reexes are usually normal. The
structural
dibrain lesions. Neurologic complications are usually
agnosis is conrmed by an elevated serum calcium
assolevel, and sometimes increased parathyroid hormone
ciated
with serum sodium levels less than 120 meq/L
Treatment
and ainclude
shortened
QT interval
on the
ECG. with
Symptoms
irritability,
delirium,
psychosis
(Figure 14), but may be seen following a rapid falllevels
to
Severe
Treatment
is
most
effective
when
the
underlying
hallucinations, depression, nausea, vomiting, abdomi130 meq/Lwhile chronic hyponatremia with levels
hypercalcemia
is treated initially
vigorousregion
intracause
nal
pain, and paresthesias
of the by
circumoral
as
HYPOCALCEMIA
venous
hydration
with
0.45%
or
0.9%
saline
and
usuof
hyponatremia
is
corrected.
Immediate
and
low as 110 meq/L may be asymptomatic.
ally
requires
central
venous
pressure
monitoring.
Pamanagement
distal extremities. The most characteristic physical
Alert Confused Stupor
Coma Seizures
tients
with
hypercalcemia
also
should
be
evaluated
signs
Plasma
130Na+
for
are those of overt or latent tetany. Neural hyperex(meq/L)
occult
cancer.
citability
is exhibited by contraction of facial muscles
120
in
110
response to percussion of the facial (VII) nerve
anterior
100
to the ear (Chvostek sign). Carpopedal spasm may
90
occur spontaneously or following tourniquet-induced
Figure 14. Relationship between plasma sodium
limb ischemia (Trousseau sign). Cataracts and paconcentration and neurologic manifestations of
pilledema are sometimes present, and chorea has
hyponatremia. (Reproduced,withpermission,
been
fromArieffAI,LlachF,MassrySG:Neuro
reported. Seizures or laryngospasm can be lifelogicmanifestationsandmorbidityof
threatenhyponatremia:correlationwithbrainwater
ing. Serum calcium levels are below 9 mg/dL (4.5
andelectrolytes.Medicine
meq/L), but calcium is also decreased in hypoalbuminemia without affecting ionized calcium and
hypocalcemia with normal ionized calcium is
asympto-
HYPERADRENALISM
18 / CHAPTER 1
matic. The ECG may show a prolonged QT interval.within 1 month. Horizontal nystagmus and ataxia,
Treatment is with intravenous calcium gluconate and
however, resolve completely in only about 40% of
seizures, if present, are treated with phenytoin or cases. The major long-term complication of Wernicke
pheencephalopathy is Korsakoff syndrome.
nobarbital.
NUTRITIONAL DISORDERS
VITAMIN B12 DEFICIENCY
The presenting symptoms are usually due to anemia

Vitamin B12 (cyanocobalamin) deciency produces peor
WERNICKE ENCEPHALOPATHY
ripheral neuropathy, subacute combined
orthostatic lightheadedness, but may also be
Wernicke encephalopathy is usually a complicationdegeneration
of
neurologic.
of the spinal cord, nutritional amblyopia (visual loss),
chronic alcoholism, but also occurs in other disorders
Distal paresthesias, gait ataxia, a bandlike sensation
and cognitive dysfunction that ranges from a mild
associated with malnutrition. It is caused by
of
condeciency
tightness around the trunk or limbs, and Lhermitte
fusional state to dementia or psychosis
of thiamine (vitamin B1). Pathologic features include
sign
(megaloblastic
neuronal loss, demyelination, and gliosis in
(an electric-shocklike sensation along the spine
madness). Neurologic abnormalities may precede the
periventricprecipidevelopment of macrocytic anemia. The most
ular gray matter. Proliferation of small blood vessels
tated by neck exion) may be present. Physical
frequent
and petechial hemorrhages may be seen. The areas
examinacause of vitamin B12 deciency is pernicious anemia,
most
tion may show low-grade fever, glossitis, lemona
Clinical
commonly involved are the medial thalamus,
yellow Findings
defect in the production of intrinsic factor associated
mammilClinical Findings
discoloration of the skin, and cutaneous
gastric atrophy and achlorhydria, which is most
lary bodies, periaqueductal gray matter, cerebellarwith
hyperpigmentaThe
classic
syndrome
comprises
the
triad
of
common
in those of northern European ancestry.
vertion. Cerebral involvement produces confusion,
ophthalmomis, and oculomotor, abducens, and vestibular
depresplegia,
nuclei. ataxia, and confusional state. The most comsion, agitation, or psychosis with hallucinations.
mon ocular abnormalities are nystagmus, abducens
Spinal
(VI)
cord involvement is manifested by impaired vibratory
nerve palsy, and horizontal or combined horizontaland joint position sense, sensory gait ataxia and
verspastic
tical gaze palsy. Ataxia affects gait primarily; ataxia of
paraparesis with extensor plantar responses.
the arms is uncommon, as is dysarthria. The mental
Associated
staperipheral nerve involvement may cause loss of
tus examination reveals global confusion with a
tendon
promireexes in the legs and urinary retention.
nent disorder of immediate recall and recent memory.
Hematologic abnormalities include macrocytic aneThe confusional state progresses to coma in a small
mia, leukopenia with hypersegmented neutrophils,
perand
centage of patients. Most patients have associated
thrombocytopenia with giant platelets. Because folate
neudeciency can produce identical changes, the
ropathy with absent ankle jerks. Hypothermia and hydiagnosis
potension may occur due to hypothalamic
Treatment
must be conrmed by the serum vitamin B12 level.
involvement.
When this is low, Schilling test determines whether
Treatment
requires prompt
administration
of
Pupillary abnormalities,
including
mild anisocoria,
or a
dethiamine.
sluggish reaction to light, are occasionally seen.
fective intestinal absorption of vitamin B12 (as in
AnThe
initial
dose of 100
mg
is given
intravenously,
peripheral
blood
smear
may
show macrocytic
pernibefore
anemia and MRI may show atrophy of the
cious anemia) is the cause. In pernicious anemia, the
or
with
dextrose,
to
avoid
precipitating
or
mammillary
urinary excretion of orally administered vitamin B12 is
exacerbating
bodies.
abnormally low, and this abnormality can be
the disorder. Parenteral thiamine is continued for several days. The maintenance requirement for thi- corrected
by coadministration of intrinsic factor.
amineabout 1 mg/dis usually available in the diet,
Diagnosis may be difcult when cerebral
although
enteric
absorption
of
thiamine
is
impaired
in
Prognosis
symptoms
alcoholics.
Following treatment, ocular abnormalities usually beoccur
without anemia or spinal cord disease,
Treatment
gin to improve within 1 day and ataxia and confusion
requiring
within a week. Ophthalmoplegia, vertical nystagmus,
Treatment
of neurologic
is by prompt
that the serum
vitamin Bmanifestations
12 level be determined
and acute confusion are entirely reversible, usuallyintramuscular
administration of cyanocobalamin,
routinely
after
in patients with cognitive disorders, myelopathy, or
peripheral neuropathy, whether or not anemia is
present.

blood is drawn to determine the serum vitamin B12turing, and extensor plantar responses. Focal
level. Daily injections are continued for 1 week, and
neurologic
Schilling test is performed to determine the cause signs
of
and focal or generalized seizures may occur.
deciency. If, as in pernicious anemia, deciency is Laboratory studies may show elevated serum bilirunot
bin, transaminases, ammonia, prothrombin time (PT)
correctable by dietary supplementation or treatment
and partial thromboplastin time (PTT), and respiratory
of
alkalosis. The most specic CSF abnormality is
intestinal malabsorption, intramuscular vitamin B12elevated
(typically 100 are given at weekly intervals for glutamine (Figure 15). The EEG may be diffusely
Treatment
slow with triphasic waves.
several months and monthly thereafter. The reversibility
Treatment includes restricting dietary protein,
of
reversing
neurologic complications depends upon their
electrolyte disturbances and hyperglycemia,
duration.
discontinuAbnormalities present for more than 1 year are less
ing drugs that may have caused decompensation,
likely to resolve with treatment. Encephalopathy may
probegin to clear within 24 hours after the rst vitamin
viding antibiotics, and correcting coagulopathy with
ORGAN
SYSTEM
FAILURE
B12 dose, but
full neurologic
recovery, when it occurs,
fresh-frozen plasma or vitamin K. Oral or rectal
may take several months.
admin-
HEPATIC ENCEPHALOPATHY
istration of lactulose, 2030 g three or four times

Hepatic encephalopathy occurs as a complication daily,
of
cirrhosis, portosystemic shunting, chronic active decreases colonic pH and ammonia absorption.
hepaNeomycin, 13 g orally four times daily, may reduce
titis, or fulminant hepatic necrosis following viral ammonia-forming bacteria in the colon. Some
hepasuccess
titis. Alcoholism is the most common underlying also has been reported with the benzodiazepine
REYE SYNDROME
disorrecepder. The syndrome may be chronic and progressiveReye
orantagonist
syndromeumazenil.
is a rare disorder
characterized
by
tor
Orthotopic
liver
acute in onset; in the latter case, gastrointestinal entransplantahemcephalopathy
laboratory
evidence
of
tion is requiredorincoma
somewith
cases.
Prognosis
in hepatic
orrhage is a frequent precipitating cause.
heenLiver disease produces cerebral symptoms by impatic
dysfunction.
It usually
in children
cephalopathy
correlates
bestoccurs
with the
severityseveral
of
pairing hepatocellular detoxifying mechanisms or by
days
after a viral
illness,
especially
varicella
or
hepatocellular
rather
than
neurologic
dysfunction.
the portosystemic shunting of venous blood. As a reinuenza
sult, ammonia and other toxins accumulate in the B. Administration of salicylates appears to be an addiblood and diffuse into the brain. Increased activitytional
of
risk factor. The incidence of Reye syndrome has
declined dramatically in recent years, at least partly

aminobutyric
(GABA)-containing
neuronal
pathas a
Symptoms
of acid
encephalopathy
may precede
systemic
Clinical Findings
ways in thesuch
brainasand
elevated
levels and
of endogenous
result Hepatic
of vaccination for
and
the
symptoms
nausea,
anorexia,
weight loss.
Othervaricella
liver
Normal
andavoidance
disease
other illnesses
benzodiazepines
may be
involvedconsumption
in the
Recent
gastrointestinal
bleeding,
of of encephalopathy
pathogenesis of
aspirin
in treating children with febrile illnesses.
high100
cerebralfoods,
symptoms.
protein
use of sedatives or diuretics, or
systemic
80
Glutamine
infection may provide a clue to the cause of clinical(mg/dL)
de60
compensation.
Physical examination may reveal systemic signs of 40
liver disease. Cognitive disturbances include somno20
lence, agitation, and coma. Ocular reexes are
usually
brisk. Nystagmus, tonic downward ocular deviation, 0
and disconjugate eye movements may be seen. The
most helpful neurologic sign of a metabolic distur- Figure 15. Range of CSF glutamine concentrations
bance, although not restricted to liver disease, is in hepatic encephalopathy. (Reproduced,with
permission,fromPlumF:TheCSFinhepatic
asterencephalopathy.ExpBiolMed
ixisa apping tremor of the outstretched hands or
1971;4:3441.)
feet that results from impaired postural control. Other
motor abnormalities include tremor, myoclonus, paratonic rigidity, spasticity, decorticate or decerebrate
pos-
20 / CHAPTER 1
rect effects on the nervous system or as a
consequence
Renal failure, particularly when acute in onset or rapof immunological impairment. Cyclosporine and
idly progressive, may produce encephalopathy or tacrolimus (FK-506) produce encephalopathy that
coma
may
with hyperventilation and prominent motor
be associated with seizures, tremor, visual
manifestadisturbances,
tions. These include tremor, asterixis, myoclonus, weakness,
and
sensory symptoms, or ataxia. MRI shows
tetany. Focal or generalized seizures and focal neuroablogic signs are common, and decorticate or
normalities in the subcortical white matter.
decerebrate
Symptoms
posturing may occur. Laboratory abnormalities
are often associated with excessively high drug levels
include
in
elevated serum urea nitrogen, creatinine and
the blood and may improve with reduction of drug
potassium,
dosage. Corticosteroids can produce psychosis, which
and metabolic acidosis, but their severity correlates
may respond to substituting dexamethasone, and
poorly with symptoms. The EEG is diffusely slow and
cortimay show triphasic waves or paroxysmal spikes orcosteroid withdrawal is sometimes associated with
sharp
lethargy, headache, myalgia, and arthralgia. OKT3
waves.
causes encephalopathy, aseptic meningitis, and
Acute management includes hydration, protein seizures.
and
salt restriction, and treatment of complications such
Gabapentin is often used to treat seizures in
as
transplant
seizures. Long-term management requires reversing
recipients because of its relative lack of pharmacokithe
netic interaction with other drugs typically given to
cause (eg, urinary tract obstruction), dialysis, or these patients.
kidney
Infections causing confusional states are most
transplantation. Although dialysis reverses the en-prominent following bone marrow transplantation, but
cephalopathy,
improvement often lags behind
PULMONARY clinical
ENCEPHALOPATHY
are also common after transplantation of other
normalization of serum urea nitrogen and creatinine.
organs.
Patients itself
with lung
disease or
or neurologic
Dialysis
can produce
an brainstem
encephalopathy,
They are comparatively rare in the rst month followdisorders
termed that affect respiratory function may develop
ing transplantation and, when they occur, usually reencephalopathy
relatedsyndrome,
to hypoventilation.
dialysis disequilibrium
that is thought to
ect preexisting infection in the recipient or in the
Symptoms
result from hypoosmolality. This is most common with
donor organ, or a perioperative complication. Within
include
headache,
confusion, and
and can
somnolence.
a patients
rst hemodialysis
be prevented
this period, the most frequent organisms are gramExamiby
negnation
shows
papilledema,
asterixis
myoclonus,
correcting
uremia
more gradually
or or
using
briefer ative bacteria, herpes simplex virus, and fungi.
and
periOpporconfusional
state
or coma.rates
Tendon
reexes
are often
ods of dialysis
at reduced
of blood
ow.
tunistic infections are more common between 1 and 6
decreased, but pyramidal signs may be present, andmonths posttransplant and include acute Listeria
meningitis or encephalitis; chronic meningitis from
seizures occur occasionally. Arterial blood gases show
respiratory
acidosis. Treatment involves ventilatoryCryptococcus or Mycobacterium tuberculosis; and
ORGAN TRANSPLANTATION
brain
Treatment
of organ failure by transplantation can lead
supMENINGITIS, ENCEPHALITIS,
abscesses related to infection with Aspergillus,
to
acute
confusional
states
as
a
consequence
of
port to decrease hypercapnia and to maintain
& SEPSIS
Nocardia,
surgical
adequate
or Toxoplasma. Beyond 6 months, cytomegalovirus,
complications,
oxygenation. immunosuppressive drug treatment,
BACTERIAL
MENINGITIS
Toxoplasma, Cryptococcus, Listeria, or Nocardia
opinfection
meningitis is a leading cause of acute confuportunistic infection, lymphoproliferative disorders,Bacterial
or
may
be
seen.
sional
states
and one in which early diagnosis greatly
transplant rejection. The problems encountered
Posttransplant
lymphoproliferative
disorder is reimproves
the
outcome.
Predisposing conditions
depend
lated
to
immunosuppression
and
may
be associated
include
on the time in relation to transplantation and on the
with
primary
central
nervous
system
lymphoma.
systemic
(especially
respiratory)
or
parameningeal
organ transplanted.
Transplant rejection may also produce
infecSurgical complications that may produce enencephalopation,
head trauma, anatomic meningeal defects, prior
cephalopathy include hypotension, hypoxia, thromthy,
especially
in recipients
of kidney
neurosurgery,
cancer,
alcoholism,
andtransplants.
other immunoboembolism, and air embolism, and are most
deciency
states.
The
etiologic
organism
varies with
common
age
with heart and liver transplants.
Immunosuppressive drugs used to prevent trans-and with the presence of predisposing conditions
113).
plant rejection can cause acute confusional states (Table
by
UREMIA
di-

Table 113. Etiologic agents and empirical antibiotic treatment in bacterial meningitis, based on age
and predisposing condition.
Age or Condition
Etiologic Agents
Antibiotics of Choice
Less than 3 months S agalactiae

E coli
L monocytogenes
Ampicillin, 100 mg/kg intravenously every 8 hours
cefotaxime, 50 mg/kg intravenously every 6 hours

or
ceftriaxone, 50100 mg/kg intravenously every 12
hours
3 months to 8 years N meningitidis
Cefotaxime, 50 mg/kg intravenously every 6 hours
S pneumoniae
or
H inuenzae
ceftriaxone, 50100 mg/kg intravenously every 12 hours
vancomycin, 15 mg/kg intravenously every 6 hours, to maximum of

4 g/d
S pneumoniae
18 to 50 years
Cefotaxime, 2 g intravenously every 6 hours
N meningitidis
or
ceftriaxone, 2 g intravenously every 12 hours
vancomycin, 15 mg/kg intravenously every 6 hours, to maximum of

4 g/d
Older than 50 years S pneumoniae
Ampicillin, 2 g intravenously every 4 hours
L monocytogenes
Gram-negative bacilli cefotaxime, 2 g intravenously every 6 hours

or
ceftriaxone, 2 g intravenously every 12
hours
L monocytogenes
Impaired cellular
Ampicillin, 100 mg/kg intravenously every 8 hours (neonate)
Gram-negative bacilli or
immunity
2 g intravenously every 4 hours (adult)
ceftazidime, 50100 mg/kg intravenously every 8 hours, to

maximum of
2 g every 8 hours
Head trauma,
Staphylococci
Vancomycin, 15 mg/kg intravenously every 6 hours, to maximum of
neurosurgery, or Gram-negative bacilli 4 g/d
CSF shunt
S pneumoniae
ceftazidime, 50100 mg/kg intravenously every 8 hours, to

maximum of
AdaptedfromQuagliarelloVJ,ScheldWM:Treatmentofbacterialmeningitis.NEnglJMed
2 g every 8 hours
1997;336:708716.
Bacteria typically gain access to the central nervous

syslease of inammatory cytokines, including
tem
by colonizing
the mucous membranes of the naPathogenesis
& Pathology
interleukins
sopharynx, leading to local tissue invasion,
1 and 6 and tumor necrosis factor that promote
bacteremia,
and hematogenous seeding of the subarachnoid blood-brain barrier permeability, vasogenic cerebral
space.
edema, changes in cerebral blood ow, and perhaps
Bacteria can also spread to the meninges directly,dithrough anatomic defects in the skull or from para-rect neuronal toxicity.
meningeal sites such as the paranasal sinuses or
Pathologically, bacterial meningitis is characterized
middle
by leptomeningeal and perivascular inltration with
ear. Polysaccharide bacterial capsules,
polymorphonuclear leukocytes and an inammatory
lipopolysacchaexudate. These changes tend to be most prominent
rides, and outer membrane proteins may contribute
over the cerebral convexities in Streptococcus
to
pneumothe bacterial invasion and virulence. The low levelsniae
of and Haemophilus infection and over the base of
antibody and complement present in the
the
subarachnoid
brain with Neisseria meningitidis. Brain edema,
space are inadequate to contain the infection. Thehydroresulting inammatory response is associated with the
cephalus, and cerebral infarction may occur, although
reactual bacterial invasion of the brain is rare.
A. SYMPTOMS AND SIGNS

At presentation, most patients have had symptoms of
meningitis for 1 to 7 days. These include fever, confusion, vomiting, headache, and neck stiffness, but the
22 / CHAPTER 1
full syndrome is often not present.
Physical examination may show fever and signs of
made because lumbar puncture yields bloody CSF in
Clinical
Findings
systemic or parameningeal infection, such as skin abthat condition. Early viral meningitis can produce
scess or otitis. A petechial rash is seen in 5060% of
polymorphonuclear pleocytosis and symptoms
paidentical
tients with N meningitidis meningitis. Signs of
to those of bacterial meningitis, but a repeat lumbar
meningeal irritation are seen in about 80% of cases,
puncture after 612 hours should demonstrate a shift
but
to lymphocytic predominance in viral meningitis, and
are often absent in the very young and very old, or
the CSF glucose level is normal.
with
profoundly impaired consciousness. These signs Prevention
include
Children should be routinely immunized against H inneck stiffness on passive exion, thigh exion upon
uenzae by vaccination. A vaccine is also available
exfor
ion of the neck (Brudzinski sign), and resistance tosome strains of N meningitidis and is recommended
pasfor
sive extension of the knee with the hip exed (Kernig
military recruits, college students, and travelers to
sign). The level of consciousness, when altered, areas
ranges
of ongoing epidemics. The risk of contracting H infrom mild confusion to coma. Focal neurologic signs,
uenzae or N meningitidis meningitis can be reduced
seizures, and cranial nerve palsies may occur.
in
B. LABORATORY FINDINGS
household and other close contacts of affected
Peripheral blood may reveal polymorphonuclear patients
leukoby
the prophylactic administration of rifampin,
Treatment
cytosis from systemic infection or leukopenia due to
20 mg/kg/d orally, given as a single daily dose for 4
Unless
physical examination
shows
focalfor 2 days
immunosuppression. The causative organism can be
days (Hthe
inuenzae)
or as two divided
doses
neurologic
cultured from the blood in 4090% of meningitis (N meningitidis).
abnormalities or papilledema, lumbar puncture
cases. X-rays of the chest, sinuses, or mastoid bones
may indicate a primary site of infection. A brain CTshould
or
MRI scan may show contrast enhancement of the be performed immediately; if the CSF is not clear and
colorless, antibiotic treatment (see below) is started
cerewithout delay. When focal signs or papilledema are
bral convexities, the base of the brain, or the
present, blood and urine should be taken for culture,
ventricular
ependyma. The EEG is usually diffusely slow, and antibiotics begun, and a brain CT scan obtained. If
the
focal
scan shows no focal lesion that would contraindicate
abnormalities suggest the possibility of focal
lumbar puncture, the puncture is then performed.
cerebritis,
The initial choice of antibiotics is empirical, based
abscess formation, or scarring.
upon
the patients age and predisposing factors (see
Although these studies may be helpful, the
Table
113). Therapy is adjusted as indicated when
essential
the
test in all cases of suspected meningitis is prompt
Gram stain or culture and sensitivity results become
lumbar
puncture and CSF examination. CSF pressure is available (Table 114). Lumbar puncture can be repeated to assess the response to therapy. CSF should
elevated
in about 90% of cases, and the appearance of the be
sterile after 24 hours, and a decrease in pleocytosis
uid
ranges from slightly turbid to grossly purulent. CSFand
white cell counts of 100010,000/mL are usually in the proportion of polymorphonuclear leukocytes
should occur within 3 days.
seen,
Prognosis
consisting chiey of polymorphonuclear leukocytes, Dexamethasone, given immediately before the
Complications
of bacterial meningitis include
onset
alheadache,
seizures,
hydrocephalus,
syndrome
of
of antibiotic treatment
and continued
every 6 hours
though mononuclear cells may predominate in
inapfor
Listeria
propriate
secretion
antidiuretic
days, can
improveofoutcome
and hormone
decrease(SIADH),
mortality
monocytogenes meningitis. Protein concentrations4of
residual
neurologic
decits
(including
cognitive disturin
100500 mg/dL
are most common. The CSF glucose
Differential
Diagnosis
bances and cranialespecially VIIInerve abnormalilevel is lower than 40 mg/dL in about 80% of casesbacterial meningitis.
ties), and death. A CT scan will conrm suspected hySigns
and of meningeal irritation may also be seen with
and uid and electrolyte status should
subarachnoid
hemorrhage,
the distinction
is drocephalus
may be too low
to measure.but
Gram-stained
smears
of
be
easily
CSF
carefully monitored to detect SIADH. N meningitidis
identify the causative organism in 7080% of cases.
CSF
culture, which is positive in about 80% of cases,

Table 114. Treatment of bacterial meningitis of known cause.
Etiologic Agents
Grams stain
Cocci
Gram-positive
Gram-negative
Bacilli
Gram-positive
Gram-negative
CSF culture
S pneumoniae
H inuenzae
N meningitidis
L monocytogenes
S. agalactiae
Duration of
Tretament
(days)
Vancomycin, 15 mg/kg intravenously every 6 hours, to maximum of
4 g/d;
substitute rifampin (600 mg/d) for vancomycin in adults receiving
dexamethasone
cefotaxime, 50 mg/kg intravenously every 6 hours (neonates)

or
ceftriaxone, 50100 mg/kg intravenously every 12 hours (children);
2g
Penicillin
G, 300,000
units/kg/d
intravenously, to maximum of 24 million
intravenously
every 12
hours (adults)
units/d
Ampicillin, 100 mg/kg intravenously every 8 hours (children); 2 g
intravenously
every 4 hours (adults)
or
penicillin G, 300,000 units/kg/d intravenously, to maximum of 24 million
units/d
gentamicin, 1.5 mg/kg intravenous loading dose followed by 12 mg/kg

Cefotaxime,
mg/kg
intravenously every 6 hours (neonates)
intravenously50
every
8 hours
or
ceftriaxone, 50100 mg/kg intravenously every 12 hours (children); 2
g
intravenously every 12 hours (adults)
or
ceftazidime, 50100 mg/kg intravenously every 8 hours, to maximum
of 2 g
every 8 hours
gentamicin, 1.5 mg/kg intravenous loading dose followed by 12

mg/kg
intravenously15
every
8 hours
Vancomycin,
mg/kg
intravenously every 6 hours, to maximum of
1014
4 g/d;
substitute rifampin (600 mg/d) for vancomycin in adults receiving
dexamethasone
cefotaxime, 50 mg/kg intravenously every 6 hours (neonates)

or
ceftriaxone, 50100 mg/kg intravenously every 12 hours (children);
2g
Ceftriaxone,
mg/kg
intravenously
every 12 hours
7
intravenously50100
every 12
hours
(adults)
(children); 2 g
intravenously every 12 hours (adults)
Penicillin G, 300,000 units/kg/d intravenously, to maximum of 24 million 7
units/d
Ampicillin, 100 mg/kg intravenously every 8 hours (children); 2 g
1421
intravenously

intravenously every 8 hours
Penicillin G, 300,000 units/kg/d intravenously, to maximum of 24 million1421
units/d
(continued)
24 / CHAPTER 1
Table 114. Treatment of bacterial meningitis of known cause. (continued)
Etiologic Agents
Duration of
Tretament
(days)
Enterobacteriaceae
Cefotaxime, 50 mg/kg intravenously every 6 hours (neonates)

21
or
ceftriaxone, 50100 mg/kg intravenously every 12 hours (children); 2 g
intravenously

intravenously
Pseudomonas
Ceftazidime,
g
every
8 hours50100 mg/kg intravenously every 8 hours, to maximum of 221
aeruginosa,
every
acinetobacter
8 hours

intravenously
AdaptedfromQuagliarelloVJ,ScheldWM:Treatmentofbacterialmeningitis.NEnglJMed
every 8 hours
1997;336:708716.
infections may be complicated by adrenal

The main nding is a basal meningeal exudate
hemorrhage
conrelated to meningococcemia, resulting in hypotension
taining primarily mononuclear cells. Tubercles may be
and often death (Waterhouse-Friderichsen syndrome).
seen on the meninges and surface of the brain. The
Morbidity and mortality from bacterial meningitis
ventricles may be enlarged as a result of
are high. Fatalities occur in about 20% of affected hydrocephalus,
adults, and more often with some pathogens (eg, S
and their surfaces may show ependymal exudate or
pneumoniae, gram-negative bacilli) than others (eg,
granular ependymitis. Arteritis can result in cerebral
H
ininuenzae, N meningitidis). Factors that worsen progfarction, and basal inammation and brosis can
Clinical
Findings
nosis include extremes of age, delay in diagnosis and
comtreatment, complicating illness, stupor or coma, press
cranialAND
nerves.
A. SYMPTOMS
SIGNS
seizures,
and
focal
neurologic
signs.
Symptoms usually have been present for less than 4
TUBERCULOUS MENINGITIS
weeks at the time of presentation and include fever,

Tuberculous meningitis must be considered in
lethargy or confusion, and headache. Weight loss,
patients
vomwho present with a confusional state, especially if
iting, neck stiffness, visual impairment, diplopia, focal
there
weakness, and seizures may also occur. A history of
is a history of pulmonary tuberculosis, alcoholism,
contact with known cases of tuberculosis is usually
corabticosteroid treatment, HIV infection, or other condisent.
tions associated with impaired immune responses. It
Fever, signs of meningeal irritation, and a confushould also be considered in patients from areas (eg,
sional state are the most common ndings on
Asia,
Africa) or &
groups
(eg, the homeless and innerPathogenesis
Pathology
physical
city
examination, but all may be absent. Papilledema,
Tuberculous
meningitis
results
from reactivadrug users) with
a high usually
incidence
of tuberculosis.
ocution of latent infection with Mycobacterium
lar palsies, and hemiparesis are sometimes seen.
tuberculosis.
ComPrimary infection, typically acquired by inhaling bacilLABORATORY
FINDINGS
plications
include
spinal subarachnoid block, hydrolus-containing droplets, may be associated with B.
Only
one-half
toedema,
two-thirds
of patients
show a and
positive
cephalus, brain
cranial
nerve palsies,
metastatic dissemination of blood-borne bacilli from
skin
test
for
tuberculosis
or
evidence
of
active
or
the lungs to the meninges and the surface of the stroke
healed
caused by vasculitis or compression of blood vessels
brain.
infection on chest x-ray. The diagnosis is
at
Here the organisms remain in a dormant state in tubercular
esthe
base
of
the brain.
tubertablished
by
CSF analysis. CSF pressure is usually incles that can rupture into the subarachnoid space at
a
later time, resulting in tuberculous meningitis.

creased, and the uid is typically clear and colorless
neurologic signs or with increased intracranial
but
pressure
may form a clot upon standing. Lymphocytic and from cerebral edema. The risk of using corticosteroids
mononuclear cell pleocytosis of 50500 cells/mL ismay be high, however, especially if tuberculous
most often seen, but polymorphonuclear pleocytosis
menincan occur early and may give an erroneous
gitis has been mistakenly diagnosed in a patient with
impression
fungal meningitis. Therefore, if fungal meningitis has
of bacterial meningitis. CSF protein is usually morenot been excluded, antifungal therapy (see below)
than 100 mg/dL and may exceed 500 mg/dL, particushould
be added along with corticosteroids.
Prognosis
larly in patients with spinal subarachnoid block. The
glucose level is usually decreased and may be lessEven with appropriate treatment, about one-third of
patients with tuberculous meningitis succumb. Coma
than
20 mg/dL. Acid-fast smears of CSF should be per- at the time of presentation is the most signicant predictor of a poor prognosis.
formed in all cases of suspected tuberculous
meningitis,
but they are positive in only a minority of cases.
SYPHILITIC MENINGITIS
Denitive diagnosis is most often made by culturing M Acute or subacute syphilitic meningitis usually occurs
tuberwithin 2 years after primary syphilitic infection. It is
culosis from the CSF, a process that usually takes most common in young adults, affects men more
several
often
weeks and requires large quantities of spinal uid than
for women, and requires prompt treatment to
maximum
However,
polymerase
chain
reacMany
otheryield.
conditions
can the
cause
a subacute
confuprevent
tion has
alsowith
been
used for diagnosis.
Finally, the
CT
sional
state
mononuclear
cell pleocytosis,
includthe irreversible manifestations of tertiary
scansyphilitic,
may show
contrast
enhancement
of the basal
ing
fungal,
neoplastic,
and partially
treated
neurosyphilis.
cisbacterial
meningitis. These can be diagnosed by
In about one-fourth of patients with Treponema palterns and cortical meninges, or hydrocephalus.
approlidum infection, treponemes gain access to the
priate smears, cultures, and serologic and cytologic
central
exnervous system, where they produce a meningitis
aminations.
Treatment should be started as early as possible; itthat
Treatment
is
usuallyFindings
asymptomatic (asymptomatic
should not be withheld while awaiting culture results.
Clinical
neurosyphilis).
The decision to treat is based on the CSF ndings deA.
SYMPTOMS ANDinvasion
SIGNS
Asymptomatic
of the central nervous system
scribed above; lymphocytic pleocytosis and
In
a
few
patients,
syphilitic
meningitis is a clinically
is
decreased
apassociated
with
CSF
pleocytosis,
elevated protein,
glucose are particularly suggestive, even if acid-fast
parent
acute
or
subacute
disorder.
At the time of preand
smears are negative.
sentation,
symptoms
such
as
headache,
nausea,
positive serologic tests for syphilis.
Four drugs are used for initial therapy, until culture
vomitand susceptibility test results are known. These are
ing, stiff neck, mental disturbances, focal weakness,
isoniazid, 300 mg; rifampin, 600 mg; pyrazinamide, seizures, deafness, and visual impairment usually
25 mg/kg; and ethambutol, 15 mg/kg, each given have
been present for up to 2 months.
orally once daily. For susceptible strains, ethambutol
can be discontinued, and triple therapy continued forPhysical examination may show signs of meningeal
irritation, confusion or delirium, papilledema, hemi2 months, followed by 410 months of treatment with
isoniazid and rifampin alone. Pyridoxine, 50 mg/d, paresis, and aphasia. The cranial nerves most
frequently
can
affected are (in order) the facial (VII), acoustic (VIII),
be used to decrease the likelihood of isoniazidB.
LABORATORY(III),
FINDINGS
oculomotor
trigeminal (V), abducens (VI), and
induced
The
diagnosis
is established
by CSF
ndings.
Opening
optic
(II)
nerves,
but other nerves
may
be involved
as
polyneuropathy.
pressure
is
normal
or
slightly
elevated.
Pleocytosis
is
well. Fever is typically absent.
Complications of therapy include hepatic dysfunclymphocytic or mononuclear in character, with white
tion (isoniazid, rifampin, and pyrazinamide), polyneucell counts usually in the range of 1001000/mL. Proropathy (isoniazid), optic neuritis (ethambutol),
tein may be mildly or moderately elevated (<200
seizures (isoniazid), and ototoxicity (streptomycin).
mg/dL) and glucose mildly decreased. CSF VDRL and
Corticosteroids (eg, prednisone, 60 mg/d orally in
serum FTA or MHA-TP tests are usually positive. Proadults or 13 mg/kg/d orally in children, tapered gradtein electrophoretograms of CSF may show discrete
ually over 34 weeks) are indicated as adjunctive
therapy in patients with spinal subarachnoid block. They

also may be indicated in seriously ill patients with
focal
26 / CHAPTER 1
globulin bands (oligoclonal bands) not visible in norwhen avoidance is impossible. A Lyme disease
mal CSF.
vaccine
is also available, but its use is controversial.
Treatment
For patients with Lyme disease and Bell palsy,
treatAcute syphilitic meningitis is usually a self-limited disorder with no or minimal sequelae. More advancedment is with doxycycline (100 mg twice daily) or
manifestations of neurosyphilis, including vascularamoxicillin (500 mg three times daily), each given
orally for 34 weeks. With meningitis or other central
and
nervous system (CNS) involvement, intravenous
parenchymatous disease (eg, tabes dorsalis, general
paresis, optic neuritis, myelitis), can be prevented treatby
ment
is indicated with ceftriaxone (2 g intravenously
adequate treatment of the early syphilitic infection.
daily),
penicillin G (2024 million units intravenously
Syphilitic meningitis is treated with aqueous penidaily
in
six divided doses), or cefotaxime (2 g intraLymeG,
disease
is6aunits
tick-borne
disorderevery
that results
cillin
24 10
intravenously
4 hours
venously every 8 hours), continued for 24 weeks.
from
for 10 days. For penicillin-allergic patients,
Symptoms typically resolve within 10 days in
systemic infection with the spirochete Borrelia
tetracycline
treated
cases. Untreated or inadequately treated
burgdoror erythromycin, 500 mg orally every 6 hours for 20
infecferi. Most
occur during
months.
days,
can cases
be substituted.
Thethe
CSFsummer
should be
tions may lead to recurrent oligoarthritis, and chronic
Priexamined
neurologic disorders including memory, language,
mary infection
bynormal.
an expanding
every
6 monthsmay
untilbe
allmanifested
ndings are
Another
and
eryLYME DISEASE
course
of therapy must be given if the CSF cell count
thematous
annular elevated.
skin lesion (erythema migrans)other cognitive disturbances; focal weakness; and
or protein remains
ataxia. In such cases, a CT scan or MRI may show hyClinical
Findings
that
drocephalus, lesions in white matter resembling those
usually appears over the thigh, groin, or axilla. Less
seen in multiple sclerosis, or abnormalities suggestive
disof
tinctive symptoms include fatigue, headache, fever,
cerebral infarction. Subtle chronic cognitive or behavneck
ioral symptoms should not be attributed to Lyme enstiffness, joint or muscle pain, anorexia, sore throat,
cephalitis
in the absence
of serologic evidence of B
VIRAL MENINGITIS
& ENCEPHALITIS
and
burgdorferi
exposure,
CSF
abnormalities, or focal neunausea. Neurologic involvement may be delayed for
Viral
infections
of
the
meninges
(meningitis) or brain
rologic signs. The peripheral neurologic
up
parenchyma
(encephalitis)
often
present as acute
to 10 weeks and is characterized by meningitis or manifestations
conof Lyme disease are discussed in Chapter 6.
meningoencephalitis and disorders of the cranial or
fusional states. Children and young adults are frepequently affected. Viral meningitis is most often
ripheral nerves or nerve roots. Cardiac abnormalities
caused
(conduction defects, myocarditis, pericarditis, carby enteric viruses (Table 115) and viral encephalitis
diomegaly, or heart failure) can also occur at this
by
stage.
childhood exanthems, arthropod-borne agents, and
Lyme meningitis usually produces prominent
herpes simplex type 1 (Table 116). Some forms of viheadache
ral encephalitis tend to show a restricted geographic
that may be accompanied by signs of meningeal
distribution. However, the speed and volume of interirritanational travel can permit these disorders to spread,
tion, photophobia, pain when moving the eyes,
as
nausea,
Pathology
was observed recently for West Nile virus in the
and vomiting. When encephalitis is present, it is Viral infections can affect the central nervous system
northusually
in
eastern United States.
mild and characterized by insomnia, emotional
three wayshematogenous dissemination of a
lability,
systemic
or impaired concentration and memory.
viral infection (eg, arthropod-borne viruses); neuronal
The CSF usually shows a lymphocytic pleocytosis
spread of the virus by axonal transport (eg, herpes
with 100200 cells/mL, slightly elevated protein, and
simnormal glucose. Oligoclonal immunoglobulin G (IgG)
plex, rabies); and autoimmune postinfectious
bands may be detected. Denitive diagnosis is
demyeliusually
nation (eg, varicella, inuenza). Pathologic changes in
Treatment
made by serologic testing for B burgdorferi,
viral meningitis consist of an inammatory meningeal
Preventive
preferably measures include avoiding tick-infestedreaction mediated by lymphocytes. Encephalitis is
areas
by enzyme-linked immunosorbent assay (ELISA) folcharand
using
insect repellents
and polymerase
protective clothing
lowed
by Western
blot, but the
chain acterized by perivascular cufng, lymphocytic inltrareaction, and microglial proliferation mainly involving subtion, which can amplify spirochetal DNA in synovialcortical gray matter regions. Intranuclear or
uid, blood, or CSF, has also been used.
intracytoplasmic inclusions are often seen.

Table 115. Etiologic agents in viral meningitis.
Virus
Seasonal
Variation
Incidence
Source
Susceptible
Population
Systemic
Involvement
Laboratory
Findings
30%
Summer, fall
Fecal-oral
Children,Maculopapular,
members ofvesicular, or
affected families petechial skin
rash; gastroenteritis
Coxsackievirus A10%
Summer, fall
Fecal-oral
rash; herpangina;
gastroenteritis
Coxsackievirus B40%
Summer, fall
Fecal-oral
rash; pleuritis,
pericarditis,
myocarditis,
orchitis; gastroenteritis
Mumps virus
Late winter,
spring
Inhalation
Children, male Parotitis, orchitis, Amylase CSF

oophoritis,glucose may
more than
pancreatitisbe or
female
Herpes simplex Uncommon

virus (type 2)
Genital infectionNeonates with Vesicular

affected
genital lesions
mothers
Adenovirus
Inhalation
Echoviruses
15%
Uncommon
Infants, children Pharyngitis,

pneumonitis
Marked CSF
pleocytosis
(100010,000
WBC/L)
LymphocyticUncommon
choriomeningitis
virus
Late fall, winterMouse
Laboratory
workers
Pharyngitis,
pneumonitis
Hepatitis virusesUncommon
Fecal-oral,
venereal,
transfusion
Intravenous
Jaundice,
drug users,
arthritis
male homosexuals, blood
recipients
Liver function
abnormalities
Epstein-Barr virus Uncommon

(infectious
mononucleosis)
Oral contact
Teenagers,
young adults
Atypical
lymphocytes,
positive
heterophil,
liver function
abnormalities
Lymphadenopathy,
pharyngitis,
maculopapular
skin rash,
palatal
petechiae,
splenomegaly
Table 116. Etiologic agents in viral encephalitis.

Type of Encephalitis
Vector
Geographic Distribution
Comments
Childhood exanthems
Measles, varicella,
mumps, rubella
Human
Arthropod-borne (Arbo) viruses

Alphaviruses
Eastern equineMosquito
Worldwide
Uncommon in USA because of

vaccination
USA (Atlantic and Gulf coasts), Children usually affected; mortality

Caribbean, South America
5075%; neurologic sequelae
common
Western equine
Mosquito
Western and central USA, South Infants and adults years

usually affected; mortality 515%;
America
neurologic sequelae uncommon
except in infants
Venezuelan equine
Mosquito
Florida, southwestern USA, Central

Adults usually affected; mortality
and South America
1%; neurologic sequelae rare
Flaviviruses
Japanese B
Mosquito
China, Southeast Asia, India, Japan

Vaccine available
St. Louis
Mosquito
Adults years most often

USA (rural west and midwest, New
Jersey, Florida,Texas), Caribbean,affected; mortality 220%;
neurologic sequelae in about 20%
Central and South America
Murray Valley
Mosquito
Australia, New Guinea
West Nile
Mosquito
Middle East, Africa, Europe, Central

Asia, northeastern USA
Rocio
Mosquito
Brazil
Kyasanur Forest
Tick
India
Powassan
Tick
New York, Ontario
Russian spring-summer
Tick
Northern Europe, Siberia
Louping-ill
Tick
United Kingdom
Mosquito
North America
Mosquito
Africa
Tick
Western and Rocky Mountain states

of USA
Bunyaviruses
California (including
LaCrosse)
Rift Valley
Orbiviruses
Colorado tick fever
Children usually affected; mortality

< 1%; neurologic sequelae
uncommon
Other
Herpes simplex (type 1) Human
Worldwide
Focal neurologic signs common;

responds to treatment with acyclovir
Herpes simplex (type 2) Human
Worldwide
Encephalitis usually affects

neonates; causes meningitis in
older children and adults
Rabies
Wild and domesticWorldwide

mammals
Invariably fatal unless vaccine and

antiserum administered before
symptoms occur following bite by
affected animal

can be used. The patient can be treated for bacterial
meningitis until the results of CSF cultures are known,
or treatment can be withheld and lumbar puncture reClinical manifestations include fever, headache, neck
peated in 612 hours. If the meningitis is viral in oristiffness, photophobia, pain with eye movement, and
gin, the second sample should show a mononuclear
mild impairment of consciousness. Patients usuallycell
do
not appear as ill as those with bacterial meningitis.pleocytosis.
Systemic viral infection may cause skin rash, pharyn-A disorder that may be clinically indistinguishable
gitis, lymphadenopathy, pleuritis, carditis, jaundice,
from viral encephalitis is the immune-mediated enorganomegaly, diarrhea, or orchitis, and these
cephalomyelitis that may follow viral infections such
ndings
as
may suggest a particular etiologic agent. Because inuenza, measles, or chickenpox. Progressive neuroviral
logic dysfunction typically begins a few days after the
encephalitis involves the brain directly, marked alterviral illness but can also occur either simultaneously
ations of consciousness, seizures, and focal
or
neurologic
up to several weeks later. Neurologic abnormalities
signs can occur. When signs of meningeal irritationreB.
LABORATORY FINDINGS
and
sult from perivenous demyelination, which often seCSF
is thecoexist,
most important
laboratory
test.
brainanalysis
dysfunction
the condition
is termed
verely affects the brainstem. The CSF shows a
Treatment
CSF
pressure is normal or increased, and a
meningoencephalitis.
lympholymphocytic
Except
for herpes usually
simplexwith
encephalitis,
which
cytic pleocytosis,
cell counts
of is disor monocytic pleocytosis is present, with cell counts
cussed
separately
(see
below),
no
specic
therapy for
50150/mL, and mild protein elevation.
usually less than 1000/mL. (Higher counts can be viral meningitis and encephalitis is available. Corticoseen
steroids are of no proven benet except in immunein lymphocytic choriomeningitis or herpes simplexmediated
enpostinfectious syndromes. Headache and
cephalitis.) A polymorphonuclear pleocytosis can fever can be treated with acetaminophen, but aspirin
occur
should be avoided, especially in children and young
early in viral meningitis, while red blood cells may adults,
be
because of its association with Reye syndrome
seen with herpes simplex encephalitis. Protein is nor(see p. 19). Seizures usually respond to phenytoin or
mal or slightly increased (usually 80200 mg/dL). Gluphenobarbital. Supportive measures in comatose pacose is usually normal, but may be decreased in tients include mechanical ventilation and intravenous
mumps, herpes zoster, or herpes simplex
or nasogastric feeding.
encephalitis.
Gram stains and bacterial, fungal, and acid-fast Prognosis
bacillus
(AFB) cultures are negative. Oligoclonal bands andSymptoms of viral meningitis usually resolve spontaCSF protein electrophoresis abnormalities may be neously within 2 weeks regardless of the causative
agent, although residual decits may be seen. The
present. An etiologic diagnosis often can be made by outcome of viral encephalitis varies with the specic
virus
isolation, polymerase chain reaction, or acute- andvirusfor example, eastern equine and herpes
simplex
convirus infections are associated with severe morbidity
valescent-phase CSF antibody titers.
and high mortality rates. Mortality rates as high as
Blood counts may show a normal white cell count,
20%
leukopenia, or mild leukocytosis. Atypical
have
also SIMPLEX
been reported
in immune-mediated
enlymphocytes
HERPES
VIRUS
(HSV)
The
differential
of meningitis
with
mononucephalomyelitis following measles infections.
in blood
smearsdiagnosis
and a positive
heterophil
(Monospot)
ENCEPHALITIS
clear
cell pleocytosis
includes
partially treated
test suggest
infectious
mononucleosis.
Serum
bacterial
HSV is the most common cause of sporadic fatal enamylase is
meningitis
as well asinsyphilitic,
tuberculous,
fungal,
cephalitis in the United States. About two-thirds of
frequently elevated
mumps; abnormal
liver
parasitic,
cases involve patients over 40 years of age. Primary
function neoplastic, and other meningitides.
Evidence
hertests are associated with both hepatitis viruses and
of
in-systemic viral infection and CSF wet mounts, pes infections most often present as stomatitis (HSV
stained
cultures,The
andEEG
cytologic
examination
fectious smears,
mononucleosis.
is diffusely
slow, type
es- 1) or a venereally transmitted genital eruption
can
(HSV
type 2). The virus migrates along nerve axons
pecially if there is direct cerebral involvement.
distinguish among these possibilities. When
to
presumed
sensory ganglia, where it persists in a latent form and
early viral meningitis is associated with a polymor-may be subsequently reactivated. It is not clear
phonuclear pleocytosis of less than 1000 white blood
whether
cells/mL and normal CSF glucose, one of two
strategies
Clinical Findings
30 / CHAPTER 1
HSV type 1 encephalitis, the most common type in
adults, represents a primary infection or a
reactivation
of latent infection. Neonatal HSV encephalitis usually
results from acquisition of type 2 virus during
passage
through the birth canal of a mother with active
genital
lesions. Central nervous system involvement by HSV
type
2 in adults usually causes meningitis, rather
Pathology
than
HSV
type 1 encephalitis is an acute, necrotizing,
encephalitis.
asymmetric hemorrhagic process with lymphocytic and
plasma cell reaction, and usually involves the medial
temporal and inferior frontal lobes. Intranuclear inclusions may be seen in neurons and glia. Patients who
recover may
show cystic necrosis of the involved
Clinical
Findings
regions.
The clinical syndrome may include headache, stiff Figure 16. T2-weighted MRI in herpes simplex
neck, vomiting, behavioral disorders, memory loss,encephalitis. Note the lack of differentiation between
anosmia, aphasia, hemiparesis, and focal or
gray and white matter, because of edema, in the left
generalized
anterior temporal lobe (arrows) compared with the
seizures. Active herpes labialis is seen occasionally,
right. (CourtesyofAGean.)
but
does not reliably implicate HSV as the cause of encephalitis. HSV encephalitis is usually rapidly progressive over several days and may result in coma or
tive diagnosis can be made by biopsy of affected
death.
brain
The most common sequelae in patients who survive
areas, with the choice of biopsy site guided by the
B.
areLABORATORY FINDINGS
EEG, CT, or MRI ndings. However, because treatThe
CSF in
HSV
type 1 disturbances,
encephalitis most
often the
shows
memory
and
behavior
reecting
ment is most effective when begun early and is
increased
pressure,
lymphocytic
or mixed
predilection
of HSV for
limbic structures.
comparlymphocytic
and polymorphonuclear pleocytosis (50100 whiteatively safe, the most common approach is to treat
blood cells/mL), mild protein elevation, and normalpatients with possible HSV encephalitis as described
glucose. Red blood cells, xanthochromia, and
below
and to reserve biopsy for those who fail to imTreatment
decreased
prove.
glucose are seen in some cases. The virus generally
The most effective drug is acyclovir, given intracanvenously at a dosage of 1015 mg/kg every 8 hours,
not be isolated from the CSF, but viral DNA has been
with each dose given over 1 hour. Treatment is
detected by the polymerase chain reaction in some
contincases. The EEG may show periodic slow-wave comued for 1421 days. Complications include erythema
plexes arising from one or both temporal lobes, and
at the infusion site, gastrointestinal disturbances,
CT
headache, skin rash, tremor, seizures, and
scans and MRI may show abnormalities in one or both
encephalopatemporal lobes. These can extend to frontal or
thy or coma. Treatment is started as early as
parietal
possible,
regions and are sometimes enhanced with the
since outcome is greatly inuenced by the severity of
Prognosis
The
symptoms and signs are not specic for herpes
infusion
dysfunction at the time treatment is initiated.
virus
infection.
The greatest
diagnostic
difculty
isPatients under the age of 30 years and those who are
of contrast
material
(Figure 16).
However,
imaging
disonly lethargic at the onset of treatment are more
studies may also be normal.
tinguishing between HSV encephalitis and brain ablikely
scess, and the two disorders often cannot be
to survive than are older or comatose patients. The
differentimortality rate is about 25% at 18 months in patients
ated on clinical grounds alone. Other CNS infections
given acyclovir.
and vasculitis can also mimic HSV encephalitis.
Deni-

pleocytosis associated with AIDS, including cryptococcal meningitis, herpes simplex encephalitis, and cerebral toxoplasmosis, must be excluded.
AIDS is caused by infection with human immunodeciency virus type 1 (HIV-1) and is characterized by2. CRYPTOCOCCAL MENINGITIS
Cryptococcal meningitis occurs in 510% of patients
opwith AIDS. Clinical features include headache, confuportunistic infections, malignant neoplasms (typically
non-Hodgkin lymphoma or Kaposi sarcoma), and asion, stiff neck, fever, nausea and vomiting, seizures,
and cranial nerve palsies. Because the CSF is
vaotherwise
riety of neurologic disturbances. Transmission occurs
normal in about 20% of patients with AIDS and crypthrough sexual activity or by transfer of virustococcal meningitis, CSF cryptococcal antigen titers
contamishould always be obtained. Laboratory abnormalities
nated blood or blood products. Individuals at particular risk of infection include those who engage in and recommended treatment are discussed in the
secunproHERPES
SIMPLEX
& VARICELLA
-ZOSTER ENCEPHALITIS
tion
on fungal
meningitis
below.
tected sexual intercourse, intravenous drug users 3.
Whereas HSV encephalitis in immunocompetent
who
share needles, hemophiliacs who have received adults is almost always due to type 1 virus, either
type 1
factor
or type 2 HSV can produce the disorder in patients
VIII transfusions, and their sexual partners.
with AIDS. The focal neurologic signs and CSF abnorNeurologic complications of AIDS include demenmalities usually associated with HSV encephalitis may
tia (see below), myelopathy (see Chapter 5),
be absent in AIDS, and the disorder may follow a
neuropamore
thy (see Chapter 6), myopathy (see Chapter 5), and
stroke (see Chapter 9). In addition to the disordersindolent course. Varicella-zoster virus, a herpesvirus
1.
HIV-1 MENINGITIS
that rarely causes encephalitis in immunocompetent
that
Patients
infected
with
HIV-1
can
develop
a
syndrome
inproduce acute confusional states in persons without
characterized
by
headache,
fever,
signs
of
meningeal
dividuals,
may do so
in patients with AIDS. Treatment
4. CYTOMEGALOVIRUS
ENCEPHALITIS
AIDS, patients with AIDS are at increased risk for diiris as described above
for HSV
encephalitis.
Cytomegalovirus,
another
herpesvirus,
has been
rect HIV infection of the nervous system, other opporritation,
cranial nerve
VII) palsies,
otherimplitunistic infections,
and(especially
certain tumors
(Table 117).
focated as a cause of retinitis and polyradiculomyelitis
Treatment of AIDS is discussed in the section on AIDS
cal
neurologic
abnormalities,
orchapter.
seizures. This usually
(see Chapter 5) in patients with AIDS. Cydementia
complex
later in this
occurs at about the time of HIV-1 seroconversion. An
tomegalovirus can also be identied in CSF and
acute confusional state is occasionally present. HIV-1
biopsy
meningitis is associated with mononuclear
specimens from patients with AIDS who are
pleocytosis
neurologi5.
CEREBRAL
TOXOPLASMOSIS
of up to about 200 cells/mL. Symptoms usually
cally
asymptomatic,
acutely confused, or demented.
Cerebral
toxoplasmosis
produces
mass
resolve
Death
usually
occurs
within
a fewintracerebral
weeks, although
Table 117. Causes of acute confusional states
spontaneously within about 1 month. Other causesleof
therapeutic responses to antiviral treatment with
in patients with AIDS.
sions
ganci-in patients with AIDS, although its frequency appears
to befoscarnet
declininghave
as antitoxoplasma
clovir and
been reported.drugs such
Meningitis
as
HIV-1 meningitis
trimethoprim-sulfamethoxazole are widely used for
prophylaxis against Pneumocystis carinii pneumonia
Encephalitis
in
Herpes simplex encephalitis
patients with AIDS. A confusional state lasting days to
Varicella-zoster encephalitis
weeks exists at the time of presentation in about 30%
Cytomegalovirus encephalitis
of patients. Other clinical features include fever, focal
Intracerebral mass lesions
neurologic abnormalities such as cranial nerve palsies
Cerebral toxoplasmosis
or
Primary central nervous system lymphoma
Metabolic encephalopathies
hemiparesis, seizures, headache, and signs of
Pulmonary encephalopathy (related to
meningeal
Pneumocystis
irritation. Serologic tests for toxoplasmosis are unrelicarinii-pneumonia)
able in patients with AIDS. MRI is more sensitive than
Drug toxicity
CT scanning and typically reveals one or more
Stroke
lesions,
Seizures
which often show a contrast enhancement of the rim
and are commonly located in the basal ganglia.
Because toxoplasmosis is readily treatable,
patients
with AIDS and intracerebral mass lesions that are not
ACQUIRED IMMUNODEFICIENCY
SYNDROME (AIDS)
32 / CHAPTER 1
obviously due to stroke should be treated for
lated with rhinocerebral mucormycosis. In contrast,
presumed
meningeal infections with Coccidioides, Blastomyces,
toxoplasmosis, as described in the section on
and
parasitic
Actinomyces usually occur in previously healthy
infections below. Up to 90% of patients respond favorindividably to therapy within the rst few weeks and the uals. Cryptococcus (the most common cause of
6.
PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA
mafungal
Primary
central
nervous
lymphoma is the meningitis in the United States) and Histoplasma
jority survive
longer
thansystem
6 months.
most
infeccommon brain tumor associated with AIDS. Systemic
tion can occur in either healthy or immunosuppressed
non-Hodgkin lymphoma also occurs with increasedpatients. Cryptococcal meningitis is the most
frequency, but usually produces lymphomatous common
meninfungal infection&ofPathology
the nervous system in AIDS, but
gitis (see below) rather than intracerebral masses.Pathogenesis
Coccidioides and Histoplasma infections can also
CliniFungi
occur reach the central nervous system by hematogecal features of primary central nervous system lymnous
from
the lungs,
heart,are
gastrointestinal
or
in thisspread
setting.
Geographic
factors
also important
phoma include confusional state, hemiparesis,
genitourinary
tract,
or
skin,
or
by
direct
extension
in
aphasia,
from
the epidemiology of certain mycoses (see Table 1
seizures, cranial nerve palsies, and headache; signs
parameningeal
sites such as the orbits or paranasal
18).
of
sinuses. Invasion of the meninges from a contiguous
meningeal irritation are uncommon. CSF commonly
focus of infection is particularly common in mucormyshows elevated protein and mild mononuclear pleocycosis but may also occur in aspergillosis and
tosis, and glucose may be low; cytology is rarely posiactinomytive. MRI is more sensitive than CT scanning and cosis.
shows single or multiple contrast-enhanced lesions, Pathologic ndings in fungal infections of the nervwhich may not be distinguishable from those seenous system include a primarily mononuclear
with
meningeal
toxoplasmosis. Patients with AIDS and one or moreexudative
inreaction, focal abscesses or granulomas in
7.
OTHER DISORDERS
tracerebral
mass lesions that fail to respond to treatthe
Pneumocystis
carinii pneumonia
in patients
with AIDS
ment for toxoplasmosis
within 3 weeks
should
Clinical
Findings
brain or spinal
epidural space, cerebral infarction remay
lead to hypoxia and a resulting confusional lated to vasculitis, and ventricular enlargement
undergo
meningitis is usually a subacute illness that
state.
brain biopsy for diagnosis of lymphoma. Although Fungal
corcaused
clinPatients
withand
AIDS,
especially
those
withprolong
centralsurnervticosteroids
radiation
therapy
may
by communicating hydrocephalus.
ically resembles tuberculous meningitis. A history of a
ous
system
involvement,
may
be
especially
sensitive
vival, most patients die within a few months.
predisposing condition such as carcinoma,
to
hematologic
drugs (eg, antidepressants) and metabolic disorders,
AIDS,
diabetes, organ transplantation,
A.a SYMPTOMS AND
SIGNS
and the antiretroviral drug zidovudine can producemalignancy,
treatment
with
corticosteroids
or cytotoxic
and agents,
lethargy
confusional state. Stroke can occur in patients withCommon symptoms include headache
proor
AIDS, especially when it is complicated by cryptococlonged antibiotic
therapy,
or intravenous
drug use or
inconfusion.
Nausea,
vomiting,
visual loss, seizures,
cal meningitis, and may produce an acute confusional
creases
the
suspicion
of
opportunistic
infection.
Pafostate. Seizures are common in patients with AIDS, estients
also should
travel
cal
weakness
maybe
beasked
noted,about
whilerecent
fever may
be
pecially those with AIDS dementia complex, cerebral
through
absent.
toxoplasmosis, or cryptococcal meningitis, and both
areas
where certain
are endemic.
In
a diabetic
patient fungi
with acidosis,
complaints of
complex partial seizures and the postictal state that
facial
folor eye pain, nasal discharge, proptosis, or visual loss
lows generalized tonic-clonic seizures are associated
should urgently alert the physician to the likelihood of
with confusional
states.
FUNGAL
MENINGITIS
Mucor infection.
In a small fraction of patients with systemic fungal in-Careful examination of the skin, orbits, sinuses,
fections (mycoses), fungi invade the central nervous
and
system to produce meningitis or focal
chest may reveal evidence of systemic fungal
intraparenchymal
infection.
lesions (Table 118). Several fungi are opportunistic
Neurologic examination may show signs of meningeal
orirritation, a confusional state, papilledema, visual
ganisms that cause infection in patients with cancer,
loss,
those receiving corticosteroids or other immunosupptosis, exophthalmos, ocular or other cranial nerve
pressive drugs, and other debilitated hosts.
palsies, and focal neurologic abnormalities such as
Intravenous
hemiparesis. Because some fungi (eg, Cryptococcus)
drug abuse is a potential route for infection with Cancan
dida and Aspergillus. Diabetic acidosis is strongly cause spinal cord compression, there may be
correevidence

Table 118. Etiologic agents in fungal meningitis.
Name
Geographic
Distribution
Cryptococcus Nonspecic
neoformans
Opportunistic
Infection
Systemic
Involvement
SometimesLungs, skin, bones,

(including AIDS) joints
Distinctive CSF
Findings
Treatment
Viscous uid, positive Amphotericin B

India ink prep, positive ucytosine
cryptococcal antigen (amphotericin B or
amphotericin B uconazole for AIDS
patients)
Coccidioides Southwestern No
immitis
USA
Lungs, skin, bones Positive complement

xation
Amphotericin B
(intravenous and
intrathecal), uconazole,
or itraconazole
Candida
species
Nonspecic
Yes
Mucous membranes,Positive Gram stain

skin, esophagus,
genitourinary tract,
heart
Amphotericin B
ucytosine
Aspergillus
species
Nonspecic
Yes
Lungs, skin
Amphotericin B
Mucor
species
Nonspecic
Yes, diabetics Orbits, paranasal

sinuses
Amphotericin B
correction of hyperglycemia and acidosis
Histoplasma Eastern and

capsulatum midwestern
USA
Sometimes
Lungs, skin, mucous

membranes, heart,
viscera
Amphotericin B
BlastomycesMississippi
dermatitidis River Valley
No
Lungs, skin, bones,

joints, viscera
Amphotericin B
Actinomyces Nonspecic
israelii1
No
Jaw, lungs, abdomen,

Sulfur granules, positive
Penicillin G or
orbits, sinuses, skin Gram stain, AFB smeartetracycline
Nocardia
species1
Yes
Lungs, skin
Nonspecic
Polymorphonuclear
pleocytosis
Positive Gram stain,
Sulfonamides
AFB smear
up to 1000
cells/mL is common, but a normal cell
count
or
polymorphonuclear
pleocytosis
can be seen
1 Actinomyces and Nocardia are lamentous bacteria that are traditionally considered together
with
in
fungi.
early fungal meningitis and normal cell counts are
comof spine tenderness, paraparesis, pyramidal signs mon
in
in immunosuppressed patients. Aspergillus
the
infeclegs,
and lossFof
sensation over the legs and trunk.tion typically produces a polymorphonuclear
B.
LABORATORY
INDINGS
Blood cultures should be obtained. Serum glucose pleocytoand
sis. CSF protein, which may be normal initially,
arterial blood gas levels should be determined in diasubsequently rises, usually to levels not exceeding
betic patients. The urine should be examined for Can200
dida. Chest x-ray may show hilar lymphadenopathy,
mg/dL. Higher levels (<1 g/dL) suggest possible subpatchy or miliary inltrates, cavitation, or pleural arachnoid block. Glucose is normal or decreased but
effurarely below 10 mg/dL. Microscopic examination of
sion. The CT scan or MRI may demonstrate intracereGram-stained and acid-fast smears and India ink
bral mass lesions associated with Cryptococcus prepa(Figure
rations may reveal the infecting organism (see Table
17) or other organisms, a contiguous infectious 118). Fungal cultures of CSF and other body uids
source
and tissues should be obtained, but are often
in the orbit or paranasal sinuses, or hydrocephalus.
negative.
CSF pressure may be normal or elevated, and the
In suspected mucormycosis, biopsy of the affected
uid is usually clear, but may be viscous in the
tispresence
sue (usually nasal mucosa) is essential. Useful CSF
of numerous cryptococci. Lymphocytic pleocytosis seroof
Nephrotoxicity is common with amphotericin B

and may force interruption of therapy for 25 days.
34 / CHAPTER 1
Newer, lipid-based formulations (eg, amphotericin B
lipid complex, amphotericin B cholesteryl sulfate,
liposomal amphotericin B) are less nephrotoxic, and can
be
used in patients who develop such toxicity on amphotericin B deoxycholate.
In patients with Coccidioides meningitis or those
not
responding to intravenous therapy, intrathecal
amphotericin B (usually administered via an Ommaya
reservoir)
T
T
is added. The drug is given as a 0.1-mg test dose
diluted
in 10 mL of CSF, with or without added
corticosteroids,
and increased to 0.250.5 mg every other day.
Because
administration of amphotericin into the CSF may produce side effects, may require instillation at multiple
sites,
and may be unsuccessful, another approach is to give
uconazole, 400600 mg/d, or itraconazole, 200 mg
Figure 17. T2-weighted MRI in cryptococcal menin- twice
gitis. Note the bilateral increase in signal in the basal daily with meals, by the oral route. In this case,
treatment
ganglia (arrows) with relative sparing of the thalami
must be continued indenitely.
(T). This is due to the presence of gelatinous fungal
pseudocysts in the territory of the lenticulostriate arter- In cryptococcal meningitis, ucytosine, 100
ies. (CourtesyofAGean.)
mg/kg/d
orally, added to amphotericin B and given in four
divided doses, reduces the duration of therapy from
12
to 6 weeks. The dose of ucytosine must be reduced
logic studies include cryptococcal antigen and Coccidin
ioides complement-xing antibody. Cryptococcal antirenal failure; the major side effect is bone marrow
gen is more sensitive than India ink for detecting supCryppression, which is usually reversible. Because of this
tococcus, and should always be looked for in both toxicity, ucytosine is usually omitted when treating
CSF
cryptococcal meningitis in patients with AIDS. For paand serum when that organism is suspected, as intients
pa- with AIDS and cryptococcal meningitis who do
tients with AIDS.
Differential
Diagnosis
not respond to amphotericin B alone, uconazole can
be added at an initial dose of 400 mg, followed by
Fungal meningitis may mimic brain abscess and other
200
subacute or chronic meningitides, such as those due
mg/d, orally or intravenously, for at least 1012
to
tuberculosis or syphilis. CSF ndings and contrast weeks
CT
PARASITIC
INFECTIONS
after CSF cultures are negative. Long-term maintescans are useful in differential diagnosis.
Protozoal
and helminthic
infections
are important
nance therapy
with uconazole,
100200
mg/d orally,
causes
may also reduce the likelihood of recurrence following
For most organisms causing fungal meningitis, treatof
central nervous
system
disease, particularly
successful
treatment
of cryptococcal
meningitisininimpament is begun with amphotericin B deoxycholate, munosuppressed
tients with AIDS. patients (including those with AIDS),
1 mg intravenously as a test dose given over 2030
and
in certain
regions
of the world (Table
RickRapid
correction
of hyperglycemia
and 119).
acidosis
minutes, followed the next day by 0.3 mg/kg intra-ettsias,
parasitic
bacteria
that cause
Rocky
must bethe
combined
with
amphotericin
B treatment
venously in 5% dextrose, given over 23 hours. The
Mountain
and
1.
MALARIA
dose is then increased daily in 5- to 10-mg
spotted
rarely affect
the nervous
system.
surgical fever,
debridement
of necrotic
tissue in
diabetics
Malaria
is caused by the protozoan Plasmodium falciincrements
with
parum or another Plasmodium species that is
until a maximal dose of 0.51.5 mg/kg/d is reached.
mucormycosis.
transferred
Treatment is usually continued for 12 weeks.
Mortality rates remain high in fungal meningitis.
The complications of therapy are frequent, and
neurologic residua are common.

Table 119. Parasitic infections of the central nervous system.
Parasite
Epidemiologic and
Geographic Factors
Clinical Syndrome
Laboratory Findings
Treatment
Protozoa
Plasmodium falciparumAfrica, South America, Acute confusional state, Anemia, organisms
Chloroquine
(malaria)
Southeast Asia, Oceania coma, seizureswithin red blood cells (chloroquine
on peripheral blood
sensitive) or quinidine
smear
or quinine sulfate
(chloroquine
resistant)
Toxoplasma gondii
Malignancy or
Single or multiple focal
Positive CT/MRI brain Pyrimethamine and
immunosuppression mass lesions;
scan; positive Sabin- sulfadiazine
(including AIDS)
meningoencephalitis;Feldman dye test;
positive IgM antibody;
encephalopathy
asterixis, myoclonus, CSF:
or normal or
lymphocytic
seizures
pleocytosis, organism
on wet mount
Naegleria fowleri
Freshwater swimming
Acute fulminant
CSF: polymorpho(primary amebic
in southeastern USA meningoencephalitis nuclear pleocytosis,
meningoencephalitis)
with prominent
motile organisms on
headache and
wet mount
meningeal signs
Acanthamoeba or
Chronic illness or
Hartmanella species immunosuppression
(granulomatous
amebic encephalitis)
Helminths
Taenia solium
(cysticercosis)
Angiostrongylus
cantonensis
(eosinophilic
meningitis)
Rickettsia
Rickettsia rickettsii
(Rocky Mountain
spotted fever)
Amphotericin B with
or without rifampin
and chloramphenicol
or ketoconazole
Subacute-chronic
CSF: lymphocytic or None proven
meningoencephalitis,polymorphonuclear
often with seizures and
pleocytosis, sluggish
focal neurologic signsorganisms on wet
mount
Latin America
Mass lesion or
CSF: lymphocytic,
Albendazole or
meningoencephalitis,pleocytosis,
praziquantel,
often presenting witheosinophilia, positive corticosteroids,
headache or seizurescomplement xation surgical excision of
or hemagglutination; solitary lesion,
calcications on soft shunting for
tissue x-rays or brain hydrocephalus
CT scan
Hawaii, Asia
Acute-subacute
Peripheral blood
meningitis with
eosinophilia; CSF:
headache; stiff neck, eosinophilic and
vomiting, fever, and lymphocytic
paresthesias in aboutpleocytosis
half of patients; selflimited course of 12
weeks
Mebendazole,
levamisole,
albendazole,
thiabendazole, or
ivermectin
Southeastern USA
Acute fever, headache,

Positive Weil-Felix
rash; confusion
reaction
uncommon
Chloramphenicol or
doxycycline
36 / CHAPTER 1
to humans by the female Anopheles mosquito.
2. TOXOPLASMOSIS
Clinical
Toxoplasmosis results from ingestion of Toxoplasma
features include fever, chills, myalgia, nausea andgondii cysts in raw meat or cat excrement and is
vomusually
iting, anemia, renal failure, hypoglycemia, and pul-asymptomatic. Symptomatic infection is associated
monary edema. Although malaria is the most
with underlying malignancy (especially Hodgkin discommon
ease), immunosuppressive therapy, or AIDS.
parasitic infection of humans worldwide, cerebral inClinical Findings
volvement is rare. Plasmodia reach the central
Systemic manifestations include skin rash, lymnervous
phadenopathy, myalgias, arthralgias, carditis, pneusystem in infected red blood cells and cause
monitis, and splenomegaly. Central nervous system
occlusion
inof cerebral capillaries. Neurologic involvement
volvement can take several forms (see Table 119).
becomes
apparent weeks after infection. In addition to acute The CSF may be normal, or it may show mild
confusional states, cerebral malaria can produce mononuclear cell pleocytosis or slight protein
elevation.
seizures
Prophylaxis
MRI is superior to CT scanning for demonstrating
and, rarely, focal neurologic abnormalities. The
toxoplasmosis, and typically shows ring-endiagno- prophylaxis is recommended for travelers cerebral
Malaria
to
lesions (Figure 18). The diagnosis is made
sis is made by nding plasmodia in red blood cellshancing
of
arperipheral
smears.
The CSF may
show of by
eas
where blood
the disease
is endemic
and consists
blood tests demonstrating a high (1:32,000) or
increased
chloropressure,
xanthochromia,
quine
phosphate,
500 mg mononuclear
orally weekly,pleocytosis,
beginningrising
Sabin-Feldman dye test titer or IgM antibodies to
or weeks before travel and continuing until 4 weeks
12
mildlyreturning.
elevated If
protein.
after
exposure to chloroquine-resistantToxoplasma by indirect immunouorescence. Accurate
strains is expected, treatment options include meodiagquine (250 mg orally weekly for 4 weeks, beginning
nosis requires appropriate serologic studies in the im12 weeks before travel and continuing until 4 weeks
munosuppressed patient who develops neurologic
after returning), doxycycline (100 mg orally daily, beginning 12 days before travel and continuing untilsymptoms.
4
weeks after returning), or atovaquone/proguanil
(250/100 mg orally daily, beginning 12 days before
travel and continuing until
1 week
afterisreturning).
Chloroquine-sensitive
cerebral
malaria
treated with
Treatment
chloroquine, 10 mg base/kg by continuous
intravenous
infusion over 8 hours followed by 15 mg base/kg over
24 hours, or 3.5 mg base/kg by the intramuscular or
subcutaneous route every 6 hours to a cumulative
dose
of mg base/kg. Chloroquine-resistant cerebral
malaria is treated with quinidine, 10 mg base/kg by
intravenous infusion over 1 hour followed by 0.02 mg
base/kg/min, or with quinine dihydrochloride (not
available in the United States), 20 mg/kg by intravenous infusion over 4 hours followed by 10 mg/kg
infused over 28 hours every 8 hours. Each of these
regimens is continued until oral therapy with chloroquine,
amodiaquine, or sulfadoxine and pyrimethamine (for
chloroquine-sensitive malaria) or with meoquine,
Figure 18. T1-weighted, gadolinium-enhanced MRI
quiin cerebral toxoplasmosis complicating HIV infection.
nine, or quinidine (for chloroquine-resistant malaria)
Note the multiple ring-enhanced lesions (arrows) with
can be substituted.
surrounding edema. (CourtesyofAGean.)
Cerebral edema is not a consistent nding in cerebral malaria, and corticosteroids are not helpful and
may be deleterious. The mortality rate in cerebral
malaria is 2050% and reaches 80% in cases complicated by coma and seizures.

manifestations of cysticercosis result from the mass
efTreatment is with pyrimethamine, 25100 mg/d orally
fect of intraparenchymal cysts, obstruction of CSF
and sulfadiazine, 11.5 g orally four times daily, and
ow
is
by intraventricular cysts, or inammation that causes
continued for 34 weeks in immunocompetent pa-basilar meningitis. They include seizures, headache,
tients and for at least several months in immunodefocient patients. Clindamycin, 600 mg orally four times
cal neurologic signs, hydrocephalus, myelopathy, and
a
subacute meningitis. Peripheral blood eosinophilia,
day, may be substituted for sulfonamides in patients
soft
who develop drug sensitivity rashes. Folinic acid (leutissue calcications, or parasites in the stool suggest
covorin), 10 mg orally daily, is added to prevent the
pyrimethamine-induced leukopenia and thrombocydiagnosis. The CSF typically shows a lymphocytic
3.
PRIMARY AMEBIC MENINGOENCEPHALITIS
topenia.
pleoThe free-living ameba Naegleria fowleri causes
cytosis (<100 cells/mL), with eosinophils usually presprimary
amebic meningoencephalitis in previously healthy ent. Opening pressure is often increased but may be
young patients exposed to polluted water. Amebasdecreased with spinal subarachnoid block; if this is
gain
entry to the central nervous system through the suspected, myelography should be performed.
Protein
cribriis increased to 50100 mg/dL, and glucose is 2050
form plate, producing a diffuse meningoencephalitis
mg/dL in most cases. Complement xation and
that affects the base of the frontal lobes and
hemagglutination studies can assist in the diagnosis.
posterior
The CT scan or MRI may show contrast-enhanced
fossa. It is characterized by headache, fever, nausea
mass lesions with surrounding edema, intracerebral
and
calvomiting, signs of meningeal irritation, and
cications, or ventricular enlargement (Figure 19).
disordered
mental status. The CSF shows a polymorphonuclear The indications for treatment of cerebral
pleocytosis with elevated protein and low glucose;cysticercosis are controversial. However, patients with symptohighly motile, refractile trophozoites can be seen on
matic neurologic involvement (usually seizures) and
4.
GRANULOMATOUS AMEBIC ENCEPHALITIS
wet
Granulomatous
amebicCSF.
encephalitis
results
from eimounts of centrifuged
The disease
is usually
ther meningitis or one or more noncalcied
infecfatal
tion
with
Acanthamoeba/Hartmanella
species
and intraparenchymal cysts should be treated.
within
1 week,
although treatment with
amphotericin
IntraventriccomB, 1 mg/kg/d intravenously, may be effective, as may
monly
occurs with chronic illness or immunosuppresular, subarachnoid, and racemose cysts respond
a
sion.
The
disorder
typically
lasts
for
from
1
week
to
combination of amphotericin B, rifampin, and chlo-poorly
3
months andorisketoconazole.
characterized by subacute or chronic
to treatment, and calcied cysts do not require treatramphenicol
ment. Albendazole, 15 mg/kg/d in three doses taken
meningitis and granulomatous encephalitis. The cerebellum, brainstem, basal ganglia, and cerebral hemiwith meals, and continued for 8 days, is the preferred
spheres are affected. An acute confusional state istherapy. Praziquantel, 50 mg/kg/d in three divided
the
most common clinical nding. Fever, headache, and
meningeal signs each occur in only about half of patients. Seizures, hemiparesis cranial nerve palsies,
cerebellar ataxia, and aphasia may occur. Pleocytosis may
be primarily lymphocytic or polymorphonuclear; pro5.
CYSTICERCOSIS
tein
is elevated, and glucose is low or normal. SlugCysticercosis
is common inmay
Mexico,
Central
and South
gishly motile trophozoites
be seen
on wet
America,
western
and
southern
Africa,
India,
China,
mounts.
and
southeast
Asia.
The
disease
follows
ingestion
of
Successful treatment has not been reported.
larFigure 19. Contrast-enhanced CT scan in cerebral
vae of the pork tapeworm (Taenia solium) and affects
cysticercosis. Note the multiple bilateral, small, rounded
the brain in 6090% of cases. Larvae undergo
areas of high density, which represent intraparenchyhematogenous dissemination, forming cysts in themal cysts. (CourtesyofAGean.)
brain, ventricles, and subarachnoid space. Neurologic
Treatment
38 / CHAPTER 1
doses, can also be used, but blood levels are reduced
and a characteristic rash that involves the palms and
by
soles and spreads centrally. Neurologic involvement,
anticonvulsants and corticosteroids, which are often
which is uncommon, produces a confusional state
also required in these patients. Patients with seizures
and,
should also receive anticonvulsants. Corticosteroids
less often, coma or focal neurologic abnormalities.
are
The
indicated for increased intracranial pressure or
CSF is normal or shows a mild mononuclear pleocytolesions
sis. Treatment is with chloramphenicol, 2550
near the cerebral aqueduct or intraventricular
mg/kg/d
foramina;
orally or intravenously in four divided doses, or doxythese may progress to cause obstructive
cycline, 200 mg/d orally or intravenously, and is con6.
ANGIOSTRONGYLUS CANTONENSIS MENINGITIS
LEPTOMENINGEAL
METASTASES
hydrocephalus.
tinued for 7 days. Neurologic
residua may occur.
Angiostrongylus
cantonensis
is
endemic
to
southeast
Single accessible intraparenchymal lesions can beDiffuse
remetastatic seeding of the leptomeninges may
Asia
moved surgically, and shunting is required for
complicate
systemic cancer (especially acute lymphoand
to Hawaii and other Pacic islands. Infection is
intravencytic
leukemia,
non-Hodgkin lymphoma, melanoma,
transmitted
by causing
ingestionhydrocephalus.
of infected raw mollusks and
tricular lesions
acute
myelogenous
leukemia, carcinoma of the
produces meningitis with CSF eosinophilia (Table
breast,
120). Most patients complain of headache, and
Hodgkin lymphoma, carcinoma of the lung, carcinoma
about
of the gastrointestinal tract, and sarcoma), producing
half report stiff neck, vomiting, fever, and
neurologic syndromes with prominent cognitive dysparesthesias.
function. Primary brain tumors may be associated
Most patients have a CSF leukocytosis of
with
1501500/mL, mild elevation of protein, and normal
glucose. The acute illness usually resolves sponta-meningeal gliomatosis, and medulloblastomas and
neously in 12 weeks, although paresthesias may pineal tumors have a particular propensity for
meningeal dissemination.
persist
Neoplastic meningitis usually occurs from 3
longer.
months
Levamisole, albendazole, thiabendazole, mebendato 5 years after the diagnosis of cancer, but may be
zole, and ivermectin have been used for treatment;
mebendazole 100 mg twice daily orally for 5 days the
presenting manifestation or occur after many years of
7. ROCKY MOUNTAIN SPOTTED FEVER
may
illnesssometimes in apparently cured patients. Its
Rocky
Mountain
spotted fever
is caused byand
Rickettsia
be preferable.
Analgesics,
corticosteroids,
most frequent symptoms are headache and cognitive
rickettsii,
reduction an intracellular parasite transmitted to hudisorders,
including lethargy, confusion, and memory
Clinical Findings
mans
tick bites.
R rickettsii
damages
endothelial
of CSFby
pressure
by repeated
lumbar
punctures
may
impairment.
Nausea, vomiting, seizures, and gait abcells,
leading to vasculitis, microinfarcts, and
be
A.
S
YMPTOMS
AND
SIGNScommon.
normalities are also
petechial
of value.
Abnormal neurologic signs are often more striking
hemorrhage. Initial symptoms include fever,
than
headache,
the symptoms and usually suggest involvement at
mulTable 120. Causes of CSF eosinophilia.
tiple
levels of Fthe
neuraxis. The symptoms and signs
B.
LABORATORY
INDINGS
most
often
seen
when
the patient
presents
with punclepThe
most
useful
diagnostic
procedure
is lumbar
Common causes
tomeningeal
metastases
are
listed
in
Table
121.
ture,
which
may
show
increased
opening
pressure,
Taenia solium (cysticercosis)
Angiostrongylus cantonensis (eosinophilic meningitis) pleoUncommon causes
cytosis and elevated protein, and markedly
Other helminthic infections
decreased or
Coccidioides immitis meningitis
even immeasurably low glucose (see Table 121).
Hematologic malignancies with meningeal inltration NeoForeign matter (including myelography dye) in
plastic meningitis is diagnosed by nding malignant
subarachnoid space
cells in the CSF; large volumes of uid and repeated
Possible causes (less well documented)
lumbar punctures increase the yield of cytologic studNeurosyphilis
ies. Several biochemical markers for leptomeningeal
metastases can be identied in CSF. These include
Nonhematologic malignancies with meningeal inltration
Lymphocytic choriomeningitis
carPolyarteritis nodosa
cinoembryonic antigen, human chorionic goAllergic reactions
nadotropin, and which are specic for
leptomeningeal metastases, as well as 2microglobulin,
and lactic dehydrogenase isozyme
V,
which also can be elevated in inammatory disorders.

Table 121. Presenting symptoms, signs, and CSF Where clinically indicated, MRI or a metrizamide CT
ndings with leptomeningeal metastases.
study of the spine, or myelography is performed to
exclude the possibility of intraparenchymal metastasis
Feature
Percentage of Patients
or
spinal
cord compression
Symptoms
Differential
Diagnosis by epidural metastasis.
Gait disturbance
46
Headache
38
Altered mentation
25
Weakness
22
Back pain
18
Nausea or vomiting
12
Radicular pain
12
Neoplastic meningitis can simulate infectious

meningitis, metabolic encephalopathy, intraparenchymal or
spinal epidural metastasis, remote effects of
carcinoma,
or chemotherapeutic drug toxicity and may coexist
with any of these
conditions.
Treatment
& Prognosis
Untreated, leptomeningeal metastases are typically

associated with death within about 2 months. LepParesthesias
10
tomeningeal leukemia and lymphoma can be
Signs
successLower motor neuron weakness
78
fully treated with radiation and chemotherapy, and
some patients with breast cancer or small-cell lung
Absent tendon reex
60
canCognitive disturbance
50
cer also respond to these approaches. However, even
with
treatment, most patients with leptomeningeal
SEPSIS
Extensor plantar response
50
metastases from solid tumors live only a few months.
Systemic sepsis can produce an encephalopathy that
Dermatomal sensory decit
50
may be related to impaired cerebral blood ow,
Ophthalmoplegia
30
disruption of the blood-brain barrier, or cerebral edema.
Facial weakness
25
Gram-negative infections are the most common
Hearing loss
20
cause.
Clinical ndings include bacteremia and often liver or
Neck meningeal signs
16
kidney failure. The EEG is often abnormal. Therapy
Seizures
14
involves supportive measures, such as assisted
ventilaPapilledema
12
tion, and treatment of the underlying infection. MorFacial sensory decit
12
tality is high, but can be prevented by prompt
VASCULAR
DISORDERS
diagnosis
Leg meningeal signs
12
and
treatment. ENCEPHALOPATHY
HYPERTENSIVE
CSF ndings
A sudden increase in blood pressure, with or without
Protein increased1
81
preexisting chronic hypertension, may result in encephalopathy and headache, which develop over a
Pleocytosis2
57
pePositive cytology
54
riod of several hours to days. Vomiting, visual disturbances, focal neurologic decits, and focal or
Opening pressure elevated3
50
generalized seizures can also occur. Blood pressure in
Glucose decreased4
31
excess of 250/150 mm Hg is usually required to
precipNormal
3
itate the syndrome in patients with chronic hyperten1
mg/dL.
sion; previously normotensive patients may be
2 white blood cells/mm3.
affected
3 mm CSF.
at lower pressures. Coexisting renal failure appears to
4 mg/dL.
DatafromPosnerJB:NeurologicComplicationsof increase the risk of hypertensive encephalopathy.
Cerebrovascular spasm, impaired autoregulation of
Cancer.Davis,1997.
cerebral blood ow, and intravascular coagulation
have
all been proposed as the cause of neurological symptoms. These processes can lead to small infarcts and
petechial hemorrhages that affect the brainstem most
40 / CHAPTER 1
prominently and other subcortical gray and white Prevention
matHypertensive encephalopathy is best prevented by
ter regions to a lesser extent.
early
Clinical Findings
treatment of uncomplicated hypertension and by
recognition of elevated blood pressure in setThe physical ndings most useful in conrming theprompt
diagnosis are those seen on ophthalmoscopy. Retinaltingssuch as acute glomerulonephritis or eclampsiain which it tends to occur in previously norartemotensive patients.
riolar spasm is almost invariably present.
Papilledema,
Treatment
retinal hemorrhages, and exudates are usually
The diagnosis of hypertensive encephalopathy is
present.
estabLumbar puncture may show normal or elevated CSF
lished
pressure and protein. Low-density areas suggestive
of when lowering the blood pressure results in
rapid
edema in the posterior regions of hemispheric white
of symptoms. This is accomplished with
matter are seen on CT scan and corresponding T2 resolution
hysodium
nitroprusside,
given by continuous
perintense areas are seen on MRI (Figure 110); the
intravenous
changes are Diagnosis
reversible with treatment. Blood studies
Differential
infusion at an initial rate of 0.5 mg/kg/min, and inare
creased to as much as 310 mg/kg/min as required.
Hypertensive
encephalopathy
is
a
diagnosis
of
excluimportant to detect uremia.
Alsion. Stroke and subarachnoid hemorrhage also produce encephalopathy with acutely elevated blood ternative approaches include diazoxide, 50100 mg
by
pressure, and when focal neurologic abnormalities are intravenous bolus every 510 minutes (to a maximum
600 mg) or 1030 mg/min by constant intravenous
present, stroke is by far the most likely diagnosis. of
Eleor labetalol, 2080 mg by intravenous bolus
vated blood pressure, headache, papilledema, andinfusion,
altered consciousness are also seen with intracranialevery 510 minutes (to a maximum of 600 mg) or
0.52 mg/min by constant intravenous infusion. The
hemorrhage; where this is a consideration, it can be patient must be carefully monitored and the infusion
rate adjusted to maintain a therapeutic effect without
excluded by CT scan or MRI.
producing hypotension. In the rst hour of treatment,
mean arterial blood pressure should be reduced by no
more than 2025% and diastolic pressure should not
Figure 110. Axial T2-weighted images of the brain of a 39-year-old woman who developed hypertensive
encephalopathy in the setting of chronic renal failure. Areas of abnormal high intensity (arrows) represent edema
affecting posterior parietal and occipital regions, white matter more than gray. Similar imaging changes can
sometimes be seen following generalized seizures and with certain drugs, particularly cyclosporine and
chemotherapeutic
agents. Imaging abnormalities typically resolve with treatment of the underlying condition. (CourtesyofHA
Rowley.)

be allowed to fall below 100 mm Hg. Treatment depression, and mania. Seizures are usually
should
generalized
be terminated immediately if neurologic function but may be focal. Less common neurologic manifestaworstions include visual impairment from optic nerve inens. Untreated hypertensive encephalopathy can volvement, ptosis, diplopia, hemiparesis, paraparesis,
result
tremor, chorea, cerebellar ataxia, and
B.
LABORATORY FINDINGS
in
stroke,
coma,
or
death
but
prompt
treatment
polyneuropathy.
SUBARACHNOID HEMORRHAGE
Laboratory
abnormalities in SLE include antinuclear
usually
antibodies,
anemia, hypocomplementemia, antinative
Subarachnoid
produces
full clinicalhemorrhage
recovery. must receive early
DNA
antibodies,
leukopenia, and autoantibodies
consideration in the differential diagnosis of an
against
ribosomal
P proteins. No laboratory nding is
acute confusional state. This disorder is disdiagnostic
of
nervous
system involvement, but CSF
cussed in Chapter 2.
shows mild elevation of protein or a modestusually
mononuclearpleocytosis in about one-third of
VERTEBROBASILAR ISCHEMIA
cases.
The EEG frequently shows diffuse slowing or focal abTransient ischemia or stroke in the distribution of the
posterior cerebral circulation can produce an acutenormalities.
conDifferential Diagnosis
fusional state. Vertebrobasilar ischemia is discussed
Even in patients with known SLE, encephalopathy can
in
be caused by a variety of factors other than cerebral
Chapter 9.
RIGHT (NONDOMINANT) HEMISPHERIC
luINFARCTION
pus per se. Coagulopathy, infection, uremia, and emboli from endocarditis must be excluded. A common
Agitated confusion of sudden onset can result from
dilemma is the need to distinguish cerebral lupus
infrom
farction (usually embolic) in the territory of the
steroid-induced psychosis in patients receiving
inferior
corticodivision of the nondominant (usually right) middle
steroid therapy for SLE. Cerebral lupus is by far the
cerebral artery. If the superior division is spared,
more
frequent problem, particularly in patients
Treatment
there is
receivno hemiparesis. Agitation may be so pronounced as
Cerebral
is treated
corticosteroids, begining low orlupus
tapering
doseswith
of steroids.
to
ning at 60 mg/d of prednisone or the equivalent. In
suggest an alcohol withdrawal syndrome, but autopanomic hyperactivity is absent. The diagnosis is contients already receiving steroids, the dose should be
rmed
by
CT
brain
scan
or
MRI.
Rarely,
isolated
anteincreased by the equivalent of 510 mg/d of predSYSTEMIC LUPUS ERYTHEMATOSUS
rior cerebral artery infarcts or posterior cerebral nisone. After symptoms resolve, steroids should be
Systemic
lupus erythematosus (SLE) is the most comartery
tamon
autoimmune
cause
of encephalopathy. SLE ispered to a low maintenance dose. Seizures are
infarcts
cause acute
confusion.
nine
treated
Prognosis
times more common in women than in men and usuwith anticonvulsants.
ally has its onset between the ages of 10 and 40 Neurologic symptoms of SLE improve in more than
years.
80% of patients treated with corticosteroids, but may
Neurologic involvement is reported in 3775% of paalso resolve without treatment. Cerebral involvement
tients. The clinical features that correlate best within
nervous system involvement are active
SLE has not been shown to adversely affect the
mucocutaneous
overall
or visceral vasculitis and thrombocytopenia, but cliniprognosis.
DISSEMINATED INTRAVASCULAR
cally active systemic disease need not be present for
COAGULATION
neurologic symptoms to occur. Neuropathologic ndings include brinoid degeneration of arterioles and
Disseminated intravascular coagulation (DIC) results
capillaries, microinfarcts, and intracerebral hemor-from pathologic activation of the coagulation and
Clinical Findings
rhages. True vasculitis of cerebral blood vessels is brirare.
nolytic systems, usually in the setting of a severe
The most common neurologic features are seizuresunderand
lying systemic disease. The principal manifestation is
an altered mental status. Cognitive disturbances hemorrhage. DIC tends to occur at the extremes of
include
age,
acute confusional states, schizophreniform psychosis,
but patients of any age can be affected. Common
ndings in the brain include small multifocal infarctions
42 / CHAPTER 1
and petechial hemorrhages involving both gray and
matter. The antiplatelet drugs ticlopidine and clopidowhite matter. Subdural hematoma, subarachnoid grel can precipitate TTP, but how this occurs is
hemunclear.
orrhage, and hemorrhagic infarction in the
Clinical Findings
distribution
of
large vessels
may also occur.
Clinical
Findings
Patients most often present with altered
Neurologic manifestations are common and include
consciousness,
confusional states, coma, focal signs, and seizures.headache, focal neurologic signs, or seizures or with
They may precede the denitive hematologic abnorcumalities of hypobrinogenemia, thrombocytopenia,taneous hemorrhages in the form of purpura, ecchybrin degradation products, and prolonged pro- moses, or petechiae. Other symptoms include
thrombin time. Microangiopathic hemolytic anemiamalaise,
may also occur.
fatigue, generalized weakness, nausea, vomiting,
diarrhea, fever, and abdominal pain. Bleeding from sites
other than the skin may occur. Neurologic symptoms
Disorders that must be excluded include metabolicmay be eeting and recurrent. The physical examinaencephalopathy, meningoencephalitis, metastatic tion
inis helpful in documenting fever, cutaneous
volvement of the brain or meninges, or stroke caused
hemorby nonbacterial thrombotic (marantic) endocarditis.
rhage, and neurologic dysfunction. TTP usually
Thrombotic thrombocytopenic purpura (TTP) is dis-follows
tinguished by its tendency to occur in previously B.
ABORATORY
FINDINGScourse but can be a chronic proan Lacute,
fulminant
healthy patients and its association with normal Hematologic
studies show
a Coombs-negative
hegressive or remitting
and relapsing
disorder lasting
plasma brinogen and normal or only slightly ele- molytic
anemia with hemoglobin levels usually less
from
vated brin degradation products.
than
months to years. What accounts for the defect in von
10
g/dL, normochromic
redprotease
blood cell
indices,
Willebrand
factor-cleaving
activity
in fragchronic
Treatment
mented
and
misshapen
erythrocytes,
and
often
cases is unknown.
Treatment is directed at the underlying disease. nucleated red cells. Platelet counts are less than
Transfusion of red blood cells, platelets, and coagulation20,000/mL in
about half the cases and less than 60,000/mL in
factors from fresh-frozen plasma may be indicated. almost
all cases; the white blood cell count is normal or eleTransvated. Coagulation studies are normal or slightly
fused platelets are often rapidly destroyed, however,
abnorand
mal in most patients: PT and PTT are normal in about
transfused coagulation factors may be converted to
90% of cases and brinogen is normal in 80%. Fibrin
andegradation products are normal in about 50% of
ticoagulant brin degradation products and worsen
cases
the
THROMBOTIC THROMBOCYTOPENIC
and
slightly elevated
in about 25%. Renal
Differential
Diagnosis
hemorrhagic tendency. Heparin sometimes has been
PURPURA
involvement
advocated
of its ability
to inhibit
theis a rare
Thromboticbecause
thrombocytopenic
purpura
(TTP)
DIC
also associated
hemolytic
or
mayiscause
hematuria,with
proteinuria,
or anemia
azotemia.
coagulamultisystem disorder dened by the pentad of thromthrombocytopenia.
Idiopathic thrombocytopenic purSpinal
tion
cascade,purpura,
but its utility
is uncertain. hemolytic
Prognosis is
bocytopenic
microangiopathic
pura
(ITP)
is notnormal,
accompanied
by microangiopathic
uid is
usually
but protein
may be elevated.
reanehemolytic
anemia
or by diagnosis
evidence of
multisystem
disAntemortem
pathologic
may
be made by
lated
to the severity
of the underlying
mia, neurologic
dysfunction,
fever, anddisease.
renal disease.
ease.
gin- The hemolytic anemias of SLE, autoimmune heIn
molytic
anemia
(AIHA), and Evans syndrome (both
gival biopsy
or splenectomy.
most cases, the cause is thought to be an IgGITP and AIHA) are Coombs-positive.
mediated
autoimmune reaction against a von Willebrand factorTreatment & Prognosis
cleaving protease, which allows unusually large multimers of von Willebrand factor to accumulate in thePlasmapheresis is the mainstay of therapy and is
someplasma, where they stimulate platelet aggregation.
times combined with prednisone and antiplatelet
The
agents (aspirin, 325 mg three times daily and dipyriresult is platelet-brin thrombus formation with occlusion of small blood vessels, especially at arteriolar-damole, 75 mg three times daily). With treatment,
of patients recover, although relapses may
capiloccur.
lary junctions. Pathologic ndings in the brain include
disseminated microinfarcts and, less frequently, petechial hemorrhages that are present mainly in gray
HEAD TRAUMA
rhage is made by CT scan or MRI. Epidural hematoma

tends to appear as a biconvex, lens-shaped, extraBlunt head trauma can produce a confusional stateaxial
or
coma. Acceleration or deceleration forces and
mass that may cross the midline or the tentorium but
physical
not the cranial sutures. Subdural hematoma is
deformation of the skull can cause shearing of white
typically
matter, contusion from contact between the inner crescent-shaped and may cross the cranial sutures
surbut
face of the skull and the polar regions of the cerebral
not the midline or tentorium. Midline structures may
hemispheres, torn blood vessels, vasomotor changes,
be displaced contralaterally.
brain edema, and increased intracranial pressure. Epidural and subdural hematomas are treated by
CONCUSSION
surgical evacuation. The decision to use surgery to
Concussion is characterized by transient loss of contreat
sciousness for seconds to minutes without
intracerebral hematoma depends upon the clinical
demonstracourse and location. Evacuation, decompression, or
SEIZURES
ble structural defects. Unconsciousness is associated
shunting for hydrocephalus may be indicated.
with normal pupillary and ocular reexes, accidity,
POSTICTAL STATE
and extensor plantar responses. The return of consciousness is followed by a confusional state that Generalized tonic-clonic (grand mal) seizures are typiTraumatic intracranial hemorrhage can be cally followed by a transient confusional state
usually
epidural, subdural, or intracerebral. Epidural
(postictal
lasts from minutes to hours, and is characterized by
hematoma most often results from a lateralstate) that resolves within 12 hours. Disturbances of
prominent retrograde and anterograde amnesia (see
skull
rebefracture that lacerates the middle meningeal artery
cent memory and of attention are prominent. When
low). Patients with simple concussion usually recover
or
postictal confusion does not clear rapidly, an
uneventfully, although headache, dizziness, or mild
vein. Patients may or may not lose consciousness explanation
cognitive impairment may persist for weeks. When
initially,
for the prolonged postictal state must be sought. This
unbut in either event a lucid interval lasting several occurs in three settings: status epilepticus, an
consciousness is prolonged, delayed in onset after a
hours to
underlying
lu12 days is followed
by the rapid evolutionover structural brain abnormality (eg, stroke, intracranial
INTRACRANIAL
HEMORRHAGE
cid interval, or associated with focal neurologic abnorhoursof headache, progressive obtundation,
hemorrhage), and an underlying diffuse cerebral
malities, the possibility of posttraumatic intracranial
hemiparedisorder
hemorrhage should be considered.
sis, and nally ipsilateral pupillary dilatation from Complex
partial
(formerly
called
temporal metabolic
lobe or
(eg,
dementia,
meningitis
or encephalitis,
COMPLEX
PARTIAL
SEIZURES
uncal
psyenherniation. Death may follow if treatment is delayed.
chomotor)
seizures
produce
in
cephalopathy).
Patients
with alterations
an unexplained
Subdural hematoma after head injury can be consciousness
prolonged
acute,
characterized
confusion
alone, orwith
by cognitive,
postictal state by
should
be evaluated
blood
subacute, or chronic. In each case, headache and affecchemistry
altered
tive,
psychomotor,
or psychosensory
symptoms.
studies,
lumbar puncture,
EEG, and CT
scan or MRI.
consciousness are the principal manifestations. Delay
Complex
in
partial seizures rarely cause diagnostic problems in
diagnosis and treatment may lead to a fatal outcome.
the paIn
tient presenting with an acute confusional state,
contrast to epidural hematoma, the time between because
trauma
spells are typically brief and stereotypical,
and the onset of symptoms is typically longer, the psychomotor
hemmanifestations are often obvious to the observer, and
orrhage tends to be located over the cerebral
paconvexities,
tients themselves may describe classic cognitive,
and associated skull fractures are uncommon.
affective,
Subdural
or psychosensory symptoms (see Chapter 8).
hematoma in the posterior fossa is uncommon.
Complex partial seizures produce a confusional
Intracerebral contusion (bruising) or hemorrhage
state
related to head injury is usually located at the frontal
that
may be characterized
by a withdrawn or
PSYCHIATRIC
DISORDERS
or
unresponSymptoms
similar
to those
associated
with acutesuch
temporal poles. Blood typically enters the CSF, resultsive state or
by agitated
behavior.
Automatisms
confuing in signs of meningeal irritation and sometimes as
hysional
statesincoherence,
agitation, distractibility,
drocephalus. Focal neurologic signs are usually
staring,
repetitive chewing, swallowing,
lip-smacking,
hyabsent
or picking at clothing are characteristic. Complex paror subtle.
tial status epilepticus, which is rare, lasts for hours to
The diagnosis of posttraumatic intracranial hemordays. The diagnosis is made or conrmed by EEG.
44 / CHAPTER 1
pervigilance, delusions, and hallucinationsalso can
Table 122. Neurologic changes in normal aging.
be
seen in a variety of psychiatric disorders. These Cognitive
include
Memory loss (benign senescent forgetfulness)
Neuroophthalmologic
psychotic disorders (schizophrenia, schizophreniform
Small, sluggishly reactive pupils
disorder, schizoaffective disorder, delusional disorder,
Impaired upgaze
brief psychotic disorder), mood (depressive and bipoImpaired convergence
lar) disorders, anxiety disorders (posttraumatic stress
Motor
disorder), and factitious disorders. Such diagnoses
Muscular atrophy (intrinsic hand and foot muscles)
may
Increased muscle tone
be mistakenly assigned to patients with acute confuFlexion (stooped) posture
sional states; conversely, patients with psychiatric Gait disorders (small-stepped or broad-based gait)
disSensory
turbances may be thoughtincorrectlyto have or-Impaired vision
Impaired hearing
ganic disease.
Impaired taste
Unlike acute confusional states, psychiatric
Impaired olfaction
disorders
vibration sense
are rarely acute in onset but typically develop over Decreased
a
Reexes
pePrimitive reexes
riod of at least several weeks. The history may reveal
Absent abdominal reexes
previous psychiatric disease or hospitalization or a Absent ankle jerks
precipitating psychological stress. Physical examination
may show abnormalities related to autonomic overactivity, including tachycardia, tachypnea, and hyperreexia but no denitive signs of neurologic dysfunction. Routine laboratory studies are normal in the The
MRI scans
(Figure
111) is also
common
normal
rst step
in evaluating
a patient
withwith
a disorder
psychiatric disorders listed above, but are useful for
aging. These ndings should not by themselves be
of
exconcognitive function is to classify the disorder as either
cluding organic disorders.
sidered
indicative of dementia.
a
Although the mental status examination in acute
disturbance of
the
level of consciousness
APPROACH
TO
DIAGNOSIS
confusional states is often characterized by
(wakefulness
disorientaor arousal), such as an acute confusional state or
tion and uctuating consciousness, patients with psycoma,
chiatric disorders tend to maintain a consistent
or a disturbance of the content of consciousness, in
degree
which wakefulness is preserved. The latter category
of cognitive impairment and to be oriented to person,
inplace, and time. Disorientation as to person,
cludes both global cognitive disorders (dementia) and
especially
more circumscribed decits, such as aphasia and
in the face of preserved orientation in other spheres,
amnestic syndromes. This distinction is important beis
cause the initial classication of the disorder
virtually diagnostic of psychiatric disease. Patientsdetermines
III.
DEMENTIA
with
the subsequent diagnostic approach. The most compsychiatric disorders exhibit a normal level of con-mon problem in this area is distinguishing dementia
sciousness,
appearing
awake and
and
Dementia is usually
an acquired,
generalized,
andalert,
usually
from an acute confusional state, such as that
memory is intact. Disturbances in the content andproduced
proform of thought
(eg, persecutory
delusions,
delusions
gressive
impairment
of cognitive function
that
affects
by drug intoxication. The clinical features presented
of reference,
loosening
associations),
perceptual
the
content, but
not theoflevel,
of consciousness.
Alin
abthough
its incidence increases with advancing ageTable
(it 11 may be useful in making this distinction.
normalities
(eg, auditory
hallucinations),
and at or
has
been estimated
to affect
520% of individuals
Another common problem is differentiating between
inover
dementia and so-called pseudodementia, such as
appropriate
affect are
common,
however.
age
65), dementia
is not
an invariable
that
Psychiatric consultation should be sought
accompaniment
produced by depression (see below).
regarding
of
aging. It reects instead a disorder that affects the
In the clinical evaluation of patients with suspected
diagnosiscortex,
and management.
cerebral
its subcortical connections, or both.
dementia, it is important to try to nd the cause,
Minor changes in neurologic function, including even
alterations in memory and other cognitive spheres, can
though only about 10% of dementias are reversible.
occur with normal aging (Table 122). EnlargementThe
of possibility of reversing or arresting the disorder
ventricles and cerebral cortical sulci seen on CT orthrough appropriate treatment and dramatically improving the quality and duration of life justies a thor-
Figure 111. CT scan in cerebrocortical atrophy, showing ventricular dilation (A) and prominent cortical sulci
(B).
ough diagnostic investigation. A diagnosis is

important
The mental status examination helps to determine
in other cases for purposes of providing a prognosis
whether it is the level or the content of consciousness
and
that is impaired and whether the cognitive
genetic counseling, or alerting family members and
dysfunction
medical personnel to the risk of a transmissible
is global or circumscribed. A disorder of the level of
disease.
consciousness is suggested by sleepiness,
As better treatments are developed for dementing
inattention,
disorimpairment of immediate recall, or disorientation as
ders that are unresponsive or poorly responsive to
History
to
curplace or time. Abnormalities in these areas are
Because
dementia
implies deterioration
in cognitive
rent therapy,
the importance
of arriving at
an
unusual
ability,
it is important to establish that the patients
etiologic
in dementia until the disorder is far advanced.
level
diagnosis of dementia will continue to increase.
To determine the scope of the cognitive
of functioning has declined. Data that can help to
dysfunction
estabor circumscribed), various spheres of
lish the cause of dementia include the time course(global
of
cognition
deare tested in turn. These include memory, language,
terioration; associated symptoms such as headache,
parietal lobe functions (pictorial construction, rightgait
left
disturbance,
or
incontinence;
family
history
of
a
General Physical Examination
discrimination, localization of objects in space), and
similar
The
general
physical examination
can contribute
to
frontal
lobe or
diffuse cerebral cortical functions
condition;
concurrent
medical illnesses;
and the use
Neurologic
Examination
the
(judgof
Certain
disorders that
produce
dementia
also affect
etiologic
diagnosis
when
reveals signsdrugs.
of a systemic
ment, abstraction,
thought
content,
the ability
to peralcohol and
prescribed
oritunprescribed
vidisease responsible for the dementia. Particularly form previously learned acts). Multiple areas of cognision,
coordination,
or motor
sensory function.
Dehelptive function
are impaired
in or
dementia.
The
ful signs are listed in Table 13.
Minimental
Status Examination (see Table 15) provides a useful
bedside screening test when dementia is suspected.
46 / CHAPTER 1
tecting such associated neurologic abnormalities can
mentias), such as depression. Drug intoxication, comhelp to establish an etiologic diagnosis. Neurologicmonly cited as a cause of dementia in the elderly,
signs
actusuggesting causes of dementia are listed in Table 13.
ally produces an acute confusional state, rather than
deLaboratory Investigations
mentia.
Laboratory studies that can help to identify the cause
CEREBRAL DISORDERS WITHOUT
of
EXTRAPYRAMIDAL FEATURES
dementia are listed in Table 17.
DIFFERENTIAL DIAGNOSIS
ALZHEIMER DISEASE
Alzheimer disease is the most common cause of

demenAlthough a wide variety of diseases can pro-tia. Its incidence rises from less than 1% per year to
duce dementia (Table 123), it is generally more than 7% per year, and its prevalence from 3%
agreed that Alzheimer disease is the most to
common cause. Dementia with Lewy bodies, whichalmost 50%, between the ages of 65 and 85 years.
has
This
been recognized as a distinct entity rather than translates into a prevalence of 1020 million cases
simply
worldwide. Men and women are affected with equal
concurrent Alzheimer disease and Parkinson disease,
frequency, when adjusted for age.
may be second in frequency. Vascular dementia,
Alzheimer disease is a progressive, degenerative
somedistimes referred to as multiinfarct dementia, is the next
order of uncertain cause, although abnormal metabomost
common.
Otherofcauses
of dementia, including
Reversible
Causes
Dementia
lism and deposition of protein appears to
rebe
Reversible
causes
of dementiasuch
versible
dementias,
are comparatively
rare. as normal
closely linked to pathogenesis (see below).
pressure hydrocephalus, intracranial mass lesions, vitamin B12 deciency, hypothyroidism, The disease is dened by characteristic histopathologic features, especially neurobrillary tangles and
and neurosyphilisare rare. They are important disorneuritic (senile) plaques. Neuritic plaques are extraders to diagnose promptly, however, because
cellular deposits that contain the proteins

treatment
presenilin
1,
presenilin
2,
1
-antichymotrypsin,
can arrest or reverse the intellectual decline.
Pathogenesis
apolipoOther Important Causes of Dementia
A. GENETICS
protein
E, disease
2-macroglobulin, and ubiquitin. NeuroAlzheimer
is usually sporadic, but a genetic
Diagnosing dementia caused by Huntington disease
brillary
tangles
are intracellular deposits containing
baalhyperphosphorylated
(a microtubule-associated
identied intau
about
5% of cases (Table 1
lows patients with this disorder (and their families)sis
to can be
protein)
and
ubiquitin.
24).
benet from genetic counseling. If Creutzfeldt-Jakob
Patients with trisomy 21 (Down syndrome) have a
dishigh
incidence of Alzheimer disease beginning in the
ease or AIDS dementia complex is diagnosed,
fourth
decade.
precautions
Familial
Alzheimer disease with autosomal domican be instituted against transmission; the course of
nant
inheritance
is genetically heterogeneous. In
AIDS dementia complex may also be modied by
some
antivifamilies there are mutations in the gene for amyloid
ral treatment. Progressive
multifocal
Controversial
Causes of Dementia
precursor protein (APP) on chromosome 21. In other
leukoencephalopathy
Some
disorders
to
which
dementia
is
often
attributed
may indicate underlying immunosuppression fromkindreds, familial Alzheimer disease has an especially
early onset and more virulent course and is linked to
may
HIV not directly cause the disorder. For example, the
mutations in the gene for presenilin 1, a transmemexistence
of
a
primary
alcoholic
dementia
is
questioninfection, lymphoma, leukemia, or another disorder.
brane protein, on chromosome 14. Mutations in anable, since dementia in alcoholic patients may be the
result of related problems such as head trauma or other transmembrane protein, presenilin 2, have
been
nutriassociated with familial Alzheimer disease in a
tional deciency.
German
Pseudodementias
kindred. Some cases of familial Alzheimer disease are
About 15% of patients referred for evaluation of not caused by these defects, and mutations at other
possisites are presumed responsible.
ble dementia instead have other disorders
Genetic factors may also modify susceptibility to
(pseudodeAlzheimer disease without being directly causal. In
lateonset familial (and to a lesser extent sporadic)
Common Causes of Dementia
Table 123. Causes of dementia.

Disorder
Cerebral disorders
Without extrapyramidal features
Alzheimer disease
Pick disease
Creutzfeldt-Jakob disease
Distinctive Features
Prominent memory loss, language impairment, visuospatial disturbance,

depression, anxiety, delusions
Apathy, disinhibition, anosognosia, logorrhea, echolalia,
palilalia
Myoclonus, ataxia, periodic EEG complexes
Normal-pressure hydrocephalus Incontinence, gait disorder

With extrapyramidal features
Dementia with Lewy bodies (includes
Fluctuating cognitive function, visual hallucinations,
diffuse Lewy-body disease and parkinsonism
Lewy-body variant of Alzheimer
disease)
Corticobasal ganglionic degeneration
Parkinsonism, apraxia (including orofacial apraxia that can mimic aphasia),
cortical
sensory loss, alien-hand syndrome)
Huntington disease
Chorea, psychosis
Progressive supranuclear palsy
Systemic disorders
Cancer
Brain tumor
Meningeal neoplasia
Infection
AIDS
Neurosyphilis
Progressive multifocal
leukoencephalopathy
Metabolic disorders
Alcoholism
Hypothyroidism
Organ failure
Dialysis dementia
Non-Wilsonian hepatocerebral
degeneration
Wilson disease
Trauma
Vascular disorders
Chronic subdural hematoma
Vascular dementia
Pseudodementia
Depression
Supranuclear ophthalmoplegia, pseudobulbar palsy, axial dystonia in

extension
Headache, focal neurologic signs, papilledema
Focal weakness or sensory decit, areexia, pyramidal signs,
headache
Opportunistic infections, memory loss, psychomotor retardation, ataxia,
pyramidal
signs, white matter lesions on MRI brain scan
Reactive CSF VDRL, psychosis, Argyll-Robertson pupils, facial tremor,
strokes, tabes
dorsalis
Visual disturbances, white matter lesions on MRI brain
scan
Prominent memory loss, nystagmus, gait
ataxia
Myxedema, hair loss, skin changes, hypothermia, headache, hearing loss,
tinnitus,
vertigo, ataxia, delayed relaxation of tendon reexes
Macrocytic anemia, low serum vitamin B12 level, psychosis, sensory
disturbance,
spastic paraparesis
Dysarthria, myoclonus, seizures
Cirrhosis, esophageal varices, uctuating mental status, dysarthria,
pyramidal and
extrapyramidal signs, ataxia
Cirrhosis, dysarthria, pyramidal and extrapyramidal signs, ataxia, KayserFleischer
pigmented corneal rings, decreased serum ceruloplasmin
Headache, variable pyramidal and extrapyramidal
signs
Headache, hemiparesis, extraaxial collection on CT or MRI brain
scan
Hypertension, diabetes, stepwise progression of decits, hemiparesis,
aphasia,
infarcts on CT or MRI brain scan
Depressed mood, anhedonia, anorexia, weight loss, insomnia or
hypersomnia, suicidality
48 / CHAPTER 1
Table 124. Genes implicated in Alzheimers disease.
Gene
Gene Locus
Protein
Genotype
Phenotype
APP
21q21.3-q22.05Amyloid A4 precursor
Various missense mutations
Familial Alzheimer disease (autosomal
protein
dominant)
PS1
14q24.3
Presenilin 1 (PS1)

dominant) with early onset (age 3555)
PS2
1q31-q42
Presenilin 2 (PS2)

dominant) in Volga Germans
APOE
19q13.2
Apolipoprotein E
APOE4 polymorphism
Multiple
21
Unknown
Trisomy 21 or chromosome
Down syndrome (early-onset
21-to-14 or 21-to-21
Alzheimer disease)
translocation
Increased susceptibility to Alzheimer

disease
Alzheimer disease, the risk of being affected and the

to 42amino acid peptide produced by proteolytic
age
cleavage of the transmembrane protein, APP (Figure
at onset are related to the number of apolipoprotein
112).
E Normal processing of APP involves its cleavage
(APOE4) alleles on chromosome 19. How the by an enzyme called to form the 40
APOE4 allele (or the absence of other APOE alleles)
amino
confers disease susceptibility is unclear. It has been
acid fragment
140, which is secreted and
speculated that apolipoprotein E produced by astrocleared from the brain. In Alzheimer disease, APP is
cytes may be taken up into neurons and interact cleaved abnormally. The rst cleavage is in the
abnorextracelmally with microtubule-associated proteins, like tau,
lular region of APP by an enzyme called

to
which has been identied as the transmembrane proproduce paired helical laments in neurobrillary tantease BACE (-site APP cleaving enzyme). Then
gles.
Other
proteins
that
may
be
involved
in
B. MYLOID
pathogen is the principal constituent of neuritic retase acts within the transmembrane region to
esis
include
2-macroglobulin and its receptor, low generplaques
and is
also deposited in cerebral and
density
lipoprotein-related
protein-1.
ate the abnormal
142, which is secreted
meningeal
and
accumulates
in
extracellular plaques. Presenilin 1
blood vessels in Alzheimer disease. is a
and 2 appear to be involved in this latter cleavage
40
step.
especially in its aggregated form, can

be
A
toxic to neurons under some circumstances. It
therefore
Extracellular
-secretase
-secretase
Intracellular
Presenilin
BACE
APP
C99
Figure 112. Molecular mechanisms of disease: Proteolytic processing of APP to form (Adapted
fromVassarR,CitronM.Ageneratingenzymes:recentadvancesin
and
research.Neuron2000;27:419422.)

has been suggested that the abnormal accumulation
cles, but such changes may also be seen in elderly
nonof
in Alzheimer disease is responsible for
demented patients. Cognitive testing may be useful
the death of selectively vulnerable neurons. However,
others have cited the lack of a clear correlation in
some cases in helping to distinguish between
between
Alzheimer
the extent of amyloid deposition in the brain and the
disease and other causes of dementia.
severity of dementia as evidence against the amyloid
Early Alzheimer disease may resemble depression or
hypothesis.
C. CHOLINERGIC DEFICIENCY
pure memory disorders such as the Korsakoff
Cholinergic neurons are lost and the acetylcholine-amnestic
synsyndrome (see below). More advanced Alzheimer disthesizing enzyme choline acetyltransferase is
ease must be distinguished from Lewy body
markedly
dementia,
depleted in the cerebral cortex and hippocampus of
multiinfarct dementia, Creutzfeldt-Jakob disease, and
paother dementing disorders (see below).
Treatment
tients with Alzheimer disease. Degeneration of the
No currently available treatment has been shown unnuequivocally to reverse existing decits or to arrest
cleus basalis of Meynert (the principal origin of
discortical
ease progression. However, memantine, an NMDAcholinergic innervation) and of the cholinergic septaltype glutamate receptor antagonist drug, may
hippocampal tract may underlie this abnormality. The
cholinergic deciency in Alzheimer disease has ledproduce
to
Clinical
Findings
modest improvement in patients with moderate or sethe therapeutic
use of acetylcholinesterase inhibitors,
vere Alzheimer disease. Because cholinergic neuronal
which
enhance
cholinergic neurotransmission by inA. EARLY
MANIFESTATIONS
pathways degenerate and choline acetyltransferase
hibiting
acetylcholine
breakdown
(see below).
Impairment
of recent memory
is typically
the rst
is
sign
depleted in the brains of patients with Alzheimer disof Alzheimer diseaseoften noticed only by family
ease, cholinergic replacement therapy has been used
members. As the memory disorder progresses, the
in
paan effort at symptomatic treatment of cognitive dystient becomes disoriented to time and then to place.
function (Table 125). The acetylcholinesterase inAphasia, anomia, and acalculia may develop, forcing
hibitors tacrine, donepezil, rivastigmine, galantamine,
the
physostigmine, metrifonate, and eptastigmine have
patient to leave work or give up the management of
all been shown to produce small (5%) improvements
famin tests of cognitive function. Among these drugs,
ily nances. The depression apparent in the earlier
tacrine, donepezil, rivastigmine, and galantamine are
stages
available in the United States. Side effects include
of the disorder may give way to an agitated, restless
naustate.
sea, vomiting, diarrhea, and dizziness; tacrine also
B.
LATE MANIFESTATIONS
Apraxias
and visuospatial disorientation ensue,
eleIn
the late stages, previously preserved social graces
causing
vates serum transaminase levels. The better sideare
the patient to become lost easily. Primitive reexes
effect
lost, and psychiatric symptoms, including psychosis
are
of donepezil and its once-daily dosage
with paranoia,
hallucinations,
orgait
delusions,
may
beprole
commonly
found.
A frontal lobe
disorder
may
beschedule
prominent.
Seizures
some
cases. steps,
come
apparent,
withoccur
short,inslow,
shufing
have made it the agent of choice. Experimental treatExamination
exed
ments under investigation include vaccines directed
at this stage
show
and
posture,
widemay
base,
andrigidity
difculty
in bradykinesia.
initiating walking.
against
and the metal chelator, clioquinol.
Rare
Several
drugs also have been tested for their ability
and usually late features of the disease include myto
Prognosis
oclonus, incontinence, spasticity, extensor plantar redelay the progression of Alzheimer disease, including
sponses, and hemiparesis. Mutism, incontinence, and
Early in the course of the disease, patients can
selegiline, idebenone, propentofylline,
a
usually
biloba, and acetyl-L-carnitine. Of these, only
bedridden state are terminal manifestations, and Gingko
remain at home and continue social, recreational, and
Investigative
Studies
and
selegiline
have
shown
evidence
death
limited professional
activities.
Early
diagnosis
canof
slight
benet.
Antipsychotic
drugs,
antidepressants,
typically
occurs
from
5
to
10
years
after
the
onset
of
allow
Laboratory investigations do not assist in the diagnoand
anxiolytics
usefulretirement
in controlling
symptoms.
patients
time tomay
planbe
orderly
from work, to
sisexcept to exclude other disorders. The CT scan
behavioral
arrange for management of their nances, and to disor
disturbances
associated
Alzheimer
disease.
cuss with physicians
andwith
family
members
the
MRI often shows cortical atrophy and enlarged ventrimanagement of future medical problems. Patients in
advanced
50 / CHAPTER 1
Table 125. Drugs used in the treatment of Alzheimers disease.
Indication
Drug Class
Drug
Cognitive
Glutamate antagonist
Memantine
dysfunction
(Namenda)
Acetylcholinesterase
Tacrine
inhibitor
(Cognex)
Behavioral
Antipsychotic
disturbance
Antidepressant
Anxiolytic
Dose
Toxicity
5 mg orally daily, increased byDizziness, headache,

5 mg each week to 10 mg orally
constipation, confusion
twice daily
10 mg orally four times per day;
Abdominal cramps, nausea,
may be increased to 20 mg vomiting, diarrhea,
orally four times per day afterhepatocellular
6
toxicity (liver
weeks
enzymes should be monitored
twice monthly for 4 months)
Donepezil
(Aricept)
5 mg orally at bedtime; may be

Nausea, diarrhea, vomiting,
increased to 10 mg orally at insomnia, fatigue, muscle
bedtime after 46 weeks
cramps, anorexia
Rivastigmine
(Exelon)
1.56 mg orally twice per day Nausea, vomiting, diarrhea,

anorexia
Galantamine
(Reminyl)
412 mg orally twice per day Nausea, vomiting, dizziness,

diarrhea, anorexia, weight loss
Haloperidol
(Haldol)
0.52 mg orally at bedtime, orParkinsonism, akathisia, tardive

every 46 hours
dyskinesia, increased cognitive
dysfunction
Loxapine
(Loxitane)
50250 mg orally daily
Parkinsonism, akathisia, tardive

dysfunction
Risperidone
(Risperdal)
24 mg orally daily

dysfunction
Thioridazine
(Mellaril)

dysfunction
Thiothixene
(Navane)
220 mg orally daily

dysfunction
Citalopram
(Celexa)
Insomnia, anorexia, ejaculatory

failure, nausea, diarrhea
Fluoxetine
(Prozac)
520 mg orally with breakfastInsomnia, anorexia, ejaculatory

failure, nausea, diarrhea
Paroxetine
(Paxil)
520 mg orally with breakfast,Insomnia, anorexia, ejaculatory

or in two divided daily doses failure, nausea, diarrhea
Carbamazepine4001200 mg orally in two

Ataxia
(Tegretol)
(extended-release form) or four
divided doses
AdaptedfromMayeuxR,SanoM:TreatmentofAlzheimersdisease.NEnglJMed1999;341:16701679.

stages of the disease may require care in a nursing
sporadic cases, an abnormal prion protein (scrapie
facilisoity and the use of psychoactive medications. These
form, or PrPSc), which differs from PrPc in its secondary
pa(folding) structure, has been proposed as the
tients must be protected and prevented from injuring
infectious
themselves and their families by injudicious actions
agent. In both circumstances, the result is
or
accumulation
decisions. Death from inanition or infection generally
of abnormal PrPSc prions in brain tissue. To explain the
FRONTOTEMPORAL
occurs 510 years afterDEMENTIA
the rst symptoms.
ability of PrPSc prions to replicate in the brain (despite
the fact that they contain no detectable nucleic
The frontotemporal dementias, including Pick
acids), it
disease,
sometimes can be distinguished from Alzheimer has been suggested that infectious PrPSc prions
induce a
disease
during life by their generally earlier onset, more conformational change in normally expressed PrPc prions that converts them to the PrPSc form.
promiPrions have also been implicated in diseases of aninent behavioral than cognitive dysfunction at
mals and in three other rare human disorders (Table
presentation, and preferential atrophy of the frontal and 126)kuru, a dementing disease of Fore-speaking
tribes of New Guinea (apparently spread by cannibalanterior
ism); Gerstmann-Straussler
syndrome, a familial
temporal lobes on CT scan or MRI of the brain. HowClinical
Findings
disorever, denitive diagnosis is usually not possible
The
clinical pictureby
may
be thatand
of aataxia;
diffuseand
central
der characterized
dementia
fatal
during
nervous
system
disorder
or
of
a
more
localized
falife, and relies instead on histopathological features.
dysfuncmilial insomnia, which produces disturbances of sleep
These include the distinctively circumscribed pattern
tion
(Table
127). Dementia
is endocrine
present in function.
virtually all
and of
autonomic,
motor, and
of
cases and may begin as a mild global cognitive
lobar atrophy, the presence of Pick cells and Pick
impairinclument or a focal cortical disorder such as aphasia,
sion bodies, the absence of amyloid plaque and neuapraxia, or agnosia. Progression to akinetic mutism or
robrillary tangles characteristic of Alzheimer
coma typically ensues over a period of months.
CREUTZFELDT-JAKOB
DISEASE
disease,
Psychiand
inclusions in neurons
that contain
Creutzfeldt-Jakob
disease and
is anglia
invariably
fatal theatric symptoms including anxiety, euphoria,
mitransmisdepression,
crotubule-associated
protein,
tau. This
latter feature
sible disorder of the central
nervous
system
labile affect, delusions, hallucinations, and changes in
accharacterpersonality or behavior may be prominent.
counts
the classication
of frontotemporal
ized by for
rapidly
progressive dementia
and variable Aside from cognitive abnormalities, the most fredementia
focal
quent clinical manifestations are myoclonus (often in126. Prion diseases.
as a tauopathy.
Familial
occurrence
frontotemporal
involvement
of the
cerebral
cortex, of
basal
ganglia, Table
duced by a startle), extrapyramidal signs (rigidity,
dementia has been documented and mapped to chroceremosomebrainstem,
17 (17q21).
There
is no
treatment.
Human diseases
bellum,
and
spinal
cord.
The annual inciCreutzfeldt-Jakob disease (sporadic)
dence is about 1:1,000,000 population. The naturally
acquired disease occurs in patients 1682 years of Creutzfeldt-Jakob disease (familial)
Creutzfeldt-Jakob disease (new variant)
age,
Fatal familial insomnia
with a peak incidence between 60 and 64 years and
Gerstmann-Straussler-Scheinker disease
an
Kuru
equal sex incidence. More than one member of a Animal diseases
family
Bovine spongiform encephalopathy
is affected in 510% of cases. Conjugal cases are Feline spongiform encephalopathy
Scrapie (sheep and goats)
rare.
Transmissible mink encephalopathy
Although transmission from humans to animals has
Wasting disease of deer and elk
been demonstrated experimentally, documented huPathogenesis
Transmissible spongiform encephalopathy of captive wild
man-to-human transmission (by corneal transplantaruminants
A
proteinaceous
infectious
particle
(prion)
is
the
etiotion, cortical electrode implantation, or administration
logic
agent.
Familial
cases,
which
are
uncommon,
of human growth hormone) is rare. The infectious
have
AdaptedfromJohnsonRT,GibbsCJ:Creutzfeldt
agent is present in the brain, spinal cord, eyes, lungs,
been
with mutations
in a and
formCSF,
of the
Jakobdiseaseandrelatedtransmissiblespongi
lymphassociated
nodes, kidneys,
spleen, liver,
butprion
not
protein
(cellular
isoform, or PrPc) that is expressedformencephalopathies.NEngl
by
other body
uids.
normal neurons but whose function is unknown. In
52 / CHAPTER 1
Table 127. Clinical features of sporadic
Creutzfeldt-Jakob disease.
Feature
Cognitive
Memory loss
Behavioral abnormalities
Other
Motor
Myoclonus
Cerebellar ataxia
Pyramidal signs
Extrapyramidal signs
Lower motor neuron signs
Visual disturbances
Periodic EEG complexes
Percentage
100
57
73
midal signs. Where subcortical involvement is prominent, Parkinson disease, cerebellar degeneration, or
progressive supranuclear palsy may be suspected.
Striking focal signs raise the possibility of an intracerebral
mass lesion. Acute metabolic disorders that produce
altered mentation and myoclonus (eg, sedative drug
withdrawal)
Prognosis can mimic Creutzfeldt-Jakob disease.
No treatment is currently available. The disease is

usually relentlessly progressive and, although transient
improvement may occur, is invariably fatal. In most sporadic cases, death occurs within 1 year after the
onset of
symptoms: the mean duration of illness in these paDatafromBrownPetal:Humanspongiform
encephalopathy:theNationalInstitutesofHealthtients is 7 months. Depending on the specic
mutation
seriesof300
NORMAL-PRESSURE HYDROCEPHALUS
casesofexperimentallytransmitteddisease.Ann present, familial forms of the disease may have
Neurol1994;35:513.
similar
Normal-pressure
hydrocephalus, a potentially
short or much longer courses.
reversible
cause of dementia, is characterized by the clinical
bradykinesia, tremor, dystonia, chorea, or athetosis),
triad
cerebellar signs, and extrapyramidal signs. Visual of dementia, gait apraxia, and incontinence. It may
eld
be
defects, cranial nerve palsies, and seizures occur less
idiopathic or secondary to conditions that interfere
often.
with cerebrospinal uid absorption, such as
A distinct variant of Creutzfeldt-Jakob disease is meningitis
thought to result from the transmission of bovine or subarachnoid hemorrhage. The dementia is often
spongiform encephalopathy (mad cow disease) to
mild and insidious in onset, and is typically preceded
humans. This variant is characterized by earlier onset
by gait disorder and incontinence. It is characterized
(mean age, about 30 years), a more prolonged course
initially by mental slowness and apathy and later by
Pathophysiology
(greater than 1 year), invariable cerebellar
global cognitive dysfunction. Deterioration of memory
Normal-pressure
hydrocephalus
is sometimes
involvement,
is common, but aphasia
and agnosia
are rare. called
communicating
(because
the
lateral,
third, and fourth
prominent early psychiatric abnormalities, and diffuse
ventricles
remain
in
communication)
or
nonobstrucamyloid
plaques.
Investigative
Studies
tive hydrocephalus (because the ow of CSF between
The EEG may show periodic sharp waves or spikesthe ventricles is not obstructed). It is presumed to be
(Figure 113), which are absent in the variant formdue to impaired CSF absorption from arachnoid grandescribed above. CSF protein may be elevated
ulations in the subarachnoid space over the convexity
(100 mg/dL) and levels of 1433, a normal brainof the hemispheres (Figure 114), eg, from meningeal
protein that is also elevated in herpes simplex virus
brosis and adhesions following meningitis or subenarachnoid hemorrhage. In contrast, noncommunicatcephalitis, are increased. MRI scans may show
ing or obstructive hydrocephalus is caused by a
hyperinblocktense signals in the basal ganglia on T2-weighted imade of CSF circulation within the ventricular system
ages. Denitive diagnosis is by immunodetection of
(eg, by an intraventricular cyst or tumor) and is
PrPSc in brain tissue obtained at biopsy or, in familial
associcases, by detection of mutant forms of PrPc in DNAated with increased CSF pressure and often with
from
lymphocytes.
headache
and papilledema.
Differential
Diagnosis
Clinical Findings
78
71
62
56
12
42
60
A variety of other disorders must be distinguished Normal-pressure hydrocephalus usually develops over
from
a
Creutzfeld-Jakob disease. Alzheimer disease is often
period
a
of weeks to months; a gait disorder is often
consideration, especially in patients with a less fulmithe
nant course and a paucity of cerebellar and
initial manifestation. This typically takes the form of
extrapyragait apraxia, characterized by unsteadiness on
standing

and difculty in initiating walking even though there
the oor, and walking, once under way, is slow and
is
shufing. Pyramidal signs, including spasticity, hyperno weakness or ataxia. The patient can perform the
reexia, and extensor plantar responses, are
leg
sometimes
movements associated with walking, bicycling, or present. Motor perseveration (the inappropriate
kickrepetiing a ball and can trace gures with the feet whiletion of motor activity) and grasp reexes in the hands
lying
and feet may occur. Urinary incontinence is a later
or sitting but is unable to do so when the legs are debearFp2-F4
ing weight. The patient typically appears to be glued
to
F4-C4
C4-P4
P4-O2
Fp2-F8
F8-T4
T4-T6
T6-O2
Fp1-F3
F3-C3
C3-P3
P3-O1
Fp1-F7
F7-T3
T3-T5
T5-O1
200
1s
Figure 113. Electroencephalogram of a patient with Creutzfeldt-Jakob disease, showing triphasic waves with
sharpened outlines; these occur repetitively about once every second.
54 / CHAPTER 1
Choroid plexus
of lateral ventricle
Interventricular
foramen of Monro
Arachnoid granulation
Choroid plexus
of third ventricle
Superior sagittal sinus
Dura mater
Arachnoid
Pia mater
Cerebral vein
Subarachnoid space
Cerebral aqueduct
Choroid plexus
of fourth ventricle
Foramen of Magendie
Foramen of Luschka
Figure 114. Circulation of cerebrospinal uid (CSF). CSF is produced by the choroid plexus, which consists of
specialized secretory tissue located within the cerebral ventricles. It ows from the lateral and third ventricles
through
the cerebral aqueduct and fourth ventricle and exits the ventricular system through two laterally situated
foramina
of Luschka and a single, medially located foramen of Magendie. CSF then enters and circulates through the subarachnoid space surrounding the brain and spinal cord. It is ultimately absorbed through arachnoid granulations
into the venous circulation.
velopment, and patients may be unaware of it; fecal

cally shows isotope accumulation in the ventricles,
indecontinence is uncommon.
layed clearance, and failure of ascent over the
cerebral
Investigative Studies
convexities. This pattern is not necessarily present in
Lumbar puncture reveals normal or low opening prespatients who respond to shunting, however. Transient
sure. The CT scan or MRI typically shows enlarged improvement
latin gait, cognitive testing, or sphincteric
eral ventricles without increased prominence of function following the removal of 3050 mL of CSF
cortical
by lumbar puncture is probably the best predictor of
sulci (Figure 115). Radionuclide cisternography a
classifavorable clinical response to shunting (see below).
Figure 115. CT scan at two levels in normal-pressure hydrocephalus, showing enlarged lateral ventricles
without
enlargement of the cortical sulci.
CEREBRAL DISORDERS WITH

Dementia
with Lewy bodies
is probably the second
A variety of conditions that produce dementia must
EXTRAPYRAMIDAL
FEATURES
most common cause of dementia, as up to one-fourth

be
elderly demented
patients
who come to autopsy
DEMENTIA
WITH LEWY
BODIES
considered in the differential diagnosis. Alzheimer of
have
disease tends to follow a longer course, often with round, eosinophilic, intracytoplasmic neuronal inclusions (Lewy bodies) in the cerebral cortex and brainpromistem. These contain a protein that is also
nent focal cortical dysfunction and enlarged cortical
sulci shown in a CT scan or MRI. Parkinsonism mayfound in Lewy bodies in Parkinson disease, and tau,
which is present in Alzheimer disease and
be simulated by the gait disorder but can be distinguished by extrapyramidal rigidity, tremor, and re-frontotemporal dementia (see above). Dementia with Lewy bodies
sponse to antiparkinsonian medications. Vascular dementia should be suspected if the disorder followsisa
found in patients with (Lewy-body variant of
stepwise course, or pseudobulbar palsy, focal sensoriTreatment
motor signs, or a history of stroke is encountered. Alzheimer disease) and without (diffuse Lewy-body
Some patients, especially those with hydrocephalus
disfrom meningitis or subarachnoid hemorrhage, recover
ease) histopathological features of Alzheimer disease,
or improve following ventriculoatrial, ventriculoperiand is probably a heterogeneous disorder. In contrast
toneal, or lumboperitoneal shunting. In idiopathic norto
mal-pressure hydrocephalus, about one-half of
Alzheimer disease, it is characterized clinically by
patients
cognihave sustained improvement and about one-third tive decline without prominent early memory impairhave
ment. Other distinctive features include uctuating
a good or excellent response (ie, return to work) after
cognitive ability, well-formed visual hallucinations,
shunting. As noted above, a favorable response toand
the
signs of parkinsonism, especially rigidity and bradykiremoval of CSF by lumbar puncture may be the best
nesia. These patients may respond well to antipredictor of successful surgery. Complications of cholinesterase drugs such as tacrine or donepezil
shunt(Table
ing occur in about one-third of patients and include
125), but are especially sensitive to extrapyramidal
shunt infection, subdural hematoma, and shunt malside effects of antipsychotic drugs, which therefore
function that necessitates replacement.
should be avoided or used with caution.
56 / CHAPTER 1
terized by prominent mental slowness, apathy,
impaired
concentration, and subtle alterations in personality.
This dementing disorder is also associated with Deparkinpending on the areas of involvement, memory
sonism, especially rigidity, bradykinesia, postural disorder,
instaaphasia, or agnosia may be seen early. Brain tumors
bility, and action (but rarely resting) tremor, as well
ul2.
MENINGEAL
NEOPLASIA
as
timately
produce
headache, seizures, or focal sensoriMeningeal
neoplasia,
discussed
as a cause
of
with a variety of asymmetric cortical motor and motor disturbances. Brain
tumorabove
is covered
in detail
confusional
states,
may
also
produce
dementia
that
is
sensory
in
commonly
associated
with
headache
as
well
as
sympdefects. These include apraxias affecting the eye Chapter 2.
toms and signs of dysfunction at multiple sites in the
moveHUNTINGTON DISEASE
ments, speech, and limbs, the latter of which may nervous system. The diagnosis is established by cytologic studies of the CSF.
Huntington
disease is an autosomal dominant
proheredoduce the alien-hand sign, in which the limb moves
degenerative
condition
characterized by a movement
seemingly of its
own accord.
disorder, psychiatric symptoms, and dementia. The
INFECTION
cause is an expanded CAG trinucleotide repeat
1. AIDS
coding
AIDS dementia complex is the most common neurofor a polyglutamine tract in the Huntington gene on
logic complication of AIDS. Although especially comchromosome 4 (4p16.3).
Dementia, which usually becomes apparent aftermon in severely immunosuppressed patients late in
the
chorea and psychiatric symptoms have been present
course of the disease, it can also be an early or
for
presenta few years, precedes chorea in about one-fourth of
cases. A memory disturbance affecting all aspectsing
of manifestation.
Pathogenesis
memory is an early and prominent feature; aphasia,
apraxia, agnosia, and global cognitive dysfunctionAIDS dementia complex results from invasion of the
brain by a retrovirus, human immunodeciency virus
tend
PROGRESSIVE SUPRANUCLEAR PALSY
type 1 (HIV-1). The virus appears to reach the central
to occur later. Huntington disease is discussed further
nervous system early in the course of systemic HIV-1
Progressive
in Chapter 7.supranuclear palsy is an idiopathic
infection; monocytes, macrophages, and microglia
degenerare
ative disorder that primarily affects subcortical gray
the principal cell types affected. Neurologic
matter regions of the brain. The classic clinical
involvement
features
are supranuclear ophthalmoplegia, pseudobulbar at this stage may be asymptomatic, or it can produce
transient symptomatic HIV-1 meningitis (see above).
palsy,
The infection then seems to be contained until
axial dystonia with or without extrapyramidal rigidity
progresof the limbs, and dementia. The disorder of
sive immunosuppression impairs the normal host demovement
SYSTEMIC
DISORDERS
is a conspicuous
feature of this syndrome, which isfense mechanisms, leading to increased HIV-1
producdisCANCER
tion in the brain and, perhaps, the emergence of
cussed further in Chapter 7.
neurotropic strains. Productive viral infection within
1. BRAIN TUMOR
the
Brain tumors produce dementia and related
brain seems to be associated with multinucleated
syndromes
cells.
by a combination of local and diffuse effects,
HIV-1 does not appear to replicate within neurons,
including
or oligodendrocytes in vivo, and the loss
edema, compression of adjacent brain structures, astrocytes,
increased intracranial pressure, and impairment of of
these cell types is not prominent in brains of patients
cerebral blood ow. The tumors most likely to produce with AIDS dementia complex. It has therefore been
suggested
that neuronal function is impaired by an
generalized cerebral syndromes are gliomas arising
in
Pathology
inthe frontal or temporal lobes or the corpus callosum.
earliest
histopathologic
sign
is might
pallor involve
of
direct
neurotoxic
mechanism.
This
cyAlthough such lesions tend to inltrate subcorticalThe
subcortical
white matter extensively, they initially give rise totokines released from HIV-infected monocytes or
and
periventricular
matter
associated
macrophages,
viral cerebral
productswhite
such as
the HIV-1
envefew
lope protein gp120, or molecules that mimic the
focal neurologic signs.
effects
The dementia associated with brain tumor is
of excitotoxic amino acids.
charac-
CORTICOBASAL GANGLIONIC
DEGENERATION

with reactive astrocytosis but few inammatory Table 128. Clinical features of AIDS dementia
changes.
complex.
More advanced cases are associated with
parenchymal
Feature
Percentage of Patients
and perivascular inltration by macrophages,
microglia,
Early Stage Late Stage
lymphocytes, and multinucleated cells; the last are
thought to result from the virus-induced fusion of Symptoms
Memory loss
80
74
macrophages. These changes affect the white matter,
Behavioral changes (eg,
30
11
basal ganglia, thalamus, and pons and are
social withdrawal)
accompanied
Depression
30
16
by reactive astrocytosis. Spongy vacuolation of white
Motor symptoms (eg, imbalance,
20
21
matter occurs infrequently. Neuronal loss has been weakness, deteriorated
rehandwriting)
Clinical Findings
ported. The spinal cord may also be affected by a Apathy
15
58
The
onset is usually insidious and is associated withConfusion
vacuo15
42
cognitive
and behavioral
symptoms,
such asthat
Hallucinations
lar myelopathy
(see Chapter
5) resembling
5
11
forgetfulcaused
ness,
apathy,
withdrawal, and motor
Signs
by vitamin
B12social
deciency.
symptoms,
Cognitive
including impaired balance, leg weakness, and
Psychomotor retardation
61
84
Dementia
deterio39
100
5
16
ration of handwriting (Table 128). Examination at Psychosis
Mutism
0
40
this early stage may also show cerebellar ataxia,
Motor
pyramiAtaxia
34
71
dal signs such as hyperreexia and extensor plantar Hypertonia
22
44
reTremor
16
45
sponses, weakness in one or both legs, postural
Paraparesis or quadriparesis 13
33
tremor,
Monoparesis or hemiparesis 5
Investigative Studies
2
and dysarthria. As the disease progresses,
Myoclonus
0
20
Antibodies
hypertonia,to HIV are detectable in the blood. The Other
CSF
usually
abnormal
and may
show a reexes,
mild to myHyperreexia
fecalisand
urinary
incontinence,
primitive
36
78
modPrimitive reexes
oclonus, seizures, quadriparesis, and organic
22
38
erate
elevation of protein (200 mg/dL), a modest, Seizures
psychosis
7
20
Incontinence
usually
mononuclear
pleocytosis
(50 cells/L),
and
with delusions
and visual
hallucinations
can occur.
0
47
oligoclonal bands. CT scans and MRI usually demonstrate cerebrocortical atrophy with ventricular dilation
Investigative studies1
and may also show diffuse involvement of subcortical
CSF
white matter (Figure 116).
Mononuclear pleocytosis
19
Increased
protein
Combination
pharmacotherapy
of
HIV
infection
can
66
Treatment
1
prolong life by inhibiting replication of HIV and im- Decreased glucose
25
proving immune function. The available drugs fall intoOligoclonal IgG bands
Imaging
three classes: nucleoside reverse transcriptase
Cerebral cortical atrophy (CT)
79
inhibitors,
Cerebral cortical atrophy (MRI)
55
nonnucleoside reverse transcriptase inhibitors, and White matter lesions (CT)
11
proWhite matter lesions (MRI)
35
tease inhibitors. Treatment must be individualized,
and
1All stages.
continually updated treatment guidelines are
AdaptedfromNaviaBAetal:TheAIDSdementia
available
complex.
1.Clinicalfeatures.2.Neuropathology.AnnNeurol
from the United States Department of Health and Hu1986;
man Services website at http://www.aidsinfo.nih.gov/
19:517524and525535,andMcArthurJC:
guidelines/. Preferred therapy for antiretroviral drugNeurologicmanifestationsofAIDS.Medicine
naive, non-pregnant patients includes a
1987;66:407437.
nonnucleoside
reverse transcriptase inhibitor-based regimen
consisting
of efavirenz, lamivudine, and either zidovudine, tenofovir DF or stavudine, and a protease inhibitor-based
regimen that employs lopinavir/ritonavir (Kaletra),
lamivudine, and either zidovudine or stavudine.
58 / CHAPTER 1
Clinical Findings
A. EARLY SYPHILIS
Syphilis is caused by Treponema pallidum transmitted
by sexual contact, which results in infection in about
one-third of encounters with infected individuals. Primary syphilis is characterized by local skin lesions
(chancres) that usually appear within 1 month of
exposure. There are no neurologic symptoms. Hematogenous spread of T pallidum produces symptoms and
signs of secondary syphilis within 16 months. These
include fever, skin rash, alopecia, anogenital skin lesions, and ulceration of mucous membranes; neurologic symptoms are still uncommon at this stage.
Meningeal syphilis, the earliest form of symptomatic
neurosyphilis, is most often seen 212 months after
primary infection. Clinical features include headache,
stiff neck, nausea and vomiting, and cranial nerve
(esB.
MENINGOVASCULAR
SYPHILIS
pecially
II, VII, or VIII)
involvement.
This delayed manifestation of neurosyphilis occurs 4
7
years into the course of the disease and usually
presents
Figure 116. T2-weighted MRI in AIDS dementia
C.
LATE
(PARENCHYMATOUS
NEUROSYPHILIS
with
transient
ischemic) attacks
or stroke (see Chapter
complex, showing extensive, bilaterally symmetrical
This
produces
the
syndromes
of general paresis and
9).
increases in signal intensity (arrows) in white matter
tabes dorsalis, which can occur separately or
(centrum semiovale) of the frontal lobes.
together
(taboparesis); either one can occur in combination
with
optic atrophy.
Side effects vary, but certain class-specic
1. General paresisA chronic meningoencephalitis
patterns
caused by active spirochetal infection, this was the
have been noted. Nucleosides can cause fatal lactic
usual cause of dementia and psychiatric disorders reacidosis with hepatic steatosis, nonnucleosides are lated to neurosyphilis in the prepenicillin era. Onset is
with gradual memory loss or altered affect,
associpersonality,
ated with skin rash (including Stevens-Johnson synor behavior. This is followed by global intellectual
drome with nevirapine), and protease inhibitors may
deteproduce gastrointestinal disturbances and increased
with grandiosity, depression, psychosis, and
blood levels of aminotransferases. Neurologic siderioration
effects of drugs used to treat HIV include myopathy focal
(zi- weakness. Terminal features include
dovudine), neuropathy (stavudine, didanosine, zal-incontinence,
citabine), paresthesias (ritonavir, amprenavir), andseizures, or strokes. Neurologic examination may
Prognosis
show
nightmares and hallucinations (efavirenz).
The course may be steadily progressive, or it can be
tremor of the face and tongue, paucity of facial
acutely exacerbated by concurrent pulmonary infecexprestion. Patients usually die 19 months after the onset
sion, dysarthria, and pyramidal signs.
of
2. TaboparesisIn taboparesisthe coexistence of
dementia from aspiration or opportunistic infection.
tabes
dorsalis (see Chapter 6) with general paresis
2. NEUROSYPHILIS
signs
and
symptoms
include Argyll Robertson pupils
Studies
Neurosyphilis was a common cause of dementia Investigative
(see
Chapter
4),
lancinating
pains, areexia, posterior
before
Treponemal
serologic
blood
tests
(FTA-ABS
MHAcolumn
sensory
decits
with
sensory
ataxiaorand
the widespread use of penicillin permitted effective
TP)
are
reactive
in
almost
all
patients
with
active
neutreatment of early syphilis. Dementia from neu- Romberg sign, incontinence, impotence, Charcot (hyrosyphilis,
nontreponemal
blood tests(hyperex(VDRL or
pertrophic)but
joints,
and genu recurvatum
rosyphilis is now rare, but the resurgence of syphilis
RPR)
can
be negative;
therefore,
a also
treponemal
blood
tended
knees).
Optic
atrophy
may
be
present.
in recent years suggests that it may become more
test should be obtained in all suspected cases. If this
common.
is

nonreactive, neurosyphilis is effectively excluded; if itThe CSF is usually normal but may show a mild inis
crease in pressure, white cell count, or protein. The
reactive, lumbar puncture should be performed to CT
conscan or MRI shows multifocal white matter abnormalirm the diagnosis of neurosyphilis and provide a ties (Figure 117). When the diagnosis is in doubt, it
basecan be established by brain biopsy.
line CSF prole against which to gauge the efcacy ofThe disorder is almost uniformly fatal, and treatsubsequent treatment. The CSF in active
ment with such antiviral agents as cytosine
neurosyphilis
arabinoside,
shows a lymphocytic pleocytosis and reactive nontreadenine arabinoside, or amantadine generally has
ponemal CSF serology in almost all cases. The excepbeen
METABOLIC DISORDERS
tions are acute syphilitic meningitis and
unsuccessful.
1. ALCOHOLISM
meningovascuCertain complications of alcoholism can cause
lar syphilis, in which pleocytosis may precede
demenseroconversion so that nontreponemal CSF tests are
tia. These include acquired hepatocerebral
falsely negative early on, and end-stage tabes
Treatment
degeneration
dorsalis, in
Neurosyphilis
is
treated
with
a
10-day
course
of
aquefrom alcoholic liver disease, chronic subdural
which the CSF can be normal. Other CSF abnormalious
penicillin
G,
24
10
6 units intravenously everyhematoma
4
from head trauma, and nutritional deties include protein elevation, increased
hours.
Tetracycline
or
erythromycin
can
be
used
for
ciency states.
and
paPellagra, caused by deciency of nicotinic acid
the presence of oligoclonal bands.
tients allergic to penicillin. Fever and leukocytosis (niacin), affects neurons in the cerebral cortex, basal
may
ganglia, brainstem, cerebellum, and anterior horns of
occur shortly after therapy is started (Herxheimer the spinal cord. Systemic involvement is manifested
reacby
tion) but are transient. Failure of the CSF to return diarrhea,
to
glossitis, anemia, and erythematous skin lenormal within 6 months requires retreatment. Neither
sions. Neurologic involvement may produce
failure of treatment nor relapse is convincingly more
Prognosis
dementia;
common in HIV-1-infected patients.
psychosis; confusional states; pyramidal,
After penicillin (or other antibiotic) treatment for general paresis, the clinical condition may improve or extrapyramidal, and cerebellar signs; polyneuropathy; and optic
stabilize; in some cases it continues to deteriorate. neuropathy. Treatment is with nicotinamide, but the
neurologic decits may persist despite treatment.
Patients
with persistent CSF abnormalities or symptomatic
progression despite therapy should be retreated.
Patients
3.
PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
with reactivemultifocal
CSF serological
tests but no pleocytosis
Progressive
leukoencephalopathy
results
are unlikely
to with
respond
to penicillincalled
therapy
but are
from
infection
a papovavirus
JC virus.
Anusually treated
nevertheless.
tibodies
are present
in most adults, but symptomatic
infection is rare. It is most common in patients with
AIDS, lymphoma or leukemia, carcinoma, sarcoidosis,
tuberculosis, or pharmacologic immunosuppression
following organ transplantation, and rare in those
with
normal immune function. The virus infects oligodendrocytes, leading to diffuse and patchy demyelination
that primarily affects white matter of the cerebral
hemispheres but also involves the brainstem and
cerebellum.
The course is subacute and progressive, leading to
Figure 117. T2-weighted MRI in progressive multifodeath in 36 months. Fever and systemic symptoms
cal leukoencephalopathy, showing abnormally high sigare
nal intensity (arrows) in white matter of the right pariabsent. Dementia and focal cortical dysfunction are
etal and occipital lobes. (CourtesyofAGean.)
prominent. Signs of the latter include hemiparesis, visual decits, aphasia, dysarthria, and sensory impairment. Ataxia and headache are uncommon and
seizures
do not occur.
60 / CHAPTER 1
Marchiafava Bignami syndrome is characterized tia
by supervenes. The EEG shows paroxysmal high-voltnecrosis of the corpus callosum and subcortical white
age slowing with intermixed spikes and slow waves;
matter and occurs most often in malnourished alcothese abnormalities can be reversed by diazepam.
holics. The course can be acute, subacute, or chronic.
AluClinical features include dementia, spasticity,
minum in the dialysate is a major etiologic suspect,
dysarthria,
and
gait disorder, and coma. The diagnosis can
removing trace metals from the dialysate has
2.
NON-WILSONIAN HEPATOCEREBRAL DEGENERATION
sometimes
decreased
Acquired
(non-Wilsonian)
be made by CT scan or MRI. No specic treatment the
is syndromes
incidence.hepatocerebral
Mean survival is 6 months.
degeneration
available, but cessation of drinking and improvement
is an uncommon complication of chronic hepatic cirof
rhosis with spontaneous or surgical portosystemic
nutrition are advised. The outcome is variable:
shunting. Symptoms may be related to failure of the
patients
liver to detoxify ammonia. Neurologic symptoms premay die, survive with dementia, or recover.
Alcoholic dementia due to direct toxic effects of cede hepatic symptoms in about one-sixth of
patients.
ethanol on the brain has been proposed to occur, but
Clinical Findings
no distinctive abnormalities have been identied in
2.
Systemic manifestations of chronic liver disease are
theHYPOTHYROIDISM
Hypothyroidism
(myxedema),
which
is
discussed
usubrains of demented alcoholics. Dementia in alcoholics
above
ally present. The neurologic syndrome is uctuating
is more likely to result from one or more of the metaas
a
cause
of
acute
confusional
states,
can
also
bolic and traumatic disorders mentioned above. but
produce
progressive over 19 years, and may be punctuated
a reversible dementia or chronic organic psychosis.
by
The
episodes of acute hepatic encephalopathy. Dementia,
dementia is a global disorder characterized by mental
dysarthria, and cerebellar, extrapyramidal, and
slowness, memory loss, and irritability. Focal cortical
pyramidal
decits do not occur. Psychiatric manifestations are
signs are the most common features. Dementia is
typically prominent and include depression, paranoia,
marked by mental slowness, apathy, impaired
visual and auditory hallucinations, mania, and
attention
suicidal
and concentration, and memory disturbance.
behavior.
Cerebellar
Patients with myxedema may complain of
signs include gait and limb ataxia and dysarthria;
headache,
nystaghearing loss, tinnitus, vertigo, weakness, or
mus is rare. Extrapyramidal involvement may
paresthesia.
produce
3.
VITAMIN B12 D
EFICIENCY
Examination
may
show deafness, dysarthria, or rigidity, resting tremor, dystonia, chorea, or athetosis.
Vitamin
decerebel- B12 deciency is a rare cause of reversibleAsmentia
and
organic
psychosis.
Like
the
acute
confular ataxia. The most suggestive nding is delayed terixis,
myoclonus,
hyperreexia, and extensor
Differential
Diagnosis
sional
relax- state associated with vitamin B12 deciency plantar reWilson
can be paraparesis
distinguished
its earlier
(see
ation of the tendon reexes. Diagnosis and treatment
sponsesdisease
are common;
is by
rare.
onset,
above),
dementia
canCognitive
occur with
or without is
hematoare discussed
above.
dysfunction
usuallyLaboratory studies show abnormal hepatic blood
Kayser-Fleischer
rings andblood
abnormal
copper
metabologic
and other
neurologic manifestations. The
reversible
with treatment.
chemistries and elevated
ammonia,
but
the delism.
Alcoholic
cerebellar
primarilyto
demengree of
abnormality
bearsdegeneration
no direct relationship
tia consists of global cognitive dysfunction with affects
the
gait
and of
is not
accompanied
by extrapyramidal
or pymental
severity
neurologic
symptoms.
The CSF is normal,
signs.
slowness, impaired concentration, and memory ramidal
except
for
increased
glutamine
and
occasional
mild
disturelePatients may benet from a low-protein diet,
bance; aphasia and other focal cortical disorders do
vation of protein.
lactulose,
not
neomycin, liver transplantation, or portosystemic
occur. Psychiatric manifestations are often prominent
shunting, and improvement following levodopa or
ORGAN
FAILURE
and include
depression, mania, and paranoid
bromocriptine therapy has been described. Death repsychosis
1. DIALYSIS DEMENTIA
from progressive liver failure or variceal
with
visual
and auditory
hallucinations.
Laboratorysults
3.
W
ILSON DISEASE
This rare
disorder
typically
occurs in patients
bleeding.
ndings
Wilson disease (hepatolenticular degeneration) is a
receivingand treatment are discussed above.
rare
chronic hemodialysis. Clinical features include
but treatable autosomal recessive hereditary disorder
dysarthria, myoclonus, and seizures. These are
of
initially
copper metabolism that produces dementia and exintermittent, but later become permanent, and
demen-

trapyramidal symptoms. The disease results from
mutations in the ATP7B gene on chromosome 13
(13q14.3q21.1), which codes for the polypeptide
of
a copper-transporting ATPase. Wilson disease is discussed
further in Chapter 7.
TRAUMA
Severe open or closed head injury, particularly when
followed by prolonged unconsciousness, may cause
impaired memory and concentration, personality
changes,
headache, focal neurologic disorders, or seizures.
Cognitive impairment is nonprogressive, and the cause is
usually obvious. Delayed, progressive posttraumatic
dementia in boxers (dementia pugilistica) is
characterized
by cheerful or labile affect, mental slowness, memory
decit, and irritability. Associated neurologic abnormalities
include
tremor, rigidity, bradykinesia,
VASCULAR
DISORDERS
dysarthria, cerebellar ataxia, pyramidal signs, andFigure 118. CT scan in chronic subdural hematoma,
1.
CHRONICNeuroradiologic
SUBDURAL HEMATOMA
seizures.
investigations may showshowing bilateral low-density collections between the
Chronic
subdural hematoma usually affects patients
corinner table of the skull and the cerebral hemispheres
aged
5070 years,
often after
head trauma. (arrows).
tical atrophy
and cavum
septi minor
pellucidi.
Other risk factors include alcoholism, cerebral
2. VASCULAR DEMENTIA
atrophy,
epilepsy, the use of anticoagulation, ventricular Vascular dementia is thought to be the third most
comshunts,
mon cause of dementia, after Alzheimer disease and
and long-term hemodialysis. The onset of symptoms
demay be delayed for months after trauma. Hematomas
mentia with Lewy bodies. Most patients with this
are
bilateral
in about one-sixth of cases.
Clinical
Findings
diagHeadache is the initial symptom in most patients. nosis have either multiple large cortical infarcts from
occlusion of major cerebral arteries or several smaller
Coninfarcts (lacunar state; see Chapter 9) affecting
fusion, dementia, hemiparesis, and vomiting may ensubcorsue. The most frequent signs are cognitive
tical white matter, basal ganglia, or thalamus.
disturbance,
hemiparesis, papilledema, and extensor plantar re- The relationship between cerebral vascular disease
sponses. Aphasia, visual eld defects, and seizuresand dementia is poorly characterized. For example,
the
are
number of strokes, their locations, and the total
uncommon, but can occur.
infarct
The hematoma can usually be seen on CT scan or
MRI (Figure 118) as an extraaxial crescent-shapedvolume required for strokes to produce dementia are
uncertain, making it often difcult to determine if
area of decreased density, with ipsilateral obliteration
strokes are the cause of dementia in a given patient.
of
Whether dementia can result from cerebrovascular
cortical sulci and often ventricular compression. The
scan should be carefully reviewed for evidence of disease without frank infarction, as is commonly prebilateral subdural collections. Isodense collections maysumed to exist when periventricular white matter
lesions are detected by neuroimaging, is also controbeTreatment
versial. Thus, the absence of neuroradiologic signs of
come more apparent after contrast infusion. In a few
Unless
contraindicatedofby
medical
problems
cerebrovascular disease argues strongly against a
cases, demonstration
the
hematoma
may or
require
spontacerebral arteriography, which should always be vascuneous
lar basis for dementia, but the presence of vascular
under- improvement, symptomatic hematomas should
be
surgically
evacuated.
lesions does not prove that they are causal. This is
taken bilaterally.
especially true when another cause of dementia, such
as Alzheimer disease, coexists with cerebrovascular
disease.
62 / CHAPTER 1
sis, cerebral vasculitis, and meningovascular syphilis
as
As classically described, patients with multiinfarct causes
deof multiple infarctions, particularly in younger
mentia have a history of hypertension, a stepwise patients or those without a history of hypertension.
progression of decits, a more or less abrupt onset ofTreatment
dementia, and focal neurologic symptoms or signs. Hypertension, when present, should be treated to reBecause extensive pathologic changes may already
duce the incidence of subsequent infarction and to
exist
preat presentation, it is assumed that patients can vent other end-organ diseases. Antiplatelet agents
remain
(disfunctionally well compensated until a new and
cussed in Chapter 9) may help to reduce the risk of
perhaps
future strokes.
PSEUDODEMENTIA
otherwise innocuous infarct tips the balance.
The neurologic examination commonly shows
Depression is the disorder most commonly mistaken
pseudobulbar palsy with dysarthria, dysphagia, and
for
pathologic
emotionality
Investigative
Studies (pseudobulbar affect), focal
dementia. Because depression is common and
motor and sensory decits, ataxia, gait apraxia,
treatable,
The
MRI (Figure 119) may show multiple small subhyperdistinguishing between the two conditions is
cortical
Extensive
of low density in
reexia,lucencies.
and extensor
plantarareas
responses.
important.
subBoth dementia and depression can be characterized
cortical white matter are seen in Binswanger disease
by
(subcortical arteriosclerotic encephalopathy), which
may be a related condition. MRI is more sensitive mental slowness, apathy, self-neglect, withdrawal,
irrithan
tability, difculty with memory and concentration,
CT for detecting these abnormalities.
and
Additional laboratory studies should be performed
changes in behavior and personality. In addition, deto exclude cardiac emboli, polycythemia,
pression can be a feature of dementing illnesses, and
thrombocytothe
two frequently coexist. Clinical features that help in
the
differentiation are listed in Table 129. When depression is being considered, psychiatric consultation
should
be obtained. If depression is identied as a signicant
IV.
AMNESTIC
problem
and is not SYNDROMES
correctable by treatment of an underlying disease or by a change in medication, it
should
A disorder of memory (amnestic syndrome) may
be
treated directly. Modes of treatment include psyoccur
chotherapy,
tricyclic
and related
antidepressants,
as one feature
of an acute
confusional
state or
selecdemen- is a complex function that can be viewed for
Memory
tive or
serotonin
reuptake
inhibitors,
monoamine
tia,
clinical
as
purposes
an isolated
as comprising
abnormality
phases
(Table
of
130). The
oxidase
latregistration,
Memory
inhibitors,
and
therapy.
ter
storage,
condition
and
retrieval.
is electroconvulsive
discussed
Autopsy
in thisand
section.
imaging studies
of
the brains of patients with memory disorders suggest
that the hippocampus and related structures, such as
the
dorsomedial nucleus of the thalamus, are important
in
memory processing. Bilateral damage to these
regions
Figure 119. T2-weighted MRI in multiinfarct demen- results in impairment of short-term memory, which is
tia, showing foci of abnormal high signal intensity adja- manifested clinically by the inability to form new
cent to the lateral ventricles (arrows) and within the
membasal ganglia (arrowheads).
ories. Long-term memory, which involves retrieval of
previously learned information, is relatively
preserved,
perhaps because well-established memories are
stored
Clinical Findings

Table 129. Dementia and the pseudodementia of depression: distinguishing features.
Dementia
Depression
Insidious onset
Abrupt onset
Progressive deterioration
Plateau of dysfunction
No history of depression
History of depression may exist
Patient typically unaware of extent of decits and does

not
complain of memory loss
Somatic complaints uncommon
Patient aware of and may exaggerate decits

and
frequently complains of memory loss
Somatic complaints or hypochondriasis common
Variable affect
Depressed affect
Few vegetative symptoms
Prominent vegetative symptoms
Impairment often worse at night
Impairment usually not worse at night
Neurologic examination and laboratory studies may be

abnormal
Neurologic examination and laboratory studies

normal
diffusely in the cerebral cortex. Some patients withsynaptic neurons, and the production of retrograde
amnestic syndromes may attempt to ll in gaps insigmemnals that act on presynaptic nerve terminals to
ory with false recollections (confabulation), which can
increase
take the form of elaborate contrivances or of genuine
transmitter release upon subsequent ring.
memories misplaced in time. The longest-standingACUTE AMNESIA
and
most deeply ingrained memories, however, such as
HEAD TRAUMA
ones
Head injuries resulting in loss of consciousness are inown name, are almost always spared in organic
variably associated with an amnestic syndrome.
memory
Patients
disturbances. In contrast, such personal memories
seen shortly after such an injury exhibit a confusional
may
state in which they are unable to incorporate new
be prominently or exclusively impaired in dissociative
memories (anterograde, or posttraumatic amnesia;
(psychogenic) amnesia.
see
The cellular basis of memory is poorly understood,
Figure 120), although they may behave in an apparbut repetitive neuronal ring produces lasting preently normal automatic fashion. In addition, retroand
grade amnesia is present, covering a variable period
postsynaptic changes that facilitate
Table 130. Causes of amnestic syndromes.
prior to the trauma. Features characteristic of
neurotransmission
transient
at hippocampal synapses (long-term potentiation).
global amnesia (see below) may be seen.
Acute
These changes appear to involve the release of glutaAs full consciousness returns, the ability to form
Accompanying acute confusional states
mate,
which stimulates the entry of calcium into postHead trauma
new memories is restored. Events occurring in the
Hypoxia or ischemia
conBilateral posterior cerebral artery occlusion
fusional interval tend to be permanently lost to memTransient global amnesia
ory, however. Exceptions are islands of memory, for a
Alcoholic blackouts
lucid interval between trauma and unconsciousness,
Wernicke encephalopathy
or
Dissociative (psychogenic) amnesia
for periods of lesser impairment in the course of a
Chronic
ucAccompanying dementias
tuating posttraumatic confusional state. The period of
Alcoholic Korsakoff amnestic syndrome
Postencephalitic amnesia
retrograde
amnesia
begins to shrink, with the most
HYPOXIA OR
ISCHEMIA
Brain tumor
reParaneoplastic limbic encephalitis
Because
of the selective
vulnerability
pyramidal
mote memories
the rst to
return. Theofseverity
of the
neuinjury tends to correlate with the duration of
rons
in the Sommer sector (h1 sector of Scholz) of the
confusion
and with the extent of permanent retrograde and
posttraumatic amnesia.
64 / CHAPTER 1
Trauma
Recovery
Normal
Level of
consciousness
Confused
Comatose
Retrograde
amnesia
Anterograde amnesia
Time
Figure 120. Retrograde and anterograde amnesia in posttraumatic memory disorders. Head trauma may
produce
transient coma, followed by a confusional state during which the patient is unable to form new memories.With
recovery, this ability is restored, but there is persistent amnesia for the period of coma and confusion (anterograde
amnesia) and for a variable period preceding the trauma (retrograde amnesia); the latter decit may improve with time.
hippocampus, conditions resulting in cerebral hypoxia

cipital cortex (Figure 121). Ischemia or infarction in
or ischemia, such as cardiac arrest or carbon
this territory, typically when bilateral, may produce a
monoxide
transient or permanent amnestic syndrome. Emboli in
poisoning, can produce amnestic syndromes.
the vertebrobasilar system (see Chapter 9) are
Amnesia
frequent
tends to occur in patients in whom coma has lasted
causes of such disorders.
at
least 12 hours. There is severe impairment of the The amnestic syndrome is usually associated with
unilateral or bilateral hemianopia and sometimes with
ability
visual agnosia, alexia without agraphia, anomia,
to incorporate new memories, with relative preservation of registration and remote memory; patients sensory
disturbances, or signs of upper midbrain dysfunction
typically appear to have an isolated disorder of short- (especially impaired pupillary light reex). Recent
memory tends to be selectively impaired, with
term
memory. A period of retrograde amnesia precedingrelative
preservation of remote memory and registration.
the
insult may occur. Patients exhibit a lack of concern The CT scan shows lucencieswhich may or may
not
be enhanced
by use of
materialin
about their impairment and sometimes confabulate.
Transient
global amnesia
is contrast
a syndrome
of acute any
combination
of
the
above-mentioned
regions.
EvaluaAmnesia following cardiac arrest may be the sole memTRANSIENT
GLOBAL
AMNESIAin Chapter 9.
tion
and
treatment
are
described
maniory loss that tends to occur in middle-aged or elderly
festation of neurologic dysfunction, or it may coexist
patients with risk factors for atherosclerotic disease,
with other cerebral watershed syndromes, such asesbibrachial paresis, cortical blindness, or visual
pecially a prior ischemic event in the posterior
agnosia
cerebral
(see Chapter 9). Recovery often occurs within several
circulation. The disorder is recurrent in fewer than
days, although decits may persist.
10% of patients.
Amnestic syndromes from carbon monoxide poi- A primary disorder of short-term memory that can
soning are frequently associated with affective disturlast for minutes or days, it typically lasts for hours.
bances. Other
associated abnormalities
PaBILATERAL
POSTERIOR
CEREBRAL include focal
cortical
and
extrapyramidal
dysfunction.
Acute
tients appear agitated and perplexed and may
ARTERY OCCLUSION
carbon
repeatThe
posterior
cerebral
supplies
the medialcolmonoxide
poisoning
is artery
suggested
by cherry-red
edly inquire about their whereabouts, the time, and
temoration of the skin and mucous membranes, elevated
the
poral
lobe, thalamus,levels,
posterior
internal
capsule, and
carboxyhemoglobin
or cardiac
arrhythmia.
The
nature of what they are experiencing. Knowledge of
ocCT brain scan may show lucencies in the basal
personal identity is preserved, as are remote
ganglia
memories
and dentate nuclei.
and registration. New memories cannot be formed,

(especially serotonin- or glutamate-mediated) neurotransmission. The disorder is self-limited and no
specic
treatment is required, but reduction of the ethanol intake should be counseled, and thiamine should be
given
to
treat possible
Wernicke encephalopathy (see p.
WERNICKE
ENCEPHALOPATHY
18).
Wernicke encephalopathy is caused by thiamine deciency and classically produces an acute confusional
state, ataxia, and ophthalmoplegia. Amnesia may be
the
major or sole cognitive disturbance, however,
especially
after thiamine treatment is begun and other cognitive
abnormalities improve. Because patients with
Wernicke
encephalopathy usually present with global confusion
rather
than isolated
amnesia, the disorder
is
DISSOCIATIVE
(PSYCHOGENIC)
AMNESIA
discussed
Amnesia
be a
manifestation
of a dissociative
more fullymay
above
(see
p. 18).
disorFigure 121. T1-weighted MRI in a patient with an
der or of malingering. In such patients a prior psychiold left posterior cerebral artery occlusion, showing tis- atric history, additional psychiatric symptoms, or a
sue loss in the medial temporal (small arrows) and
preoccipital (large arrows) lobes and associated dilation cipitating emotional stress can often be identied.
of the temporal and occipital horns of the lateral ventriDissociative amnesia is characterized by an isolated
cle. (CourtesyofAGean.)
or a
disproportionate loss of traumatic or stressful
personal
however, which accounts for the patients repetitive
memories. Dissociative amnesia is usually localized in
questions. Retrograde amnesia for a variable period
time to the immediate aftermath of a traumatic
preexpericeding the episode may be present, but this period
ence or selective for some but not other events
shrinks as the episode resolves.
during
The patients obvious concern about the condition
such a period. Less frequent patterns include systemdistinguishes transient global amnesia from most
atized amnesia restricted to certain categories of
other
infororganically based amnestic syndromes and may give
mation, continuous amnesia for events from some
rise
time
to the suspicion that amnesia is psychogenic. A CT
in the past up to and including the present, and
scan or MRI may demonstrate focal thalamic or temgenerporal lobe abnormalities. Diffusion-weighted MRI has
alized amnesia. In some cases, patients may be
shown signal abnormalities in the temporal lobe
unable
during
to remember even their own namean exceedingly
spells of transient global amnesia. These are
rare nding inAMNESIA
organic amnesia. Despite such
CHRONIC
compatible
ALCOHOLIC BLACKOUTS
disorienwith cellular edema and may be related to spreading
ALCOHOLIC
KORSAKOFF
tation to person,
orientation to place and time may
Short-term consumption
of large
amounts of ethanol
depressiona
wave of cellular
depolarization
AMNESTIC
SYNDROME
be
by
accompapreserved. In addition, recent memories may be less
alcoholic
or nonalcoholic
individuals
nied
by cellular
swelling in
the brain.may lead to The Korsakoff amnestic syndrome, which occurs in
than remote memoriesthe reverse of the
blackoutstransient amnestic episodes that areaffected
not
chronic
alcoholism and other malnourished states, is
patdue to global confusion, seizures, head trauma, orthought
the
to be caused by thiamine deciency. It is usutern customarily seen in amnesia caused by organic
Wernicke-Korsakoff syndrome. These spells are
ally preceded by one or more episodes of Wernicke
disease. Examination under hypnosis or after
characenadministerized by an inability to form new memories, without
cephalopathy, but such a history may be lacking. The
tration of amobarbital sodium may be helpful in
impairment of long-term memory or immediate recall.
memory disorder may be related to bilateral
estabAlthough the cause is unknown, alcoholic blackouts
degeneralishing that amnesia is of psychogenic origin.
may result from ethanol-induced depression of
tion of the dorsomedial thalamic nuclei.
synaptic
as a remote effect of systemic cancer. When limbic

structures are primarily affected, the clinical picture is
that of an amnestic syndrome. The disorder is
66 / CHAPTER 1
thought
to be autoimmune in origin since, as in other
An amnestic syndrome of variable severity follows
paraneorecovery from Wernicke encephalopathy in about plastic neurologic syndromes, antineuronal autoantithree-fourths of cases and is often associated withbodies can be detected.
polyneuropathy and other residua such as nystagmus
Paraneoplastic limbic encephalitis is most often asor
sociated with small-cell cancer of the lung, and sympgait ataxia. The essential defect is an inability to form
toms typically precede diagnosis of the underlying
new memories, resulting in signicant impairmentcanof
short-term memory. Long-term memory is also fre-cer. Histopathologic ndings include neuronal loss,
quently affected, although to a lesser extent.
reactive gliosis, microglial proliferation, and
Registraperivascution is intact. Patients are typically apathetic and lack
lar lymphocytic cufng. Gray matter of the hippocaminsight into their disorder. They may attempt to reaspus, cingulum, piriform cortex, inferior frontal lobes,
sure the physician that no impairment exists and try
insula, and amygdala is characteristically affected.
to
Symptoms develop over several weeks. The disorder
explain away their obvious inability to remember. is
Concharacterized by profound impairment of recent
fabulation is often, but not invariably, a feature. memKorsakoff syndrome can be prevented or its
ory, corresponding to the inability to learn new mateseverity
rial. Remote memory is less impaired, and
decreased by prompt administration of thiamine toregistration
paPOSTENCEPHALITIC AMNESIA
is unaffected; confabulation occurs in some cases. Aftients with Wernicke encephalopathy. Patients withfective symptoms, either anxiety or depression, are
Patients
who recover from acute viral encephalitis
escommon early features. Hallucinations and complex
partablished Korsakoff syndrome should also receive thipartial or generalized seizures may occur. In many inticularly
caused
herpes simplex
virusmay
amine tothat
prevent
theby
progression
of decits,
although
stances, the amnestic syndrome progresses to a
be
existing decits are unlikely to be reversed.
global
left with a permanent and static amnestic syndrome.
dementia. Depending upon the extent to which gray
The
matter regions outside the limbic system are
syndrome is similar to that produced by chronic alcoholism in that an inability to form new memories isinvolved,
its
cerebellar, pyramidal, bulbar, and peripheral nerve
outstanding feature. Remote memories are affected
disto a
turbances
may coexist with the amnestic disorder.
lesser extent than are recent ones, and registration
is
The
CSF
may also show a modest mononuclear
inpleocytosis
and mildly elevated protein. Diffuse slowtact. Confabulation may occur. Often there is total
ing
or
bitemporal
slow waves and spikes are
amnesometimes
sia for the period of the acute encephalitis.
seen on EEG. An MRI may reveal abnormal signal inPatients may also exhibit other symptoms of limbic
tensity in the medial temporal lobes. About 60% of
system disease. These include docility, indifference,
patients have antineuronal antibodies in serum or
atBRAIN TUMOR
CSF.
ness of mood and affect, inappropriate jocularity and
Anti-Hu
antibodies are most common and are usually
Brain tumor
is a rare
cause of amnestic
syndrome.
Tusexual
allusions,
hyperphagia,
impotence,
repetitive
associated
with small-cell lung cancer and anti-Ta
mors that can
present
in thisand
manner
includeof
those
stereotyped
motor
activity,
the absence
goalantithat
oribodies
are seen in patients with testicular cancer; in
are
located
in the
third ventricle
or that compress
its
ented
activity.
Complex
partial seizures,
with or withboth groups, prognosis is poor. Patients with neither
oor
or walls from
without. Themay
amnestic
out secondary
generalization,
occur. syndrome
closely resembles Korsakoff syndrome. In addition,anti-Hu nor anti-Ta antibodies have a better outcome
and often improve after treatment of the underlying
patumor.
tients with deep midline tumors often exhibit marked
lethargy, headache, endocrine disturbances, visual The paraneoplastic amnestic syndrome can be
static,
eld
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Headache & Facial

Pain
CONTENTS
Approach to diagnosis, 70
Pathophysiology of
headache & facial pain, 70
History, 70
Physical examination, 73
Neurologic examination, 74
Headaches of acute onset, 74
Subarachnoid
hemorrhage, 74
Other cerebrovascular
disorders, 79
Meningitis or encephalitis, 80
Other causes of acute

headache, 80
Headaches of subacute
onset, 81
Giant cell arteritis, 81
Intracranial mass, 82
Idopathic Intracranial
Hypertension, 83
Trigeminal neuralgia, 83
Glossopharyngeal
neuralgia, 84
Postherpetic neuralgia, 84
Hypertension, 85
Atypical facial pain, 85
Chronic headaches, 85
Migraine, 85
Analgesic withdrawal
headache, 90
Cluster headache, 90
Tension-type headache, 91
Ice pick pain, 92
Cervical spine disease, 92
Sinusitis, 92
Dental disease, 92
KEY CONCEPTS
Headache results from disorders that affect painsensitive structures of the head and neck, such as
meninges, blood vessels, nerves, and muscle.
Headaches that are new in onset or different from
previous headaches are those most likely to be
caused by a serious illness, whereas headaches of
long standing usually have a benign cause.
Signs of meningeal irritationsuch as neck stiffness on passive exion in the anteroposterior
direction or hip and knee exion in response
to passive neck exionmust be sought in
patients with acute headache; detecting these
signs is critical in the rapid diagnosis of meningitis, and directs the diagnostic evaluation toward
urgent lumbar puncture and away from imaging

procedures.
Subarachnoid hemorrhage from a ruptured
intracranial aneurysm often can be diagnosed by
the presence of subarachnoid blood on a noncontrast CT scan; however, in the absence of this
nding, a lumbar puncture showing no blood in
the cerebrospinal uid is required to exclude the
diagnosis.
High blood pressure alone does not cause chronic

headache.
For maximum effect, drugs for migraine should
be taken immediately at the onset of symptoms.
69
Copyright 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
70 / CHAPTER 2
Headache occurs in all age groups and accounts for
Table 21. Causes of headache and facial pain.
12% of emergency department evaluations and for
up
Acute onset
to 4% of medical ofce visits; the causes are myriadCommon causes
(Table 21). Although most often a benign condition Subarachnoid hemorrhage
(especially when chronic and recurrent), headache of Other cerebrovascular diseases
Meningitis or encephalitis
new onset may be the earliest or the principal
Ocular disorders (glaucoma, acute iritis)
manifesLess
common causes
tation of serious systemic or intracranial disease and
Seizures
therefore requires thorough and systematic
Lumbar puncture
evaluation.
Hypertensive encephalopathy
An etiologic diagnosis of headache is based on un- Coitus
derstanding the pathophysiology of head pain;
Subacute onset
obtainGiant cell (temporal) arteritis
Intracranial mass (tumor, subdural hematoma, abscess)
ing a history, with characterization of the pain as
Pseudotumor cerebri (benign intracranial hypertension)
acute,
subacute, or chronic; performing a careful physical Trigeminal neuralgia (tic douloureux)
APPROACH
TO DIAGNOSIS
Glossopharyngeal neuralgia
exPosttherpetic neuralgia
amination; and formulating a differential diagnosis.
Hypertension (including pheochromocytoma and the
use of monoamine oxidase inhibitors plus tyramine)
Atypical facial pain
Chronic
Migraine
Cluster headache
Headache is caused by traction, displacement, Tension headache
inammation, vascular spasm, or distention of Cervical spine disease
the pain-sensitive structures in the head or
Sinusitis
neck. Isolated involvement of the bony skull, most ofDental disease
PATHOPHYSIOLOGY OF HEADACHE
& FACIAL PAIN
Pain-Sensitive Structures
the dura, or most regions of brain parenchyma does

not
produce pain.
A. PAIN-SENSITIVE STRUCTURES
WITHIN THE CRANIAL VAULT
These include the venous sinuses (eg, sagittal sinus);
this area may also be referred to the ear or throat
the anterior and middle meningeal arteries; the dura
(eg,
at
glossopharyngeal neuralgia).
the base of the skull; the trigeminal (V),
The upper cervical nerves transmit stimuli arising
glossopharynfrom infratentorial and cervical structures; therefore,
geal (IX), and vagus (X) nerves; the proximal portions
pain from posterior fossa lesions projects to the
of the internal carotid artery and its branches nearsecond
the
and
third cervical dermatomes (Figure 21).
HISTORY
B.
EXTRACRANIAL
AIN-S
ENSITIVE STRUCTURES
Circle
of Willis; Pthe
brainstem
periaqueductal gray
Classication & Approach
These
the
periosteum
the skin;
matter;include
and the
sensory
nucleiofofthe
theskull;
thalamus.
to the Differential Diagnosis
the
subcutaneous tissues, muscles, and arteries; the
A. ACUTE HEADACHES AND FACIAL PAIN
neck
Headaches that are new in onset and clearly
muscles; the second and third cervical nerves; the
different from any the patient has experienced
eyes,
ears, teeth, sinuses, and oropharynx; and the mucous previously are commonly a symptom of serious
Radiation or Projection of Pain
illness and therefore demand prompt evaluation. The
membranes of the nasal cavity.
The trigeminal (V) nerve carries sensation from sudden onset of the worst headache Ive ever had in
my life (classic subarachnoid hemorrhage), diffuse
intracranial structures in the anterior and middle fossae ofheadache with neck stiffness and fever (meningitis),
and head pain centered about one eye (acute
the
glaucoma)
skull, above the cerebellar tentorium. Discrete
are striking examples. Acute headaches may also acintracracompany more benign processes such as viral synnial lesions in these locations can produce pain that
dromes or other febrile illnesses.
radiates in the trigeminal nerve distribution (Figure 21).
The glossopharyngeal (IX) and vagus (X) nerves
supply part of the posterior fossa; pain originating in
HEADACHE & FACIAL PAIN / 71

Anterior fossa
V1
V1, 2, 3
C2
C2, 3
Middle fossa
C1, 2, 3
V2
C3
Tentorium cerebelli
C2, 3
Posterior fossa
V3
C4
C3, 4
Figure 21. Innervation of pain-sensitive intracranial compartments A and corresponding extracranial sites of pain
radiation B.The trigeminal (V) nerve, especially its ophthalmic (V1) division, innervates the anterior and middle
cranial fossae; lesions in these areas can produce frontal headache.The upper cervical nerve roots (especially C2)
innervate the posterior fossa; lesions here can cause occipital headache.
B. SUBACUTE HEADACHES AND FACIAL PAIN

Precipitating Factors
Subacute headaches occur over a period of weeks to
months. Such headaches may also signify serious Precipitating factors can provide a guide to the cause
of headache. Such factors include recent eye or
meddental
ical disorders, especially when the pain is progressive
surgery; acute exacerbation of chronic sinusitis or
or
hay
when it develops in elderly patients. Inquiries should
fever; systemic viral infection; tension, emotional
be
stress, or fatigue; menses; hunger; ice cream; foods
made about recent head trauma (subdural hematoma
or postconcussive syndrome); a history of malaise,containing nitrite (hot dogs, salami, ham, and most
sausage), phenylethylamine (chocolate), or tyramine
fever, or neck stiffness (subacute meningitis); other
neurologic abnormalities or weight loss (primary or(cheddar cheese); and bright lights. Precipitation of
metastatic brain tumor); symptoms of vasculitis, headache by alcohol is especially typical of cluster
headache. Chewing and eating commonly trigger
espegloscially giant cell arteritis; and medical conditions (eg,
sopharyngeal neuralgia, tic douloureux, and the jaw
C.
CHRONIC
HEADACHES
AND F
ACIAL PAIN cutaneous herpes
optic
neuritis
in multiple
sclerosis;
Headaches
that have
occurred for
zoster)
or medications
predisposing
to years
any of(eg,
the claudication of giant cell arteritis; these activities also
pain in patients with temporomandibular joint
a
disor-migraine or tension headaches) usually have trigger
dysfunction.
The use of oral contraceptive agents or
benign
cause,
although
each
acute
attack
may
ders listed in Table 21.
other
drugs
such
as nitrates may precipitate or
be profoundly disabling. When treating these
exacerpatients,
it is important to determine whether the present bate migraine and even lead to stroke. Intense
can occur in response to coughing in paheadache is similar to those suffered previously orheadache
is
tients
with
structural lesions in the posterior fossa; in
newand thus represents a different process.
other instances no specic cause for cough headache
can be identied.
72 / CHAPTER 2
Prodromal Symptoms and Auras
Associated Symptoms
Prodromal symptoms or auras, such as scintillatingManifestations of underlying systemic disease can aid
scoin the etiologic diagnosis of headache and should altomas or other visual changes, often occur with miways be sought.
graine; they may also occur in patients with a seizureRecent weight loss may accompany cancer, giant
disorder who present with postictal headaches.
cell arteritis, or depression.
Fever or chills may indicate systemic infection or
Characteristics of Pain
meningitis.
Headache or facial pain is most often described as Dyspnea or other symptoms of heart disease raise
throbbing; a dull, steady ache; or a jabbing,
the possibility of subacute infective endocarditis and
lancinating
repain. Pulsating, throbbing pain is frequently ascribed
sultant brain abscess.
to migraine, but it is equally common in patients withVisual disturbances suggest an ocular disorder (eg,
tension headache. A steady sensation of tightnessglaucoma),
or
migraine, or an intracranial process
pressure is also commonly seen with tension
involving
headache.
the optic nerve or tract or the central visual
The pain produced by intracranial mass lesions is pathways.
typiNausea and vomiting are common in migraine and
cally dull and steady. Sharp, lancinating pain
posttraumatic headache syndromes and can be seen
suggests
in
a neuritic cause such as trigeminal neuralgia. Ice the course of mass lesions. Some patients with
pickmigraine
like pain may
be described
by patients
with migraine,
Unilateral
headache
is an invariable
feature
of cluster
also report that diarrhea accompanies the attacks.
cluster headache,
or giant
arteritis.
headache
and occurs
in thecell
majority
of migraine
Photophobia may be prominent in migraine and
Headache
of virtually any description can occuracute
in
attacks;
Location
of Pain
meningitis or subarachnoid hemorrhage.
patients
with migraine
or brain
tumors,
however,
so Myalgias often accompany tension headaches,
most
patients
with tension
headache
report
bilateral
that the character of the pain alone does not provide
pain.
viral
a Ocular or retroocular pain suggests a primary ophsyndromes, and giant cell arteritis.
reliable
etiologic
guide.
thalmologic
disorder
such as acute iritis or glaucoma,
Other
Features
of Headache
Ipsilateral
rhinorrhea
and lacrimation during atoptic (II) nerve disease (eg, optic neuritis), or retroortacks typify cluster headache.
TEMPORAL PATTERN OF HEADACHE
bital inammation (eg, Tolosa-Hunt syndrome). It isA. Transient
loss of consciousness may be a concomiHeadaches
from mass lesions are commonly maximal
also common in migraine or cluster headache.
tant of both migraine and glossopharyngeal
Paranasal pain localized to one or several of theon
si-awakening, as are sinus headaches. Headaches
neuralgia.
from
nuses, often associated with tenderness in the
mass lesions, however, increase in severity over
overlying
periosteum and skin, occurs with acute infection ortime.
Cluster headaches frequently awaken patients from
outlet obstruction of these structures.
sleep; they often recur at the same time each day or
Headache from intracranial mass lesions may be
night. Tension headaches can develop whenever
focal (it hurts right here), but even in such cases itstressis
ful situations occur and are often maximal at the end
reB.
of CONDITIONS RELIEVING HEADACHE
placed by bioccipital and bifrontal pain when the inMigraine
headaches
are frequently
a workday.
Migraine headaches
are relieved
episodicby
and may
tracranial pressure becomes elevated.
darkness,
be
Bandlike or occipital discomfort is commonly assosleep,
vomiting,
or pressing
the ipsilateral
worse during
menses
(Figureon
22).
ciated with tension headaches. Occipital localization
temporal
can also occur with meningeal irritation from infection
artery, and their frequency is often diminished during
or hemorrhage and with disorders of the joints, muspregnancy. Postlumbar-puncture and low-pressure
cles, or ligaments of the upper cervical spine.
headaches are typically relieved by recumbency,
Pain within the rst division of the trigeminal nerve
whereas
(Figure 21B), characteristically described as burning
C.
CONDITIONS
EXACERBATING
HEADACHEmass lesions may
headaches
caused
by intracranial
in
Discomfort
exacerbated
by
rapid changes in head
be
quality, is a common feature of postherpetic
posiless severe with the patient standing.
neuralgia.
tion or by events that transiently raise intracranial
Lancinating pain localized to the second or third dipresvision of the trigeminal nerve (Figure 21B) suggests
sure, such as coughing and sneezing, is often
tic douloureux.
associated
The pharynx and external auditory meatus are the
with an intracranial mass but can occur in migraine.
most frequent sites of pain caused by
Anger, excitement, or irritation can precipitate or
glossopharyngeal
neuralgia.

B. PULSE
Tachycardia can occur in a tense, anxious patient
with a
tension headache or accompany any severe pain.
Tension headache
Paroxysmal headache associated with tachycardia and
C.
BLOOD PRESSURE
perspiCluster headache
Hypertension
per se rarely
causes headache unless
ration is characteristic
of pheochromocytoma.
the
blood pressure elevation is acute, as with
Brain tumor
pheochromocytoma, or very high, as with early hypertensive encephalopathy. Chronic hypertension, however, is the
0
3
6
9
12
major risk factor for stroke, which can be associated
with acute headache. Subarachnoid hemorrhage is
Time (months)
commonly followed by marked acute blood pressure
D. RESPIRATION
Figure 22. Temporal patterns of headache. Migraine elevation.
headache is episodic and may occur at varying inter- Hypercapnia from respiratory insufciency from any
vals.Tension headache may be present every day. Clus- cause can elevate intracranial pressure and produce
ter headache occurs in bouts separated by symptom- headache.
Migraine
free periods. Headache caused by brain tumor often

increases in severity with time.
General Physical Examination
A. WEIGHT LOSS
Weight loss or cachexia in a patient with headache
worsen both migraine and tension headaches. Stoopsuging, bending forward, sneezing, or blowing the nose
gests the presence of cancer or chronic infection.
characteristically worsens the pain of sinusitis.
Polymyalgia rheumaticagiant cell arteritis syndromes
Postural
headache (maximal when upright, nearly absent can also be accompanied by weight loss.
B. SKIN
when
Focal cellulitis of the face or overlying the skull indilying down) occurs with low cerebrospinal uid (CSF)
cates local infection, which may be the source of inpressure caused by lumbar puncture, head injury, or
tracranial abscess or venous sinus thrombosis. Cutaspontaneous spinal uid leak.
neous abnormalities elsewhere may suggest
Fluctuations in intensity and duration of the
vasculitis
headache with no obvious cause, especially when
(including that from meningococcemia), endocarditis,
assoor cancer. The neurobromas or caf-au-lait spots of
D.
H
ISTORY OF HEADACHE
ciated with similar uctuations in mental status, are
von Recklinghausen disease (neurobromatosis) may
The
characteristics
of
the
present
headache
should
seen with subdural hematoma.
be
be
associated with benign or malignant intracranial tucompared with those of previous occurrences, since
mors that can produce headache. Cutaneous
headache with features different from those
angiomas
previously
sometimes accompany arteriovenous malformations
experienced calls for careful investigation.
PHYSICAL EXAMINATION
(AVMs) of the central nervous system and may be
assoA general physical examination is mandatory, since
ciated with chronic headacheor acute headache if
headache is a nonspecic accompaniment of many
C. SCALP, FACE, AND HEAD
they bleed. Herpes zoster that affects the face and
sysScalp tenderness is characteristic of migraine
head
temic disorders. If possible, the patient should be obheadache,
most often involves the eye and the skin around the
served during an episode of headache or facial pain.
subdural hematoma, giant cell arteritis, and postherpeVital Signs
petic neuralgia. Nodularity, erythema, or tenderness
riorbital tissue, causing facial pain.
over the temporal artery suggests giant cell arteritis.
A. TEMPERATURE
LoAlthough fever suggests a viral syndrome, meningitis,
calized tenderness of the supercial temporal artery
encephalitis, or brain abscess, headache from these
also
causes can occur without fever. Moreover, headache
accompanies acute migraine. Recent head trauma or
can
a
accompany any systemic infectious illness.
mass lesion can cause a localized area of tenderness.
Paget disease, myeloma, or metastatic cancer of
the
skull may produce head pain that is boring in quality
74 / CHAPTER 2
and associated with skull tenderness. In Paget
hemorrhage in adults. Ischemic retinopathy may be
disease,
found in patients with vasculitis.
arteriovenous shunting within bone may make the Progressive oculomotor nerve palsy, especially
scalp feel warm.
when
Disorders of the eyes, ears, or teeth may cause it causes pupillary dilatation, may be the presenting
headache. Tooth percussion may reveal periodontal
sign of an expanding posterior-communicating-artery
abaneurysm, or it may reect increasing intracranial
scess. Sinus tenderness may indicate sinusitis. A bruit
presover the orbit or skull suggests an intracranial AVM,
sure
a and incipient herniation. Decreased pupillary
carotid artery-cavernous sinus stula, an aneurysm,
reacor a
tivity occurs in optic neuritis. Extraocular muscle
meningioma. Lacerations of the tongue raise the palsies occur in Tolosa-Hunt syndrome. Proptosis sugpossigests an orbital mass lesion or carotid arterybility of postictal headache. Ipsilateral conjunctivalcavernous
inD.
NECK lacrimation, Horner syndrome, and rhinorrhea
jection,
sinus stula.
Cervical
muscle
spasms
occurTemporomandibular
with tension and mi- Decreased sensation over the area of painmost
occur with
cluster
headache.
graine
headaches,
cervical
spine
injuries, cervical commonly the rst division of the trigeminal nerve
joint
arthridisease is accompanied by local tenderness and is
Examination
tis,
or meningitis. Carotid bruits may be associatedMotor
crepitus.
found in postherpetic neuralgia. Trigger areas eliciting
with cerebrovascular disease.
Asymmetric
motorthe
function
or gait
ataxia
in a patient
pain in and about
face and
pharynx
suggest
Meningeal signs must be carefully sought, eswith
a
history
of
subacute
headache
demands
trigempecially if the headache is of recent onset. complete
inal and glossopharyngeal neuralgia, respectively.
Meningeal irritation causes nuchal rigidity evaluation to exclude intracranial mass lesions.
mainly in the anteroposterior direction, whereas Sensory Examination
cerviFocal or segmental sensory impairment or diminished
cal spine disorders restrict movement in all
corneal sensation (corneal reex) is strong evidence
directions.
against a benign cause of pain.
Discomfort or hip and knee exion during neck
exion
(Brudzinski sign) readily indicates meningeal irritation
(Figure 23).
Meningeal signs may be absent or difcult to HEADACHES OF ACUTE ONSET
E.
HEART AND LUNG
demonstrate
in the early stages of subacute (eg,
Brain
abscess
may be associated with congenital
tuberheart
culous) meningitis, in the rst few hours after sub-Sudden onset of new headache may be a symptom of
serious intracranial or systemic disease; it must be indisease,
which
is evidenced
bycomatose
murmurs or
cyanosis.
arachnoid
hemorrhage,
and in
patients.
vestigated promptly and thoroughly.
Lung abscess may also be a source of brain abscess.
Spontaneous (nontraumatic) subarachnoid
hemorrhage
SUBARACHNOID HEMORRHAGE
NEUROLOGIC EXAMINATION
(bleeding into the subarachnoid space) is usually the
result of a ruptured cerebral arterial aneurysm or an
During the mental status examination, patients with
AVM. Rupture of a berry aneurysm accounts for about
acute headache may demonstrate confusion, as is75% of cases, with an annual incidence of 6 per
com100,000. Rupture occurs most often during the fth
monly seen with subarachnoid hemorrhage and and sixth decades, with an approximately equal sex
menindisgitis. Dementia may be the major feature of
tribution. The risk of rupture of an intracranial
intracranial
aneurysm varies with patient age, and aneurysm site
Cranial Nerve Examination
tumor, particularly one in the frontal lobe.
and size. Hypertension has not been conclusively
Cranial nerve abnormalities may suggest and localize
demonstrated to predispose to the formation of
an
aneurysms, but acute elevation of blood pressure (eg,
intracranial tumor or other mass lesion. Papilledema,
at
the hallmark of increased intracranial pressure, may
orgasm) may be responsible for their rupture.
be
Intracraseen in space-occupying intracranial lesions, carotid
nial AVMs, a less frequent cause of subarachnoid
arhemtery-cavernous sinus stula, pseudotumor cerebri,orrhage
or
(10%), occur twice as often in men and
hypertensive encephalopathy. Supercial retinal (subusually
hyaloid) hemorrhages are characteristic of
bleed in the second to fourth decades, although a sigsubarachnoid
nicant incidence extends into the 60s. Blood in the
Figure 23. Brudzinski sign. With the patient supine and the examiners hand on the patients chest, passive
neck
exion (arrow at right) results in exion at the hips (arrows at left), which is often asymmetric.The sign is
present
with meningeal irritation from disorders such as infectious meningitis or subarachnoid hemorrhage.
branching. These aneurysmal dilatations arise from

subarachnoid space can also result from intracerebral
inhemorrhage, embolic stroke, and trauma.
tracranial arteries about the Circle of Willis at the
base
of the brain (Figure 24) and are multiple in about
Pathology
20% of cases. Other congenital abnormalities, includCerebral artery aneurysms are most commonly ing polycystic kidney disease and coarctation of the
congenaorta, may be associated with berry aneurysms.
ital berry aneurysms, which result from
Occadevelopmensionally, systemic infections such as infective
tal weakness of the vessel wall, especially at sites endocardiof
tis disseminate to a cerebral artery and cause
aneurysm
76 / CHAPTER 2
Anterior communicating artery (15%)
Anterior cerebral
artery (9%)
Posterior
communicating
artery (6%)
Middle
cerebral
artery (29%)
Internal
carotid
artery (16%)
Posterior
cerebral
artery (3%)
Basilar
artery (14%)
Figure 25. Peripapillary intraretinal (streak-like) and

Vertebral
artery (6%)
preretinal or subhyaloid (globular) hemorrhages associated with a sudden increase in intracranial pressure
caused by aneurysmal rupture. (CourtesyofWF
Hoyt.)

Figure 24. Frequency and distribution of intracranial The classic (but not invariable) presentation of subarachnoid hemorrhage is the sudden onset of an
aneurysms.
Clinical
Findings
unusually severe generalized headache (the worst
formation; such mycotic aneurysms account for headache I
23% of aneurysmal ruptures. Mycotic aneurysms ever
are had in my life). The absence of headache
usually more distal (along the course of cerebral essentially precludes the diagnosis. Loss of consciousness
arterat
ies) than are berry aneurysms.
onset is frequent, as are vomiting and neck stiffness.
AVMs consist of abnormal vascular
Symptoms may begin at any time of day and during
communications
Rupture
of an
intracranial
artery
intracranial
eithat permit
arterial
blood to
enterelevates
the venous
system
pressure
and distorts
pain-sensitive
structures,
without passing
through
a capillary bed.
They are ther rest or exertion.
producThe most signicant feature of the headache is
most
Pathophysiology
ing
headache.
pressure
may
reach
that
common
in theIntracranial
middle cerebral
artery
distribution.
systemic
it is new. Milder but otherwise similar headaches may
perfusion pressure and acutely decrease cerebral have occurred in the weeks prior to the acute event.
blood
These earlier headaches are probably the result of
ow; together with the concussive effect of the
small
rupture,
prodromal hemorrhages (sentinel, or warning, hemorthis is thought to cause the loss of consciousness that
rhages) or aneurysmal stretch.
occurs at the onset in about 50% of patients. Rapid The headache is not always severe, however, espeelecially if the subarachnoid hemorrhage is from a rupvation of intracranial pressure can also produce subtured AVM rather than an aneurysm. Although the
hyaloid retinal hemorrhages (Figure 25).
duration of the hemorrhage is brief, the intensity of
Because aneurysmal hemorrhage is usually
the headache may remain unchanged for several
conned
days
to the subarachnoid space, it does not produce a and may subside only slowly over the next 2 weeks.
focal
A recrudescent headache usually signies recurrent
cerebral lesion. Prominent focal ndings on
bleeding.
neurologic
Blood pressure frequently rises precipitously as a
examination are accordingly uncommon except with
remiddle cerebral artery aneurysms. Ruptured AVMs,sult of the hemorrhage. Meningeal irritation may inhowever, produce focal abnormalities that correspond
duce temperature elevations to as high as 39C
to their parenchymal location.
(102.2F) during the rst 2 weeks. There is frequently

confusion, stupor, or coma. Nuchal rigidity and other
tered consciousness. Intracerebral or intraventricular
evidence of meningeal irritation (see Figure 23) are
blood, associated hydrocephalus, and infarction can
common, but these signs may not occur for several
also be identied. Aneurysms may not be evident on
hours after the onset of the headache. Preretinal the CT scan, but most AVMs can be seen with conglobutrast. Magnetic resonance imaging (MRI) is especially
lar subhyaloid hemorrhages (found in 20% of cases)
useful in detecting small AVMs localized to the brainare
stem (an area poorly seen on CT scan). If the CT scan
most suggestive of the diagnosis (see Figure 25). fails
Be- to conrm the clinical diagnosis of subarachnoid
cause bleeding occurs mainly in the subarachnoid hemorrhage, lumbar puncture is performed.
space
The CSF examination usually reveals markedly elein patients with aneurysmal rupture, prominent focal
vated opening pressure; the uid is grossly bloody
signs are uncommon on neurologic examination. and
When present, they may bear no relationship to the
contains from 100,000 to more than 1 million red
site
cells/mm3. As a result of the breakdown of
of the aneurysm. An exception is oculomotor nervehemoglobin
palsy occurring ipsilateral to a posterior communicatfrom red cells, the supernatant of the centrifuged CSF
ing artery aneurysm. Bilateral extensor plantar re-becomes yellow-tinged (xanthochromic) within
B.
LABORATORY
FINDINGS
sponses
and VI
nerve palsies are frequent. Ruptured
several
Patients
presenting
subarachnoid
hemor-hours (certainly by 12 hours) following the
AVMs may produce
focal with
signs,
such as hemiparesis,
rhage
investigated
rstelds.
by computed to-hemorrhage
aphasia,
or aare
defect
of the visual
mography (CT) scan (Figure 26), which will (see Chapter 11). White cells are initially present in
usually conrm that hemorrhage has occurred andthe
may
spinal uid in the same proportion to red cells as in
help to identify a focal source. CT brain scanning will
the
detect subarachnoid blood in more than 90% of paperipheral blood. The chemical meningitis caused by
tients with aneurysmal rupture. The test is most blood in the subarachnoid space, however, may prosensiduce a pleocytosis of several thousand white blood
tive on the day bleeding occurs and in patients with
cells
alduring the rst 48 hours and a reduction in CSF glucose between the fourth and eighth days after the
hemorrhage. In the absence of pleocytosis, CSF glucose
following subarachnoid hemorrhage is normal. The
peripheral blood white count is often modestly
elevated
Figure 26. A: Nonenhanced brain CT scan from a patient with an acute aneurysmal subarachnoid hemorrhage.
Areas of high density (arrows) represent blood in the subarachnoid space at the base of the brain (most
aneurysms
occur in this region about the Circle of Willis; see Figure 24). B: A normal unenhanced brain CT scan of the same
region. Interpeduncular cistern, arrow; suprasellar cistern, small arrow. (CourtesyofCJungreis.)
78 / CHAPTER 2
but rarely exceeds 15,000 cells/mm3. The
in vessels surrounded by subarachnoid blood and can
electrocardiolead to parenchymal ischemia in more than one-third
gram (ECG) may reveal a host of abnormalities: of cases. Clinical ischemia typically does not appear
peaked
beor deeply inverted T waves, short PR interval, or tall
fore
U Day 4 after the hemorrhage, peaks at Day 1014,
waves.
and then spontaneously resolves. The diagnosis can
Once the diagnosis is conrmed, four-vessel
be
cerebral
conrmed by transcranial Doppler or cerebral angiogarteriography is undertaken. Cerebral angiographyraphy.
of
The severity of spasm is related to the amount
both the carotid and vertebral arteries should be perof
formed to visualize the entire cerebral vascular subarachnoid blood, and therefore is less common
D.
ACUTE
OR SUBACUTE HYDROCEPHALUS
anatomy, since multiple aneurysms occur in 20% of
where
less
blood is usually seen, such as in traumatic
Acute
or
subacute
hydrocephalus
pasubarachnoid
hemorrhage
or AVM.may develop during
the
rst
dayor
after
several
weeksas a result of
tients and AVMs are frequently supplied from multiple
imvessels. Angiography can be performed at the
paired CSF absorption in the subarachnoid space. Proearliest
gressive somnolence, nonfocal ndings, and impaired
time convenient for radiology department personnel;
emergency studies in the middle of the night are upgaze should suggest the diagnosis.
E. SEIZURES
rarely
Seizures occur in fewer than 10% of cases and only
indicated. Angiography is a prerequisite to the
folThe
history of a sudden severe headache with confurational
lowing damage to the cerebral cortex. Decorticate or
sion
or obtundation,
nuchal rigidity,
nonfocal not
neuroplanning
of surgical treatment
and isatherefore
decerebrate posturing is common acutely, and may
logic
nec- examination, and bloody spinal uid is highly
be
specic
forpatients
subarachnoid
hemorrhage.
essary for
who are
not surgical candidates,
F.
OTHER COMPLICATIONS
mistaken
for seizures.
eg,Hypertensive intracerebral hemorrhage is also Although inappropriate secretion of antidiuretic hormanithose who are deeply comatose.
mone and resultant diabetes insipidus can occur,
fested by obtundation and hemorrhagic spinal uid,
they
A.
MEDICAL TREATMENT
but there are prominent focal ndings. Bacterial Medical
are uncommon.
treatment is directed toward preventing
meningitis is excluded by the CSF examination. Rupelevatured mycotic aneurysm is suggested by other signs
Treatment
tion of arterial or intracranial pressure that might reof
rupture the aneurysm or AVM. Typical measures inendocarditis. Traumatic spinal puncture can be ex-clude absolute bed rest with the head of the bed
cluded as the cause of bloody CSF by examinationelevated
of
1520 degrees, mild sedation, and
the centrifuged CSF specimen. Because blood thatanalgesics
results from traumatic lumbar puncture has not yet unfor headache. Drugs impairing platelet function (eg,
dergone enzymatic breakdown to bilirubin,
ascentrifugapirin) should be avoided. Because patients who are
tion of the spinal uid specimen reveals a colorlesshyComplications & Sequelae
supernatant.
pertensive on admission have an increased mortality
A. RECURRENCE OF HEMORRHAGE
risk, reducing the blood pressure (to approximately
Recurrence of aneurysmal hemorrhage (20% over 160/100 mm Hg) is prudent. Bed rest and mild seda1014 days) is the major acute complication and tion are often adequate in this regard. Hypotension
roughly doubles the mortality rate. Recurrence of should be prevented, however, to ensure adequate
hemcereorrhage from AVM is less common in the acute
bral perfusion. Intravenous uids should be adminisB.
INTRAPARENCHYMAL EXTENSION OF HEMORRHAGE
period.
tered with care, since overhydration can exacerbate
Although it is common for hemorrhages from an AVM
cerebral swelling. Intravenous uids should be isoosto involve the cerebral parenchyma, this is far less
motic to minimize free water exacerbating brain
comedema.
mon with aneurysm. Nevertheless, rupture of an
Normal saline can be given in amounts to ensure noraneurysm of the anterior cerebral or middle cerebral
movolemia. Hyponatremia is frequently seen, and
arusutery may direct a jet of blood into brain parenchyma,
ally represents, at least in part, cerebral salt wasting;
producing hemiparesis, aphasia, and sometimes
it
C.
ARTERIAL VASOSPASM
transtentorial
herniation.
Delayed arterial narrowing, termed vasospasm, should be managed with sodium replacement such as
NaCl orally or 3% normal saline intravenously rather
occurs
than uid restriction. Prophylactic use of the calcium
channel antagonist drug nimodipine, 60 mg orally (or
by nasogastric tube) every 4 hours for 21 days, may
re-

duce the ischemic sequelae of cerebral vasospasmconvenient
in
time after the bleeding
paepisode.
tients with a ruptured aneurysm. Vasospasm is
Prognosis
treated
by induced hypertension with phenylephrine or The mortality rate from aneurysmal subarachnoid
hemorrhage is high. About 20% of patients die before
dopamine; this intervention is more safely performed
reaching a hospital, 25% die subsequently from the
after denitive surgical treatment of the aneurysm.
Although seizures are uncommon after aneurysmalinitial hemorrhage or its complications, and 20% die
rupture, the hypertension accompanying a seizurefrom rebleeding if the aneurysm is not surgically corincreases the risk of rerupture; a prophylactic anti-rected. Most deaths occur in the rst few days after
convulsant (eg, phenytoin, 300 mg/d) is therefore the
B.
SURGICAL TREATMENT
hemorrhage. The probability of survival following
recommended
routinely.
1. AneurysmDenitive surgical therapy of a rupaneurysmal rupture is related to the patients state of
tured aneurysm consists of clipping the neck of the
consciousness and the elapsed time since the hemoraneurysm or the endovascular placement of a coilrhage.
to
On Day 1, the prognosis for survival for sympintom-free and somnolent patients is, respectively, 60%
duce clotting. The neurologic examination is used and
to 30%; such patients still alive at 1 month have
grade the patients clinical state relative to surgical
surcanvival probabilities of 90% and 60%, respectively. Of
didacy (Table 22). In patients who are fully alert survivors, half have permanent brain injury. Recovery
(grades I and II) or only mildly confused (grade III),from subarachnoid hemorrhage resulting from
surgery has been shown to improve the clinical outrupture
come. In contrast, stuporous (grade IV) or comatose
of intracerebral AVMs occurs in nearly 90% of pa(grade V) patients do not appear to benet from the
tients, and although recurrent hemorrhage remains a
procedures. Although there is some controversy Familial
Intracranial management
Aneurysms compares
danger, conservative
about
favorably
Families with two or more affected persons should
the optimal timing of surgery, current evidence supwith surgical therapy.
have
ports early intervention, within about 2 days following
the hemorrhage. This approach reduces the periodall
atmembers screened. Both autosomal and recessive
patterns
of inheritance occur.
risk for rebleeding and permits aggressive treatment
OTHER CEREBROVASCULAR DISORDERS
of
vasospasm with volume expansion and
Headache may be associated withor rarely may be
pharmacologic
the presenting symptom ofthrombotic or embolic
elevation of blood pressure.
stroke. Compression of pain-sensitive structures is
Treatment of unruptured aneurysm is individual-the
ized. Surgery is favored by young age, previous mechanism of headache in intracranial hemorrhage,
rupture,
whereas pain-sensitive receptors in large cerebral
family history of aneurysmal rupture, observed
arteraneurysm growth, and low operative risk. Decreased
ies are responsible for headache in thrombotic and
life expectancy and asymptomatic small aneurysms
em(<7
bolic stroke. Lacunar strokes, which affect small
cms) favor conservative management.
arterial
2. AVMsSurgically accessible AVMs may be re-branches deep in the brain, are not as frequently
moved by en bloc resection or obliterated by ligation
associof
Table 22. Clinical grading of patients with aneurysmal
hemorrhage.
ated subarachnoid
with headache.
feeding vessels or embolization via local intraarterialHeadaches associated with ischemic stroke are
catheter.
risk of an early second
hemorGrade Because
Level ofthe
Consciousness
Associated
Clinical Features
Surgical Candidate
typirhage is much less with AVMs than with aneurysms,
surgical
treatment
can be undertaken
electively
at a
I
Normal
None
or mild headache
and stiff neck
Yes
II
Normal
Yes
Confusional state
Moderate headache and stiff neck; minimal

neurologic
decit (eg, cranial nerve palsy) in some cases
Focal neurologic decits in some cases
III
IV
Stupor
Focal neurologic decits in some cases
No
Coma
Decerebrate posturing in some cases
No
Yes
80 / CHAPTER 2
cally mild to moderate in intensity, ipsilateral to the
Treatment of meningitis or encephalitis caused by
involved hemisphere, and nonthrobbing in character.
these
Their location is determined by the pain projectiondifferent organisms is discussed in Chapter 1.
sites of the involved arteries: posterior fossa strokes
OTHER CAUSES OF ACUTE HEADACHE
usually present with occipital headache, whereas
SEIZURES
carotid lesions usually produce frontal (trigeminal 1.
disheadache that follows generalized tonictribution) pain. Transient ischemic attacks may be Postictal
asclonic
sociated with headache in as many as 50% of cases;
seizures is frequently accompanied by resolving
in
perhaps one-third of these, headaches precede thelethargy, diffuse muscle soreness, or tongue
laceration.
other
Although this headache requires no specic
symptoms.
treatment,
Headache accompanying retinal artery embolism
it is important to differentiate it from subarachnoid
or
hemorrhage
and meningitis. If doubt exists, lumbar
2.
LUMBAR PUNCTURE
posterior cerebral artery spasm or occlusion may be
puncture
should
be undertaken.
Postlumbar-puncture
headache is diagnosed by a hiserroneously diagnosed as migraine because of the tory of lumbar punctureand by the characteristic
marked increase in pain in the upright position and
associreated visual impairment.
lief with recumbency. The pain is typically occipital,
Headache also occurs following carotid endarterectomy and may be associated with focal sensory orcomes on 2448 hours after the procedure (although
it
momay be later), and lasts 12 days, but may be protor signs of contralateral hemispheric ischemia. This
longed. Headache is caused by persistent spinal subsyndrome occurs in the presence of a patent carotid
arachnoid leak with resultant traction on painarHeadache is a prominent feature of inammation of
tery
on
the
second
or
third
postoperative
day
and
the brain (encephalitis) or its meningeal coveringssensitive
structures at the base of the brain. The risk of this
typi(meningitis)
caused
by bacterial, viral, or other infecMENINGITIS
OR
ENCEPHALITIS
comcally
produces
intense
throbbing
anterior
headache
tions; granulomatous processes; neoplasms; or
plication can be reduced by using a small-gauge
that
chemical
is
often associated
nausea.
irritants.
The pain iswith
caused
by inammation of in-needle
Headache
disorders associated
with
ischemic
or(22 gauge or smaller) for the puncture and removing
tracranial
pain-sensitive
structures,
including
blood
only as much uid as needed for the studies to be
hevespermorrhagic
cerebral
infarction
require
direct
treatment
sels at the base of the brain. The headache syndrome
formed. Lying at afterward, for any length of time,
of
the
cerebral
lesion
combined
with
the
use
of
analproduced is commonly throbbing in character, bilatdoes not lessen the incidence. Low-pressure
gesics
for
symptomatic
relief.
eral, and occipital or nuchal in location. The headache
headache
is increased by sitting upright, moving the head, comsyndromes are usually self-limited. When this is not
pressing the jugular vein, or performing other maneuthe
vers (eg, sneezing, coughing) that transiently
case, they may respond to the administration of cafincrease
feine sodium benzoate, 500 mg intravenously, which
intracranial pressure. Photophobia may be prominent.
The headache rarely presents suddenly but more can be repeated after 45 minutes if headache
persists or
commonly develops over hours to days, especially withrecurs upon standing. In persistent cases, the
subarachsubnoid rent can be sealed by injection of autologous
acute infections (eg, tuberculous meningitis).
blood into the epidural space at the site of the puncNeck stiffness and other signs of meningeal irritature;
this requires
an experienced anesthesiologist.
3. HYPERTENSIVE
ENCEPHALOPATHY
tion (see Figure 23) must be sought with care, since
similar
character
to that
caused in
byblood
may
bein
due
to a sudden
elevation
they may not be obvious either early in the courseHeadache
of
lumbar
pressure
caused
by
pheochromocytoma,
sexual
interthe illness or when the brain parenchyma, rather than
puncture
occasionally
occurs
spontaneously.
T1course,
the
combination
of
monoamine
oxidase
inmeninges, is the predominant site of involvement.
weighted,
gadolinium-enhanced
may
show
and
tyramine-containing MRI
foods
such
as
Lethargy or confusion also may be a prominent hibitors
smooth
enhancement
of
the
pachymeninges
and a
cheddar
feature.
sagcheese,
orthe
most
important
causemalignant
hyThe diagnosis is suggested by a CSF examination
ging
brain)
(Figure
27);
the
enhancement
may
be
pertension.
Blood
pressures
of
250/150
mm
Hg
or
that shows an increased white blood cell count.
confused with disorders
highercharacteristic
ofproducing
malignantleptomeningeal
hypertension inBacterammation.
Low
CSF
pressure
can
also
produce this
produce
cerebral
edema
and
displace
pain-sensitive
ial, syphilitic, tuberculous, viral, fungal, and parasitic
MRI
picture
in
the
absence
of
headache.
structures.
The
pain
is
described
as
severe
and throbinfections may be distinguished by CSF VDRL, Gram
stain, acid-fast stain, India ink preparation and
cryptococcal antibody assays, and cultures (see Table 19).
Figure 27. Spontaneous intracranial hypotension in a 27-year-old woman presenting with severe postural
headaches.
Sagittal and axial T1-weighted images obtained after gadolinium injections show features of sagging brain:
downward
displacement of the cerebellar tonsils into the foramen magnum (arrows, left image), effacement of the
brainstem cisterns (left image; compare with normal sagittal MRI in Figure 113), and diffuse dural enhancement (arrows, right
image). MRI abnormalities and symptoms reversed following an epidural blood patch. (CourtesyofHA
Rowley.)
bing. Other signs of diffuse or focal central nervous

rhage is found, prophylactic treatment with insysdomethacin, 50 mg orally prior to intercourse, may
tem dysfunction are present, such as lethargy, hemibe
paresis,
or
focal
seizures;
on
CT
or
MRI
images,
posteeffective.
4. COITUS
5. OCULAR DISORDERS
rior
white
matter
changes
may
be
seen
(see
Figure
Headache during sexual intercourse has been
Pain about the eye may occur in migraine and cluster
110).
Treatment is with antihypertensive drugs (see
described
headache and is also the presenting feature of iritis
Chapter
1), but care
must
be taken to avoid
hypotenas the presenting
sign
of subarachnoid
hemorrhage;
sion,
which
can result
cerebral
and ofand
however,
headache
in in
this
settingischemia
is more often
a
glaucoma.
Acute iritis produces extreme eye pain
stroke.
bethat
nign nature. Men are more often affected than
is associated with photophobia. The diagnosis is conwomen.
rmed by slit lamp examination; acute management
The pain may be either a dull, bilateral pain occurring
induring sexual excitement or a severe, sudden
volves pharmacologic dilatation of the pupil. Angleheadache
closure glaucoma produces pain within the globe that
occurring at the time of orgasm, presumably caused
radiates to the forehead. When it occurs after middle
by
age, such a pain syndrome should prompt diagnostic
a marked increase in systemic blood pressure.
tonometry. Acute treatment is with glycerol, 1 mL/kg
Persistent
orally, followed by pilocarpine, 2%, two drops every
headache following orgasmworse in the upright 15
posminutes.
HEADACHES OF SUBACUTE
turehas also been described. In the latter case, the
symptoms are reminiscent of postlumbar-punctureONSET
headache and patients have low opening pressures at
lumbar puncture. Each of these headachesexcept
GIANT CELL ARTERITIS
for
those associated with aneurysmal ruptureis benign
This disorder, also known as temporal arteritis, is
and subsides over minutes to days.
charPatients reporting severe headache in association
with orgasm should be evaluated for possible
subarachnoid hemorrhage as described on p 75. If no hemor-
82 / CHAPTER
acterized
by a 2
subacute granulomatous inammation
(consisting of lymphocytes, neutrophils, and giant
usually after 12 months, depending upon the clinical
cells)
that affects the external carotid arterial system, response. Some centers begin with intravenous
methylparticuprednisolone (5001000 mg every 12 hours for two
larly the supercial temporal artery, and the vertebral
days). The sedimentation rate returns rapidly toward
artery. Inammation of the pain-sensitive arterial wall
with prednisone therapy and must be mainproduces the headache. Thrombosis may occur in normal
the
tained
within
normal limits as the drug dose is
most severely affected arteries.
tapered.
This syndrome, which affects women twice as freTherapy should not be withheld pending biopsy diagquently as men, is uncommon before age 50 and is
nosis and should be continued despite negative
frequently associated with malaise, myalgia, weight biopsy
ndings if the diagnosis can be made with condence
loss,
arthralgia, and fever (the polymyalgia rheumatica on clinical grounds. Tapering of prednisone therapy
recom12 years. Although dramatic improvement in
plex). The headache can be unilateral or bilateral, quires
INTRACRANIAL
MASS
headache
occurs within 23 days after institution of
fairly
therapy,
blindness
is usually
irreversible.
onset
of headache
in middle
or later life
severe, and boring in quality. It is characteristicallyThe
lo- new the
should
always
raise
concern
about
a
mass
lesion. A
calized to the scalp, especially over the temporal
mass
arteries. Scalp tenderness may be especially apparent lesion, such as a brain tumor (Table 23), subdural
hematoma, or abscess, may or may not produce
when
headache depending upon whether it compresses or
lying with the head on a pillow or brushing the hair.
distorts pain-sensitive intracranial structures. Only
Pain or stiffness in the jaw during chewing (jaw
30% of patients with intracranial tumor present with
claudiheadache as the rst symptom, although 80% have
cation) is highly suggestive of giant cell arteritis and
such a complaint at the time of diagnosis. Subdural
is
hematoma frequently presents with conspicuous
due to arterial ischemia in the muscles of
headache, since its large size increases the likelihood
mastication.
of
Involvement of the ophthalmic artery leads to permaimpinging
upon pain-sensitive areas. Headaches
nent blindness in 50% of untreated patients; in half
of
associthese, blindness will become bilateral. The visual loss
ated with brain tumors are most often nonspecic in
is
most often sudden in onset. Although episodes of character, mild to moderate in severity, dull and
steady
tranin nature, and intermittent. The pain is characteristisient prodromal blindness have been reported, blindness is unusual as an initial symptom; however, it cally bifrontal, worse ipsilaterally, and aggravated by
a
often
change in position or by maneuvers that increase inoccurs within the rst month.
tracranial pressure, such as coughing, sneezing, and
The diagnosis is made by biopsy of affected
straining at stool. The headache is classically
temporal arteries, which are characteristically thickened maximal
on awakening in the morning and is associated with
and
nausea and vomiting.
nonpulsatile as well as dilated and tender. The
An uncommon type of headache that suggests
Table 23. Symptoms of brain tumors.
temporal
brain
arteries may be affected in a patchy manner, and
tumor is characterized by a sudden onset of severe
serial
Percent with Symptom
pain
sections may be necessary to demonstrate histologic
reaching
maximal
seconds,
persisting
Symptom The erythrocyte sedimentation
Low-Grade Glioma
Malignant
Gliomaintensity within
Meningioma
(Benign)
vasculitis.
rate (ESR)
for
minutes
to
hours,
and
subsiding
rapidly.
Altered
is
Headache
40
50
almost invariably elevated. The mean
Westergren
ESR
Seizure
6595
1525
is about 100 mm/h in giant cell arteritis (range,
Hemiparesis
515
3050
29144 mm/h) and in polymyalgia
rheumatica (range,
58160
mm/h).
The normal upper 10
limit of the WesterAltered mental
status
4060
gren ESR in elderly patients is reported to be only as
ModifiedfromDeAngelisLM:Braintumors.NEnglJMed2001;344:114.
high as 40 mm/h.
Consideration of this diagnosis demands prompt
evaluation to avoid visual loss. Initial therapy is with
prednisone, 4060 mg/d orally. The dose is
decreased,
36
40
22
21

consciousness or drop attacks may be associated.
lumbar puncture; removal of 2040 ml CSF may tranAlsiently relieve headache. Cells, glucose, and protein
though classically associated with third ventricularcontent of the CSF are normal.
colIf a specic cause is identied (Table 24), it must
loid cysts, these paroxysmal headaches can be
be treated appropriately. Treatment with
associated
acetazolamide
with tumors at many different intracranial sites. 12 g/d or, furosemide 4060 mg twice daily, is the
Suspicion of an intracranial mass lesion demands
mainstay of treatment. Corticosteroids are effective
prompt evaluation, preferably with CT scan or MRI;but
brain
tumorIntracranial
is excluded by
a normal contrasthave untoward side effects and papilledema tends to
Idiopathic
Hypertension
enhanced
reIdiopathic
intracranial hypertension (pseudotumorbound when they are discontinued. In refractory
brain MRI scan.
cerebri) is characterized by a diffuse increase in in-cases,
tracranial pressure causing headache, papilledema,
optic
nerve sheath
fenestration, or lumboperitoneal
TRIGEMINAL
NEURALGIA
pulor
satile tinnitus, visual loss and diplopia as a result of
Trigeminal
neuralgia shunting
(tic douloureux)
a facial-pain
ventriculoperitoneal
may beisneeded
to
absynprotect
ducens nerve palsy. Although intracranial
drome
of unknown
that develops in middle to
vision and
decreasecause
headache.
hypertension
late
can accompany many disorders (Table 24), most life. In many instances, the trigeminal nerve roots are
cases
close to a vascular structure, and microvascular
are idiopathic. In the idiopathic variety, women arecompresafsion of the nerve is believed to cause the disorder.
fected much more commonly than men, with a peak
Pain is
incidence in the third decade. Most patients are conned mainly to the area supplied by the second
obese.
and
Diffuse headache is almost always a presenting third divisions of the trigeminal nerve (Figure 28). Insympvolvement of the rst division or bilateral disease
tom. Transient visual obscurations (lasting for
occurs
seconds)
in less than 5% of cases. Characteristically,
and visual blurring occur in most cases. Visual acuity
lightninglike
is
momentary jabs of excruciating pain occur and
normal in most patients at presentation; moderatespontato
severe papilledema is seen in almost all. Visual loss
neously abate. Occurrence during sleep is rare. Painfrom increased intracranial pressure, like that of glaufree
coma, is characterized by gradually constricting intervals may last for minutes to weeks, but longvisual
term
elds with late loss of central acuity.
spontaneous remission is rare. Sensory stimulation of
The symptomatic intracranial hypertension is
generally self-limited over several months. Even though the
papilledema may disappear, CSF pressure remains
elePain
vated
for years
and recurrent
symptomatic
episodes
Table 24.
Disorders
associated
with intracranial
occur
in 10%. Differentiating idiopathic pseudotumor
hypertension.
cerebri from intracerebral mass lesions and from the
disorders listed in Table 24 is critical; evaluation
Intracranial venous drainage obstruction (eg, venous
must
sinus
include
MRI or
CT trauma,
brain scanning
and lumbar puncthrombosis,
head
polycythemia,
ture. Imaging studies may show small (slitlike) ventrithrombocytosis)
cles and demonstrate
anobesity,
empty sella
in 70%
of inEndocrine
dysfunction (eg,
withdrawal
from
steroid
stances. Dilation of the optic nerve sheath and
therapy; Addison
disease;
hypoparathyroidism)
attening
of the back
of the
globe are characteristic.
Vitamin
and drug therapy (eg, hypervitaminosis A and 13
Elcis
evation of intracranial pressure can be documented
Figure 28. Distribution of symptoms in trigeminal
byretinoic acid in children and adolescents; severe iron
neuralgia.
deciency anemia; tetracycline, minocycline, nalidixic acid)
Other (eg, chronic hypercapnia, severe right heart failure,
chronic meningitis, hypertensive encephalopathy)
Idiopathic
84 / CHAPTER 2
trigger zones about the cheek, nose, or mouth by virus in patients with a history of varicella infection. It
touch,
does not occur before age 50 and becomes
cold, wind, talking, or chewing can precipitate the increasingly
pain.
common with advancing age (70% in those over 70
Physical examination discloses no abnormalities. years), in immunocompromised patients, and in paRarely,
tients with certain malignant diseases (eg, leukemia,
similar pain may occur in multiple sclerosis or
lymphoma). Postherpetic neuralgia is characterized
brainstem
by
tumors, and these possibilities should thus be
constant, severe, stabbing or burning, dysesthetic
considered
pain
in young patients and in all patients who show neurothat may persist for months or years in a minority of
logic abnormalities on examination.
paIn idiopathic cases, CT scan and MRI fail to showtients, especially the elderly. Pain occurs in the same
any abnormality, and arteriography is similarly
dernormal.
matomal distribution as a previous bout of herpes
Any vascular structure compressing the nerve roots
zoster,
is
conforming to the distribution of the involved
generally too small to be seen by these means. nerve root, where residual scars may be present.
Remission of symptoms with carbamazepine, When
4001200 mg/d orally in three divided doses, occurs
the head is involved, the rst division of the
within 24 hours in a high percentage of cases. Rarely,
trigeminal
blood dyscrasia occurs as an adverse reaction to nerve is most commonly affected, so that pain is
carbausually
mazepine. The recent availability of oxcarbazepinelocalized to the forehead on one side (Figure 29).
(6001800 mg/d in two divided doses) appears
Careequally
ful testing of the painful area reveals decreased cutaeffective;
blood
dyscrasias
have
not
been
reported.
neous sensitivity to pinprick. The other major
Patients with glossopharyngeal neuralgia, an
Incomplicauncommon
travenous
administration
of
phenytoin,
250
mg,
will
tion of trigeminal herpes is decreased corneal
pain
syndrome, present with
either a paroxysmal pain
GLOSSOPHARYNGEAL
NEURALGIA
abort
an
acute
attack,
and
phenytoin,
200400
mg/d
sensation
that is identical in quality to that of trigeminal
orally,
may be effective alone or in combination with
with impaired blink reex, which can lead to corneal
neuralgia,
carbamazepine
if
a
second
drug
is
necessary.
or a continuous burning or aching discomfort. The abrasion, scarring, and ultimate loss of vision.
LamotrigThe intensity and duration of the cutaneous erupScars
pain
ine
400
mg/d
or
baclofen
10
mg
three
times
daily
tion
is localized to the oropharynx, the tonsillar pillars, the and the acute pain of herpes zoster are reduced
20
mgoffour
daily
hasauditory
been used
in refractory
base
the times
tongue,
or the
meatus.
The by 7
cases.
Posterior
fossa
microvascular
decompressive
to 10 days of treatment with acyclovir (800 mg 5
trigger
Pain and
surtimes
hypesthesia
areas are usually around the tonsillar pillars, so that
gery
has been
in drug-resistant
daily), famcicloviror, or valacyclovir, but this
symptoms
are used
initiated
by swallowingcases.
or by talking.
Paroxysms of pain can occur many times daily andtreatment
has not been shown to lessen the likelihood of
may
be accompanied by syncopal episodes caused by postherpetic neuralgia. Corticosteroids (60 mg/d prednisone,
transient
orally for 2 weeks, with rapid tapering) taken during
bradyarrhythmias. Men are affected more often than
the
women, and symptoms begin at a somewhat younger
acute herpetic eruption also reduce the incidence of
age
than in trigeminal neuralgia. The diagnosis is
established
by the history and by reproducing pain through
stimulation of the trigger zones (usually about the tonsillar
regions). Examination reveals no abnormal neurologic
signs.
Application NEURALGIA
of local anesthetics to the trigger
POSTHERPETIC
area
Herpes
zostera
vesicular
skin
eruption in
may block
the pain
response.
Carbamazepine
or
Figure 29. Distribution of symptoms and signs in
dermatomal
phenydistribution,
accompanied
and
followed
by
local
pain
toin therapy (as described above for trigeminal postherpetic neuralgia.
and
tendernessis due to reactivation of varicellaneuralgia)
zoster
usually produces dramatic relief; microvascular
decompression has been used.

acute herpetic pain, but have an uncertain effect on
MIGRAINE
postherpetic pain. Once the postherpetic pain
Migraine is manifested by headache that is usually
syndrome
is established, the most useful treatment has beenunilateral and frequently pulsatile in quality; it is often
with tricyclic antidepressants such as amitriptyline,
as25150 mg/d orally, which are thought to act directly
sociated with nausea, vomiting, photophobia, phonoon central nervous system pain-integration pathways
phobia, and lassitude. Visual or other neurologic
(rather than via an antidepressant effect);
auras
amitriptyline
may be better tolerated. Tricyclic antidepressant occur in about 10% of patients. Two-thirds to threefourths of cases of migraine occur in women; the
drugs
onset
may be more effective when combined with a
is early in lifeapproximately 25% beginning during
phenoththe rst decade,
55% by 20 years of age, and more
Genetics
of Migraine
iazine, as in the commercially available preparation
than
TriThe
of migraine
within families
has long
90%aggregation
before age 40.
A family history
of migraine
is
avil. Gabapentin (18003600 mg/d) has shown some
been
recognized,
although
consistent
mendelian
patpresent
in
most
cases.
effect. Carbamazepine and phenytoin in
terns of inheritance have not been found among the
anticonvulsant
collective group of familial migraineurs. Presumably
doses also have been used. Postherpetic neuralgiathis reects a variety of inheritance patterns, variable
subpenetrance, and possibly multiple genes interacting
sides within 612 months in many patients but in with environmental factors in the multigenic/multifac50%
torial pattern characteristic of complex diseases. Conof those over 70 years the pain persists. Lidocaine-cordance rates in monozygotic twins of only 2852%
priloattest to the genetic component, but also predict a
HYPERTENSION
caine 2.5% cream, or lidocaine 5% gel or cutaneous
sigChronic
hypertension
is often
invoked
as a
patch, is
effective
topical therapy.
Topical
application
nicant environmental contribution.
cause of headache, but evidence to support
of
A rare subtype of migraine with aura, familial hemisuch
capsaicin cream (eg, Zostrix 0.025%), which depletes
plegic migraine, has a straightforward autosomal
a connection
is sparse.
In contrast,sensory
headache
pain-mediating
peptides
from peripheral
neudomiis
rons, also can be helpful but is poorly tolerated. Innant, highly penetrant inheritance pattern indicative
a
well-established complication of paroxysmal
othof
hypertenerwise intractable cases, weekly intrathecal
a
strong genetic
component. and
Three
genetic loci
for faIntracranial
vasoconstriction
extracranial
vasodision
such as seen in patients with
administramilial
hemiplegic
migraine
have
been
identied:
latation have long been held to be the respectiveone
pheochromocytoma
tion of methylprednisolone may reduce pain.
on
or those ingesting tyramine-rich foods while beingcauses
chromosome
19p13
(associated
missenseThis
mutaof the aura and
headache
phaseswith
of migraine.
treated with monoamine oxidase inhibitors. In
tions
in
a
brain-expressed,
voltage-gated
P/Q
calcium
Pathogenesis
thepheochromocytoma, headache attacks are brief. They
channel
gene)
and two
neighboring
lociofon chromoory received
support
from
the efcacy
last less than 15 minutes in one-half of patients and
some 1q.
vasoconstricare
ATYPICAL FACIAL PAIN
characteristically associated with perspiration andtive ergot alkaloids (eg, ergotamine) in aborting the
acute migraine attack and vasodilators such as amyl
Constant,
boring, mainly unilateral lower facial pain
tachyfor
cardia. The headache is usually bilateral and may nibe
trite in abolishing the migraine aura. More recent
which no cause can be found is referred to as atypical
prefacipitated by urination if the bladder is involved. studies of regional cerebral blood ow during migraine atcial pain. Unlike trigeminal neuralgia, it is not
tacks have demonstrated a reduction in regional ow,
conned
which begins in the occipital region, during the aura
to the trigeminal nerve distribution and is not
phase. The spreading depression in cerebral blood
paroxysmal. This idiopathic disorder must be distinguishedow, however, proceeds according to
cytoarchitectural
from similar pain syndromes related to
patterns in the cerebral cortex and does not reect
nasopharyngeal
carcinoma, intracranial extension of squamous cellthe
distribution of major vascular territories (Figure 210).
carIn addition, the areas of decreased blood ow do not
cinoma of the face, or infection at the site of a tooth
correspond to the cortical areas responsible for the
exCHRONIC
HEADACHES
partraction. Treatment
is with amitriptyline, 20250 mg/d
orally, alone or in combination with phenelzine, ticular aura, and regional cerebral blood ow may remain depressed after focal neurologic symptoms
3075 mg/d orally. Dilantin can be an effective
have
alternaresolved and headache has begun (Figure 211).
tive, especially if a tricyclic is inappropriate.
Later
86 / CHAPTER 2
tion in the brainstem. Brainstem stimulation in the
periaqueductal gray and dorsal raphe nucleus produces
migraine-like headache in humans.
Serotonergic neurons ramify extensively
throughout
the brain, and many effective antimigraine drugs act
as
Occipital
antagonists or partial agonists at central serotonin repole
ceptors. Serotonin in platelets decreases and urinary
serotonin increases during the acute phase of a migraine attack. Depletion of serotonin by reserpine
may
A. MIGRAINE WITH AURA (CLASSIC MIGRAINE)
precipitate
migraine.
The headache
andby
other
Classic migraine
headache
is preceded
transient
manifesneutations
of migraine mayaura.
thus The
reect
a disorder
rologic symptomsthe
most
commonof censerotonergic
neurotransmission.
A
link
between
Figure 210. Direction of spread (arrows) and maxi- tral
auras
initiation
and
trigeminovascular-mediated
mal extent (colored region) of depressed cerebral bloodneuronal
are visual alterations, particularly hemianopic eld
pain
ow (CBF) in migraine with and without aura.These
demay be calcitonin gene-related peptide (CGRP),
processes may be initiated by contralateral brainstem a
fects
andFindings
scotomas and scintillations that enlarge and
Clinical
structures as increases in brainstem CBF during migraine
potent
vasodilator
present
increased
spread
peripherally
(Figure in
212).
A throbbing unilatpersist after headache treatment with sumatriptan.
concentrations
eral headache ensues (Figure 213) with or following
in
venous
blood during
migraine
and cluster
these
prodromal
features.
The frequency
of headache
headache,
varies, but more than 50% of patients experience no
and
decreased
levels
after
theThe
administration
moreatthan
one attack
per
week.
duration of of
in the headache phase, blood ow increases to parts
seroepisodes is greater than 2 hours and less than 1 day
of
tonin
receptor agonists such as sumatriptan.
in
the cortex (cingulate, auditory, and visual association
most patients. Remissions are common during the
areas) and the contralateral brainstem (serotonergic
secdorsal raphe nucleus and adrenergic nucleus
ond and third trimesters of pregnancy and after
ceruleus);
menopause. Especially in the elderly, prodromal
treatment with effective agents (sumatriptan, ergotasympmine) attenuates the cortical but not brainstem
toms may occur without headache (migraine equivachanges. These data imply that cerebral blood ow
lents). Although hemicranial pain is a hallmark of
changes and headache generation in migraine may
clasbe
sic migraine, headaches can also be bilateral.
secondary to a primary disturbance in neuronal funcBilateral
Aura
Headache
headache, therefore, does not exclude the diagnosis
of
migraine, nor does an occipital locationa
characterisCerebral
Increased
blood flow
tic commonly attributed to tension headaches. During
the headache, prominent associated symptoms
include
Normal
nausea, vomiting, photophobia, phonophobia,
irritability, osmophobia, and lassitude. Uncommonly, miDecreased
graines are associated with frank neurologic decits
that
Time
accompany, or persist beyond, resolution of the pain
phase. These may include hemiparesis, hemisensory
Figure 211. Time course of changes in cerebral
loss, speech dysfunction, or visual disturbance. Vasoblood ow in migraine with aura. (Adaptedfrom
motor and autonomic symptoms are frequent; lightOlesenJetal:Timingandtopographyof
cerebralbloodflow,aura,andheadachedur headedness, vertigo, ataxia, or altered consciousness
may represent vertebrobasilar ischemia. All these
ingmigraineattacks.AnnNeurol
phe1990;28:791798.)
nomena may be distinguished from stroke both by
their gradual onset (migrainous march) and spontaneous resolution. Stroke may very exceptionally occur
as a consquence of migraine alone.
Central sulcus
15
30
Time (min)
Figure 212. Successive maps of scintillating scotoma to show the evolution of fortication gures and
associated
scotoma in a patient with classic migraine. As the fortication moves laterally, a region of transient
blindness
remains.
B. MIGRAINE WITHOUT AURA (COMMON MIGRAINE)

muscle contraction can compound the symptoms.
The common migraine headache lacks the classic Scalp tenderness is often present during the episode.
aura,
Vomiting may occasionally terminate the headache.
is usually bilateral and periorbital, and is seen more A useful bedside test for both common and classic
fremigraine is reducing headache severity by
quently in clinical practice. The pain may be
compressing
described
the ipsilateral carotid or supercial temporal artery.
as throbbing. As the pain persists, associated cervical
Precipitating Factors
Migraine attacks can be precipitated by certain foods
(tyramine-containing cheeses; meat, such as hot
dogs or
Pain
bacon, with nitrite preservatives; chocolate
containing
phenylethylamine but not chocolate alone) and by
food
additives such as monosodium glutamate, a
commonly
used
avor enhancer. Fasting, emotion, menses,
Treatment
drugs (esAcute
migraine
attacks mayagents
respond
simple analpecially
oral contraceptive
andtovasodilators
gesics
(eg,
aspirin,
acetaminophen,
naprosyn).
If not,
such as
they
usually respond
to ergot
preparations
or to the
nitroglycerin),
and bright
lights
may also trigger
5attacks.
hydroxytryptamine (5-HT) agonist sumatriptan.
These drugs (Table 25A) must be taken immediately at the onset of symptoms to be
maximally effective. Rapidly absorbed forms (eg,
parenteral) are superior to oral or sublingual preparations. In severe cases, subcutaneous, nasal,
intramuscuFigure 213. Distribution of pain in migraine. Hemi- lar, or intravenous administration is used. Unfortucranial pain (the pattern shown) is most common, but nately, nausea, which is a prominent feature of
the pain can also be holocephalic, bifrontal, or unilateralmigraine, is also a common side effect of some drugs
frontal in distribution or, less commonly, localized to the(particularly ergot alkaloids) so that concomitant
occiput or the vertex of the skull.
administration of an antiemetic (eg, metoclopramide,
10 mg subcutaneously or intravenously) may be
necessary. Ergot alkaloids and 5-HT agonists are potent
vasoconstrictors and are contraindicated in patients
88 / CHAPTER 2
Table 25. Drug treatment of migraine headache.
Drug
A. Acute Treatment
Simple analgesics
Aspirin
Naproxen sodium
Ibuprofen
Acetaminophen
Route1
PO
PO
PO
PO
Strength
Recommended Dose
Comments
325 mg
6501300 mg
250, 375, 500 mg 375750 mg
300, 400, 600, 800 mg
400800 mg
325 mg
6501300 mg
May cause gastric pain or bleeding and

rebound headache if used frequently
Ergot preparations
Ergotamine/caffeine PO
(Cafergot)
1/100 mg
26 tablets; max.
10 per week
May cause nausea and vomiting;

contraindicated by pregnancy or
coronary or peripheral vascular disease
PR
2/100 mg
1 42
Dihydroergotamine IM, SC, 1 mg/mL

IV
NS
4 mg/1 mL
(2 mg/treatment)
Narcotic analgesics
Codeine/aspirin
Codeine/
acetaminophen
Meperidine
Butorphanol
suppositories;
max. 5 per week
12 mg IM or SC;Use dihydroergotamine with
0.751.25 mg IVmetoclopramide (see below)
1 spray to each nostril
repeated in 15 minutes
PO
PO
15, 30, 60/325 mg 30120 mg codeine

7.5, 15, 30, 60/300 mg
30120 mg codeine
PO, IM
NS
50, 100 mg
10 mg/mL
(1 mg/spray)
50200 mg
1 spray every
34 hours as needed
5, 20 mg/spray
25, 50, 100 mg
6 mg
5, 10 mg
2.5, 5 mg
1, 2.5 mg
6.25, 12.5 mg
2.5 mg
20, 40 mg
40 mg/24 hours
200 mg/24 hours
12 mg
30 mg/24 hours
10 mg/24 hours
5 mg/24 hours
25 mg/24 hours
7.5 mg/24 hours
80 mg/24 hours
5-HT agonists
Sumatriptan (Imitrex)
NS
PO
SC
Rizatriptan (Maxalt) PO
Zolmitriptan (Zomig)PO
PO
Naratriptan (Amerge)
Almotriptan (Axert) PO
Frovatriptan (Frova) PO
Eletriptan (Relpax) PO
Other agents
Isometheptene/PO65/100/325 mg
dichloralphenazone/
acetaminophen
(Midrin)
Caffeine/butalbital/PO40/50/325 mg
aspirin (Fiorinal)
ProchlorperazinePR, IM, IV 2.5/10/10 mg
B. Prophylactic Treatment
Antiinammatory agents
AspirinPO
Naproxen sodiumPO
325 mg
275, 550 mg
10% incidence nausea, vomiting;

contraindicated by pregnancy or
coronary or peripheral vascular disease,
and with monoamine oxidase inhibitors
25 capsules
12 tablets or
capsules
2.510 mg
650 mg bid
500825 mg bid
Can cause hypotension and druginduced dystonia
May cause gastric pain or bleeding

(continued)

Table 25. Drug treatment of migraine headache. (continued)
Drug
Route1
Tricyclic antidepressants
Amitriptyline2PO
Nortriptyline
Protriptyline
Doxepin
PO
PO
PO
Receptor antagonists
PropranololPO
Nadolol
Atenolol
Timolol
Metoprolol
PO
(long
acting)
PO
PO
PO
PO
Recommended Dose
Comments
10, 25, 50, 75, 100, 10175 mg hs

150 mg
10, 25, 50, 75 mg 10150 mg hs
5, 10 mg
540 mg qhs
10, 25, 30, 75, 100, 10150 mg hs
150 mg
May cause dry mouth, urinary retention,

and sedation; contraindicated in
glaucoma or prostatism
10, 20, 40, 60, 80, 20160 mg bid

90 mg
60, 80, 120, 160 mg60320 mg qd
Listed in descending order of efcacy;

symptomatic bradycardia may occur at
high doses; contraindicated in asthma
and congestive heart failure; not to be
used with calcium blockers
40,
50,
10,
50,
80, 120, 160 mg40240 mg qd

100 mg
50200 mg bid
20 mg
1030 mg bid
100 mg
50200 mg qd
Ergot alkaloids
Methergine
PO
0.2 mg
0.20.4 mg tid
Occurrence of retroperitoneal brosis

with urethral obstruction and mediastinal brosis, although uncommon, should
be monitored with creatinine, ultrasonography, or intravenous urograms,
and chest x-rays every 6 months; a drug
holiday every 6 months is prudent
Cyproheptadine
PO
4 mg
48 mg tid
Drowsiness common early in treatment
Anticonvulsants
Phenytoin
Valproic acid
Topiramate
Gabapentin
PO
PO
PO
PO
100 mg
200400 mg qd
250, 500 mg
2501000 mg bid
15, 25, 100, 200 mg50100 mg qd
100, 300, 400, 600, 9002400 mg qd
800 mg
Calcium channel antagonists

VerapamilPO
PO (long
acting)
NicardipinePO
FlunarizinePO
C. Other Agents
Prochlorperazine
Hydroxyzine
Metoclopramide
Strength
40, 80, 120 mg

240 mg
80160 mg tid
240 mg qd-bid
20 mg
5, 10 mg
2040 mg tid
515 mg/d
PO, IM, IV 2.510 mg

IM25100 mg
PO, IV, SC 10 mg
Contraindicated by severe left ventricular dysfunction, hypotension, sick sinus

syndrome without articial pacemaker,
or second- or third-degree AV nodal
block; constipation is most common
side effect; not for use with

Adjunct to treatment; improves enteric

drug absorption and reduces nausea;
dystonia and akathisia may occur and
respond to IV benadryl
PO, oral; SL, sublingual; PR, rectal; IM, intramuscular; IV, intravenous; SC, subcutaneous; NS, nasal spray; bid, twice
daily; hs, at
bedtime; qd, every day.
2 Other tricyclic agents such as imipramine and desipramine may also be used, are available in similar strengths, and are
prescribed in similar doses.
with signicant hypertension or cardiac disease.

Established migraine headaches may respond to dihydroergotamine, triptans, or narcotic analgesics (eg,
90 / CHAPTER 2
meperidine, 100 mg intramuscularly).
A common, frequently unsuspected, cause of inFive classes of drugs have prophylactic effects in
tractable headache is overuse of analgesics. The
mipatient,
graine: beta blockers, tricyclic antidepressants,
in futile attempts at relief, takes increasing amounts
anticonof
vulsants, calcium channel blockers, and ergot
medications (both prescription and over-the-counter
alkaloids
drugs). When the high blood levels drop, even
(Table 25B). Prophylactic treatment is indicated for
slightly,
patients who have frequent headaches (more than
the headache rebounds; the result is daily, virtually
one
conper week), acute attacks that are difcult to manage,
stant,
headache,
whichheadache
may be syndrome
Clusteratypical
headache
is a common
or
superimposed
seen much more frequently in men than in women.
those for whom the ergot alkaloids or triptans used
on
an underlying
pattern. Caffeine-containCluster
headachesmigraine
characteristically
begin at a later
for
ing
ageanalgesics are particularly responsible. The
acute treatment are poorly tolerated or
patient
than does migraine, with a mean age at onset of 25
contraindicated.
should be abruptly withdrawn from all such medicaThree structurally unrelated agentspropranolol, years. There is rarely a family history of such
tions and caffeine. After a few weeks of drug withamitriptyline, and valproic acidare the mainstaysheadaches.
of
drawal
symptoms
the underlying,
less
severe,
The syndrome
presents
as clustersusually
of brief,
very
CLUSTER
HEADACHE
therapy. Each is effective in a substantial fraction of
headache
pattern
will
reveal
itself
and
can
be
more
severe,
paapunilateral, constant nonthrobbing headaches that last
tients, and patients refractory to one agent may repropriately
treated. to
Headaches
withdrawal
from a few minutes
less than during
2 hours.
Unlike mi-can
spond to another. The initial choice of medication is
be
managed
with
oral
triptans
or
parenteral
headaches, cluster headaches are always
usually inuenced by consideration of clinical side graine
efdihydroerunilatfects and the patients other medical conditions (eg,
gotamine
if needed.
eral, and usually
recur on the same side in any given
hypatient.
The
headaches
commonly occur at night,
pertension, asthma). Propranolol, imipramine, and
awakening
the
patient
from
sleep, and recur daily,
amitriptyline may be sedating, especially at the onset
often
of
at nearly the same time of day, for a cluster period of
treatment. The
properweeks to months. Between clusters, the patient may
ties of propranolol often preclude its use in patients
be
with congestive heart failure, asthma, or insulin-dependent diabetes. It may also be associated with free from headaches for months or years. Functional
MRI imaging during attacks has shown activation of
depresthe ipsilateral hypothalamic gray.
sion, hypotension, exercise intolerance, and
The headache may begin as a burning sensation
impotence.
over
The anticholinergic actions of amitriptyline may comthe lateral aspect of the nose or as a pressure behind
plicate glaucoma and prostatism. Valproic acid should
the
be introduced gradually as nausea can be a problem;
eye (Figure 214). Ipsilateral conjunctival injection,
it
is also particularly contraindicated in pregnancy. lacrimation, nasal stufness, and Horner syndrome
Calcium channel antagonists such as verapamil are
or
nicardipine are also efcacious in the prophylactic commonly associated with the attack (Figure 215).
Episodes are often precipitated by the use of alcohol
treatment of migraine. Drugs available in other counor
tries or approved in the United States only for other
vasodilating drugs, especially during a cluster siege.
inAt the onset of a headache cluster, treatment indications include nimodipine and unarizine;
volves
measures both to abort the acute attack and
however,
to
both common and classic migraine respond to these
drugs. As discussed above, potential side effects prevent subsequent ones. Acute relief of pain within
minutes may be achieved by sumatriptan (Table 2
should
5A),
be taken into account in the choice of therapy. Vera100% oxygen (810 L/min for 1015 minutes), or dipamil, which has pronounced effects on cardiac and
gastrointestinal calcium channels, may exacerbatehydroergotamine (Table 25A).
Several drugs used in the treatment of migraine
atri(see
oventricular, nodal heart block and congestive heart
Table 25), including 5-HT agonists, ergotamine, diANALGESIC
WITHDRAWAL
HEADACHE
failure and frequently
causes constipation.
hydroergotamine, methysergide, and calcium channel
Nimodipine,
antagonists are also useful for preventing recurrent
which is more selective for vascular smooth muscle,
symptoms during an active bout of cluster headache.
is
The most widely used is verapamil sustained-release
associated with a higher incidence of headache, light(240480 mg/d). Ergotamine rectal suppositories or

and should be maintained below 1.2 meq/L to reduce
the likelihood of adverse effects (nausea, diarrhea,
polyuria, renal failure, hypothyroidism, tremor,
dysarthria, ataxia, myoclonus, and seizures). Chronic
rather than episodic cluster headaches may respond
dramatically to indomethacin, 25 mg three times
Pain
daily.
A bilateral variant, hypnic headache, lacking the
Ptosis, miosis
autonomic components, occurs in the elderly. It is
Tearing
reponsive
TENSION-TYPE HEADACHE
to lithium.
Tension headache is the term used to describe
Nasal stuffiness
and discharge
chronic
headaches of inapparent cause that lack features
characteristic of migraine or cluster headache. The
underlying
pathophysiologic mechanism is unknown, and tension
is unlikely to be primarily responsible. Contraction of
neck and scalp muscles, which has also been
proposed
as the cause, is probably a secondary phenomenon.
In
its classic form (Figure 216), tension headache is a
cluster headache.
chronic disorder that begins after age 20. It is characterized by frequent (often daily) attacks of nonthrobbing, bilateral occipital head pain that is not
subcutaneous dihydroergotamine at bedtime may be
associated
eswith nausea, vomiting, or prodromal visual disturpecially helpful for nocturnal headaches. Dramatic
bance. The pain is sometimes likened to a tight band
imaround the head. Women are more commonly
provement can be seen with administration of predaffected
nisone at the beginning of a cluster cycle: 4080
than men. Although tension headache and migraine
mg/d
have been traditionally considered distinct disorders,
orally for 1 week, discontinued by tapering the dose Pain
many patients have headaches that exhibit features
over the following week. Pain may resolve within
of
hours, and most patients who respond do so within 2
days. Alternatively, lithium carbonate or lithium
citrate
syrup, 300 mg orally one to three times daily, is
highly
effective in many cases. Serum lithium levels should
be
measured at weekly intervals for the rst several
weeks
Pain and
spasm
Figure 215. Right ptosis during acute cluster
headache.
tension headache.
92 / CHAPTER 2
both. Thus, some patients who are classied as ammation in the ethmoidal or sphenoidal sinuses
having
protension headaches experience throbbing headaches,
duces a deep midline pain behind the nose. Sinusitis
unilateral head pain, or vomiting with attacks. In conpain is increased by bending forward and by
sequence, it may be more accurate to view tension
coughing
headache and migraine as representing opposite or sneezing. Tenderness and accentuation of pain on
poles
percussion over the frontal or maxillary area are
of a single clinical spectrum.
present
Drugs used in the treatment of tension headache
on examination.
inSinusitis is treated with vasoconstrictor nose drops
clude many of the same agents used for migraine (eg, phenylephrine, 0.25%, instilled every 23 hours),
(see
antihistamines, and antibiotics. In refractory cases, siTable 25). Acute attacks may respond to aspirin, nus drainage may be necessary.
other
Patients who complain of chronic sinus headache
nonsteroidal antiinammatory drugs, acetaminophen,
rarely have recurrent inammation of the sinuses;
ergotamine, or dihydroergotamine. For prophylactic
they
DENTAL DISEASE
treatment, amitriptyline or imipramine are often are much more likely to have migraine or tension
Temporomandibular
joint dysfunction is a poorly deeffecheadaches.
ned
syndrome
that
is characterized by preauricular
tive, and propranolol is useful in some cases.
faSelective
cial pain, limitation of jaw movement, tenderness of
serotonin reuptake inhibitors (eg, sertraline or uoxethe muscles of mastication, and clicking of the jaw
tine) are not useful. Although many patients respond
ICE
PICK
PAIN
with movement. Symptoms are often associated with
to
malocclusion, bruxism, or clenching of the teeth, and
benzodiazepines
as pains
diazepam,
530
mg/d
orally,
Very
brief, sharp, such
severe
located
in the
scalp
may result from spasm of the masticatory muscles.
or
outSome patients benet from local application of heat,
chlordiazepoxide,
1075
mg/d orally,
drugs
side
of the trigeminal
distribution
are these
named
by their
jaw exercises, nocturnal use of a bite guard, or nonshould characteristic as ice pick pains. They may
dening
steroidal antiinammatory drugs.
be used sparingly because of their addictive
potential.
single or repetitive or occur in clusters, either at a Infected tooth extraction sites can also give rise to
pain, which is characteristically constant, unilateral,
Psychotherapy, physical therapy, and relaxation techsingle
niquesorcan
provideover
additional
benet
selected
point
scattered
the scalp.
The in
pains
are and aching or burning in character. Although radiologic studies may be normal, injection of a local anescases.
electriclike jabs maximal in intensity in less than a secondthetic at the extraction site relieves the symptoms.
Treatment is with jaw bone curettage and antibiotics.
and
then resolving rapidly; they are severe enough to REFERENCES
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Aurora SK, Welch KM: Migraine: imaging the aura. Curr Opin
involuntary inching. They are more common in mi- Neurol 2000;13:273276.
Brew BJ, Miller J: Human immunodeciency virus-related
graine and cluster patients, but occur in some
headache-free individuals as well. Patients frequentlyheadache. Neurology 1993;43:10981100.
CERVICAL
SPINE DISEASE
Broadley SA, Fuller GN: Lumbar puncture neednt be a headache.
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bouts of pain
are repetitive,
treatment
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degenerative
disease
processes
involvingCaselli RJ, Hunder GG: Giant cell (temporal) arteritis. Neurol
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may
the
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LM: Brain tumors. N Engl J Med 2001;344:114123.
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indicated;
the
syndrome
responds
to
indomethacin
upper neck can produce pain in the occiput or
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referred
arachnoid hemorrhage. N Engl J Med 2000;342:2936.
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abnorFriedman DI et al: Diagnostic criteria for idiopathic intracranial
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ipsiGoadsby PJ et al: Migrainecurrent understanding and treatment.
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musClin North Am 1997;81:195219.
cle spasm may occur, however.
SINUSITIS
Acute pain of cervical origin is treated with
immobiAcute
sinusitis can produce pain and tenderness
lization
local- of the neck (eg, using a soft collar) and analgesics
antiinammatory
drugs.
ized to or
the
affected frontal or
maxillary sinus areas.
In-

Katusic S et al: Incidence and clinical features of trigeminal neuralRaskin NH: Chemical headaches. Annu Rev Med 1981;32:6371.
gia, Rochester, Minnesota, 19451984. Ann Neurol
Raskin NH: Headache, 2nd ed. Churchill Livingstone, 1988.
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Pringsheim T: Cluster headache: evidence for a disorder of circaKelly AM: Migraine: pharmacotherapy in the emergency depart- dian rhythm and hypothalamic function. Can J Neurol Sci
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sopharyngeal) neuralgia: a study of 217 cases. Arch Neurol
Lance JW, Goadsby PJ: Mechanism and Management of Headache,1981;38:201205.
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Schwartz BS et al: Epidemiology of tension-type headache. JAMA
May A, Goadsby PJ: The trigeminovascular system in humans:
1998;279:381383.
pathophysiologic implications for primary headache syn- Solomon S, Cappa KG: The headache of temporal arteritis. J Am
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Cereb Blood Flow Metab 1999;19:115127.
Tomsak RL: Ophthalmologic aspects of headache. Med Clin North
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Am 1991;75:693706.
that
Weiller C et al: Brainstem activation in spontaneous human mistart in elderly people. J Neurol Neurosurg Psychiatry
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Engl J Med 1994;331:16891692.
Disorders of
Equilibrium
CONTENTS
Approach to diagnosis, 95
History, 101
General physical examination, 102
Neurologic examination, 102
Investigative studies, 106
Peripheral vestibular
disorders, 107
Benign positional vertigo,
107
Mnire disease, 108
Acute peripheral vestibulopathy, 109
Otosclerosis, 110
Head trauma, 110
Cerebellopontine angle
tumor, 110
Toxic vestibulopathies, 111
Acoustic neuropathy, 112

Cerebellar & central vestibular
disorders, 112
Acute disorders, 113
Drug intoxication, 113
Wernicke encephalopathy,
113
Vertebrobasilar ischemia
& infarction, 113
Cerebellar hemorrhage,
115
Inammatory disorders,
115
Chronic disorders, 116
Multiple sclerosis, 116
Alcoholic cerebellar
degeneration, 116
Phenytoin-induced cerebellar degeneration,

117
Hypothyroidism, 117
Paraneoplastic cerebellar
degeneration, 118
Autosomal dominant
spinocerebellar
ataxias, 118
Friedreich ataxia, 120
Ataxia-telangiectasia, 121
Wilson disease, 121
Creutzfeldt-Jakob disease,
121
Posterior fossa tumors,
122
Posterior fossa malformations, 123
Sensory ataxias, 124
KEY CONCEPTS
Disorders of equilibrium can be produced by disorders that affect vestibular pathways, the cerebellum, or sensory pathways in the spinal cord or
peripheral nerves.
Cerebellar hemorrhage and infarction produce

disorders of equilibrium that require urgent diagnosis, because surgical evacuation of the
hematoma or infarct can prevent death from
brainstem compression.
Disorders of equilibrium present with one or both

of two cardinal symptoms: vertigoan illusion of
bodily or environmental movement, or ataxia
incoordination of limbs or gait.
94
Copyright 2005, 2002 by The McGraw-Hill Companies, Inc. Click here for terms of use.
DISORDERS OF EQUILIBRIUM / 95
for briefer periods, and produces more distress than
vertigo of central origin. Nystagmus (rhythmic oscillaAPPROACH TO DIAGNOSIS
tion of the eyeballs) is always associated with
peripheral
Equilibrium is the ability to maintain orientation ofvertigo; it is usually unidirectional and never vertical
(see
the body and its parts in relation to external space.
It below). Peripheral lesions commonly produce additional symptoms of inner ear or acoustic nerve dysdepends on continuous visual, labyrinthine, and sofunction, ie, hearing loss and tinnitus.
matosensory (proprioceptive) input and its
2. Central vertigo may occur with or without nysintegration
tagmus; if nystagmus is present, it can be vertical,
in the brainstem and cerebellum.
uniDisorders of equilibrium result from diseases that
directional, or multidirectional and may differ in charaffect central or peripheral vestibular pathways, the
acter in the two eyes. (Vertical nystagmus is
cerebellum, or sensory pathways involved in propriooscillation
ception.
Such disorders usually present with one of two in a vertical plane; that produced by upgaze or
downgaze is not necessarily in the vertical plane.)
clini1.
ERTIGO
CencalVproblems:
vertigo or ataxia.
Vertigo is the illusion of movement of the body or the
tral lesions may produce intrinsic brainstem or
2.
ATAXIA
environment. It may be associated with other sympcerebelis incoordination
of movement
toms, such as impulsion (a sensation that the bodyAtaxia
is
lar signs,
such as motor or
or clumsiness
sensory decits,
hyperthat
is
not
the
result
of
muscular
weakness.
It is or
being hurled or pulled in space), oscillopsia (a visual
reexia, extensor plantar responses, dysarthria,
caused
illimb
by
vestibular, cerebellar, or sensory (proprioceptive)
lusion of moving back and forth), nausea, vomiting,
ataxia.
disor
orders. Ataxia can affect eye movement, speech (progait ataxia.
Distinction Between Vertigo
ducing dysarthria), individual limbs, the trunk, stance,
& Other Symptoms
or gait (Table 32).
Vestibular Ataxia
Vertigo must be distinguished from nonvertiginous

Vestibular ataxia can be produced by the same
dizziness, which includes sensations of light-headedcentral
ness, faintness, or giddiness not associated with an
and peripheral lesions that cause vertigo. Nystagmus
illuis
sion of movement. In contrast to vertigo, these
frequently present and is typically unilateral and most
sensations are produced by conditions that impair the pronounced on gaze away from the side of vestibular
involvement. Dysarthria does not occur.
brains
supply of blood, oxygen, or glucoseeg, excessive Vestibular ataxia is gravity dependent: Incoordination of limb movements cannot be demonstrated
vagal
when
stimulation, orthostatic hypotension, cardiac arrhyththe patient is
examined lying down but becomes
Cerebellar
Ataxia
mias, myocardial ischemia, hypoxia, or hypoDifferential Diagnosis
apparglycemiaand may culminate in loss of
Cerebellar
ataxia
is produced
of walk.
the
ent when the
patient
attemptsby
tolesions
stand or
consciousness
A.
ANATOMIC ORIGIN
cerebel(syncope;
seein
Chapter
8).
The
rst step
the differential
diagnosis of vertigo
is or its afferent or efferent connections in the cerelum
to localize the pathologic process in the peripheralbellar
or
peduncles, red nucleus, pons, or spinal cord
central vestibular pathways (Figure 31).
(FigPeripheral vestibular lesions affect the labyrinth ure
of 32). Because of the crossed connection between
the inner ear or the vestibular division of the acoustic
the frontal cerebral cortex and the cerebellum, unilat(VIII) nerve. Central lesions affect the brainstem eral frontal disease can also occasionally mimic a
vestibular nuclei or their connections. Rarely, vertigo
disoris
der of the contralateral cerebellar hemisphere. The
of cortical origin, occurring as a symptom associated
clinA.
YPOTONIA
with complex partial seizures.
icalHmanifestations
of cerebellar ataxia consist of
Cerebellar
ataxia
is rate,
commonly
associated
with
B. SYMPTOMS
irregularities
in the
rhythm,
amplitude,
and force
hypotoCertain characteristics of vertigo, including the presof voluntary movements.
nia, which results in defective posture maintenance.
ence of any associated abnormalities, can help
Limbs are easily displaced by a relatively small force
differentiate between peripheral and central causes (Tableand,
3 when shaken by the examiner, exhibit an
increased
1).
range of excursion. The range of arm swing during
1. Peripheral vertigo tends to be intermittent, lasts
96 / CHAPTER 3
Medial
rectus
Lateral
rectus
Oculomotor (III) nerve

Oculomotor (III) nucleus
Medial longitudinal fasciculus
Abducens
(VI) nerve
Fastigial
nucleus of
cerebellum
Abducens
(VI) nucleus
Inferior
cerebellar
pedicle
Flocculonodular
lobe of cerebellum
Vestibular
(VIII) nucleus
Vestibular
(VIII) nerve
Semicircular canals
Vestibulospinal
tracts
Figure 31. Peripheral and central vestibular pathways.The vestibular nerve terminates in the vestibular nucleus
of
the brainstem and in midline cerebellar structures that also project to the vestibular nucleus. From here,
bilateral
pathways in the medial longitudinal fasciculus ascend to the abducens and oculomotor nuclei and descend to
walking may be similarly increased. Tendon reexes
the
take on
a pendular quality, so that several oscillations
spinal
cord.
of
B. INCOORDINATION
the limb may occur after the reex is elicited,
In addition to hypotonia, cerebellar ataxia is
although
associated
neither the force nor the rate of the reex is
with incoordination of voluntary movements. Simple
increased.
movements are delayed in onset, and their rates of
When muscles are contracted against resistance that
acis
celeration and deceleration are decreased. The rate,
then removed, the antagonist muscle fails to check
rhythm, amplitude, and force of movements
the
uctuate,
movement and compensatory muscular relaxation
producing a jerky appearance. Because these
does
irregularinot ensue promptly. This results in rebound
ties are most pronounced during initiation and termimovement
nation of movement, their most obvious clinical maniof the limb.
D. ANATOMIC BASIS OF DISTRIBUTION OF CLINICAL SIGNS
Various anatomic regions of the cerebellum (Figure
33) are functionally distinct, corresponding to the somatotopic organization of their motor, sensory,
Peripheral
Central
visual,
Vertigo
Often intermittent; Often constant; and auditory connections (Figure 34).
severeusually less severe
1. Midline lesionsThe middle zone of the cerebellumthe vermis and occulonodular lobe and
Nystagmus
Always present; May be absent;
their
unidirectional, uni- or
never vertical
bidirectional, may associated subcortical (fastigial) nucleiis involved in
the control of axial functions, including eye movebe vertical
ments, head and trunk posture, stance, and gait. MidAssociated ndings
line cerebellar disease therefore results in a clinical
Hearing loss or Often present
Rarely present
syntinnitus
drome characterized by nystagmus and other
Intrinsic brainAbsent
Typically present disorders
stem signs
of ocular motility, oscillation of the head and trunk
(titubation), instability of stance, and gait ataxia
(Table
33). Selective involvement of the superior cerebellar
festations include terminal dysmetria, or overshoot
as commonly occurs in alcoholic cerebellar
when the limb is directed at a target, and terminalvermis,
indetention tremor as the limb approaches the target.
generation, produces exclusively or primarily ataxia
More
complex movements tend to become decomposedof
gait, as would be predicted from the somatotopic
into
a succession of individual movements rather than map
a
of the cerebellum (see Figure 34).
sin2. Hemispheric lesionsThe lateral zones of the
gle smooth motor act (asynergia). Movements that inC.
A
SSOCIATED OCULAR ABNORMALITIES
cerebellum
(cerebellar hemispheres) help to
volve rapid changes in direction or greater
Because
of
the
cerebellums
prominent
role
in
the
coordinate
physiologic
conmovements and maintain tone in the ipsilateral limbs.
complexity, such as walking, are most severely
trol
of
eye
movements,
ocular
abnormalities
are
a
fre- hemispheres also have a role in regulating ipsilatThe
affected.
quent consequence of cerebellar disease. These eral gaze. Disorders affecting one cerebellar
include
hemisphere
nystagmus and related ocular oscillations, gaze cause ipsilateral hemiataxia and hypotonia of the
pareses,
limbs
and defective saccadic and pursuit movements. as well as nystagmus and transient ipsilateral gaze
pareTable 32. Characteristics of vestibular, cerebellar,sis
and
sensory
ataxia.
(an
inability
to look voluntarily toward the affected
side). Cerebellar dysarthria may also occur with paramedian
lesions in the left cerebellar
hemisphere.
Vestibular
Cerebellar
Sensory
3. Diffuse diseaseMany cerebellar disorders
Vertigo
Present
May be present
Absentand degenerative conditypically toxic, metabolic,
tionsaffect
the
cerebellum
Nystagmus
Present
Often present
Absent diffusely. The clinical picture in such states combines the features of midline
Dysarthria
Absent
May be present
Absent
and
bilateral
hemisphere
disease.
Limb ataxia
Absent
Usually present
(one
limb, unilateral,
Present
(typically legs)
Table 31. Characteristics of central
and peripheral vertigo.
legs only, or all limbs)

Stance
May be able to stand with feetUnable to stand with feet together

Often able to stand with feet
together; typically worse with eyes and eyes either open or closed
together and eyes open but not
closed
with eyes closed (Romberg sign)
Vibratory and Normal

position sense
Normal
Impaired
Ankle reexes
Normal
Depressed or absent
Normal
98
Superior cerebellar peduncle
Middle cerebellar peduncle
Inferior cerebellar peduncle
Dorsal
thalamus
2
Red
nucleus
1, 8
3
Vestibular nucleus
Ascending limb
Descending limb
Decussation
26
Cuneate nucleus
Cerebral
peduncle
Trigeminal nucleus
Lateral reticular
nucleus
Inferior olivary
nucleus
Arcuate nucleus
4
Pontine
nuclei
Medial
reticular
nucleus
Nucleus dorsalis
of Clarke
Afferent tract
1 Ventral spinocerebellar
Efferent tracts
2 Cerebellothalamic
3 Cerebellorubral
4 Cerebelloreticular
Afferent tract
Corticopontocerebellar
Afferent tracts
1 Vestibulocerebellar
2 Cuneocerebellar
3 Nucleocerebellar
4 Reticulocerebellar
5 Olivocerebellar
6 Arcuatocerebellar
7 Dorsal spinocerebellar
Efferent tract
8 Cerebellovestibular
Figure 32. Cerebellar connections in the superior, middle, and inferior cerebellar peduncles.The peduncles are indicated by gray shading and the
areas
to which they project by blue shading.
and
from
A
Anterior
Posterior
Vermis
Hemisphere
Lingula
Anterior
lobe
Central lobule
Culmen
Declive
Folium vermis
Posterior
lobe
Tuber vermis
Pyramis
Uvula
Tonsil
Focculonodular
lobe
Nodulus
Figure 33. Anatomic divisions of the cerebellum in midsagittal view (A); unfolded (arrows) and viewed from
behind (B).
100 / CHAPTER 3
Anterior lobe
Posterior lobe
Hemisphere
Vermis
Figure 34. Functional organization of the cerebellum.The view is similar to that in Figure 33B but is of a monkey
rather than a human cerebellum.The three cerebellar homunculi represent areas to which proprioceptive and
tactile
stimuli project, and the stripes represent areas to which auditory and visual stimuli project.
tions of joint position and movement (kinesthesis)

originate in pacinian corpuscles and unencapsulated
Sensory ataxia results from disorders that affect the
nerve endings in joint capsules, ligaments, muscle,
proand
prioceptive pathways in peripheral sensory nerves,periosteum. Such sensations are transmitted via
senheavily
sory roots, posterior columns of the spinal cord, ormyelinated A bers of primary afferent neurons,
mewhich
dial lemnisci. Thalamic and parietal lobe lesions are
enter the dorsal horn of the spinal cord and ascend
rare causes of contralateral sensory hemiataxia. unTable 33. Clinical patterns of cerebellar ataxia.
Sensacrossed in the posterior columns (Figure 35). Proprio-
Sensory Ataxia
Pattern of Involvement
Midline
Superior vermis
Cerebellar hemisphere
Pancerebellar
Signs
Causes
Nystagmus, head and trunk titubation, gaitTumor, multiple sclerosis

ataxia
Gait ataxia
Wernicke encephalopathy, alcoholic cerebellar
degeneneration, tumor, multiple sclerosis
Nystagmus, ipsilateral gaze paresis,
Infarction, hemorrhage, tumor, multiple
dysarthria
sclerosis
(especially left hemisphere lesion), ipsilateral
hypotonia, ipsilateral limb ataxia, gait ataxia,
falling to side of lesion
Nystagmus, bilateral gaze paresis,
Drug intoxications, hypothyroidism, hereditary
dysarthria,
cerebellar degeneration, paraneoplastic
bilateral hypotonia, bilateral limb ataxia, gait
cerebellar degeneration,Wilson disease, infecataxia
tious and parainfectious encephalomyelitis,
Creutzfeldt-Jakob disease, multiple sclerosis

ceptive information from the legs is conveyed in the
Parietal cortex
medially located fasciculus gracilis, and information
from the arms is conveyed in the more laterally
situated
fasciculus cuneatus. These tracts synapse on secondorder sensory neurons in the nucleus gracilis and
nucleus
Ventral
cuneatus in the lower medulla. The second-order neuposterolateral
rons decussate as internal arcuate bers and ascendnucleus of
Mesencephalon
thalamus
in
the contralateral medial lemniscus. They terminate in
the ventral posterior nucleus of the thalamus, from
which third-order sensory neurons project to the pariPons
etal cortex.
Sensory ataxia from polyneuropathy or posterior
column lesions typically affects the gait and legs in
symmetric fashion; the arms are involved to a lesserMedial lemniscus
extent or spared entirely. Examination reveals impaired
Upper medulla
sensations of joint position and movement in the afHISTORY
fected limbs, and vibratory sense is also commonly Gracile nucleus
(leg)
disSymptoms & Signs
turbed. Vertigo, nystagmus, and dysarthria are
Cuneate nucleus
A.
VERTIGO
(arm)
characLower medulla
True
vertigoabsent.
must be distinguished from a lightteristically
headed
Cuneate fasciculus
or presyncopal sensation. Vertigo is typically
(arm)
described
as spinning, rotating, or moving, but when the
Cervical
Gracile fasciculus
spinal cord
descrip(leg)
tion is vague, the patient should be asked specically
if
Dorsal root
the symptom is associated with a sense of
Lumbar
ganglion cell
spinal cord
movement.
The circumstances under which symptoms occur may
also be diagnostically helpful. Vertigo is often brought
Figure 35. Pathway mediating proprioceptive sensaon by changes in head position. The occurrence oftion.
symptoms upon arising after prolonged recumbency
is
a common feature of orthostatic hypotension, and
of a companion for support. They thus nd that they
nonare much more unsteady in the dark and may experivertiginous dizziness related to pancerebral
ence particular difculty in descending stairs.
hypoperfusion may be immediately relieved by sitting or lying
Onset & Time Course
down. Such hypoperfusion states can lead to loss of
Establishing the time course of the disorder may sugconsciousness, which is rarely associated with true
B. ATAXIA
gest its cause. Sudden onset of disequilibrium occurs
verAtaxia associated with vertigo suggests a vestibular
with infarcts and hemorrhages in the brainstem or
tigo. If the problem is identied as vertigo, associated
disceresymptoms may help to localize the site of
order, whereas numbness or tingling in the legs is bellum (eg, lateral medullary syndrome, cerebellar
involvement.
comhemorrhage or infarction). Episodic disequilibrium of
Complaints of hearing loss or tinnitus strongly
mon in patients with sensory ataxia. Because proprioacute onset suggests transient ischemic attacks in
suggest
ceptive decits may, to some extent, be
the
a disorder of the peripheral vestibular apparatus
compensated
basilar artery distribution, benign positional vertigo,
(labyrinth or acoustic nerve). Dysarthria, dysphagia,
for by other sensory cues, patients with sensory or
diplopia, or focal weakness or sensory loss affecting
ataxia
Mnire disease. Disequilibrium from transient isthe
may report that their balance is improved by
chemic attacks is usually accompanied by cranial
face or limbs indicates the likelihood of a central
watching
nerve
(brainstem) lesion.
their feet when they walk or by using a cane or thedecits, neurologic signs in the limbs, or both.
arm
Mnire
102 / CHAPTER 3
disease is usually associated with progressive hearing
degenerations. Dementia with sensory ataxia
loss and tinnitus as well as vertigo.
suggests
Chronic, progressive disequilibrium evolving over
syphilitic taboparesis or vitamin B12 deciency.
weeks to months is most suggestive of a toxic or
Korsakoff amnestic syndrome and cerebellar ataxia
nutriare associated with chronic alcoholism.
tional disorder (eg, vitamin B12 or vitamin E
Stance & Gait
deciency,
nitrous oxide exposure). Evolution over months to Observation of stance and gait is helpful in
years is characteristic of an inherited spinocerebellar
distinguishdeMedical History
ing between cerebellar, vestibular, and sensory
generation.
ataxias.
The medical history should be scrutinized for
In any ataxic patient, the stance and gait are wideevidence
based
of diseases that affect the sensory pathways (vitamin
A.
STANCE
and
unsteady, often associated with reeling or
B12
The
ataxic patient asked to stand with the feet
lurching
deciency, syphilis) or cerebellum (hypothyroidism,
together
movements.
paraneoplastic syndromes, tumors), and drugs that
may show great reluctance or an inability to do so.
proWith persistent urging, the patient may gradually
duce disequilibrium by impairing vestibular or
move
cerebel-History
Family
the feet closer together but will leave some space belar function (ethanol, sedative drugs, phenytoin, tween them. Patients with sensory ataxia and some
A
hereditary degenerative
be the cause
aminoglycoside
antibiotics,disorder
quinine,may
salicylates).
with vestibular ataxia are, nevertheless, ultimately
of
able
chronic, progressive cerebellar ataxia. Such disorders
to stand with the feet together, compensating for the
inloss of one source of sensory input (proprioceptive or
clude spinocerebellar degenerations, Friedreich B. GAIT
labyrinthine)
with another
(visual).
Thisiscompensation
1. The gait seen
in cerebellar
ataxia
wide-based,
ataxia,
GENERAL PHYSICAL EXAMINATION
is
demonstrated
when
the
patient
closes
eyes,
often with a staggering quality that mightthe
suggest
ataxia-telangiectasia, and Wilson disease.
elimidrunkenness. Oscillation of the head or trunk (titubaVarious features of the general physical examination
nating
visual
cues. With
or vestibular
tion) may
be present.
If asensory
unilateral
cerebellar hemimay provide clues to the underlying disorder. Orthodisorders,
sphere lesion is responsible, there is a tendency to
static hypotension is associated with certain sensory
unsteadiness increases and may result in falling
disorders that produce ataxiaeg, tabes dorsalis, devi(Romberg
With
vestibular
lesion,
ate towardsign).
the side
ofathe
lesion when
thethe
patient
polyneuropathiesand with some cases of spinoceretendency
bellar degeneration. The skin may show oculocuta-attempts to walk in a straight line or circle or
is
to fall toward the side of the lesion. Patients with
marches
neous telangiectasia (ataxia-telangiectasia), or it may
cerebellar
ataxia
unable
to compensate
for their
in place with
eyesare
closed.
Tandem
(heel-to-toe)
gait,
be
decit
by
using
visual
input
and
are
unstable
on their
dry, with brittle hair (hypothyroidism) or have a which requires walking with an exaggerated narrow
feet
theimpaired.
eyes are open or closed.
base,whether
is always
lemon-yellow coloration (vitamin B12 deciency). Pigmented corneal (Kayser-Fleischer) rings are seen in 2. In sensory ataxia the gait is also wide-based and
tandem gait is poor. In addition, walking is typically
Wilson disease (see Chapter 7).
characterized by lifting the feet high off the ground
Skeletal abnormalities may be present. Kyphoscoliosis is typical in Friedreich ataxia; hypertrophic orand
hyperextensible joints are common in tabes dorsalis;slapping them down heavily (steppage gait) because
of
and
impaired proprioception. Stability may be
pes cavus is a feature of certain hereditary
dramatically
neuropathies.
improved by letting the patient use a cane or lightly
Abnormalities at the craniocervical junctions may be
rest
associated with Arnold-Chiari malformations or other
NEUROLOGIC
EXAMINATION
a hand on the examiners arm for support. If the
congenital anomalies that involve the posterior fossa.
patient
is made to walk in the dark or with eyes closed, gait
An acute confusional state with ataxia characterizes
is
ethanol or sedative drug intoxication and Wernickemuch more impaired.
en3. Gait ataxia may also be a manifestation of
cephalopathy.
converDementia with cerebellar ataxia is seen in Wilsonsion disorder (conversion disorder with motor
disease, Creutzfeldt-Jakob disease, hypothyroidism,
symptom
paraneoplastic syndromes, and some spinocerebellar
or decit) or malingering. Determining this can be
particularly difcult, since isolated gait ataxia without
ataxia

of individual limbs can also be produced by diseases
gaze away from the involved side. Central vestibular
that
disorders can cause unidirectional or bidirectional
affect the superior cerebellar vermis. The most
horihelpful
zontal nystagmus, vertical nystagmus, or gaze
observation in identifying factitious gait ataxia is that
paresis.
such patients often exhibit wildly reeling or lurching
Cerebellar lesions are associated with a wide range of
movements from which they are able to recover ocular abnormalities, including gaze pareses,
without
defective
falling.
In
fact,
recovery
of
balance
from
such
saccades or pursuits, nystagmus in any or all
Oculomotor (III), Trochlear (IV), Abducens
awkward
directions,
(VI), & Acoustic (VIII) Nerves
positions requires excellent equilibratory function. and ocular dysmetria (overshoot of visual targets
C.
HEARING
Abnormalities of ocular and vestibular nerve function
during
Preliminary
of the acoustic (VIII) nerve
are typically present with vestibular disease and saccadic eyeexamination
movements).
should
include
otoscopic
of the
auditory
often
2. Pendular nystagmus inspection
is usually the
result
of visual
canals
and
tympanic
membranes,
assessment
of
present with lesions of the cerebellum. (Examination
impairment that begins in infancy.
audiof
cranial nerves III, IV, and VI is discussed in more tory acuity in each ear, and Weber and Rinne tests
A.
OCULAR ALIGNMENT
perdetail
The
eyes
are
examined
in
the
primary
position
of
formed with a 256-Hz tuning fork.
in Chapter 4.)
gaze
1. In the Weber test, unilateral sensorineural hear(looking directly forward) to detect malalignment in
ing loss (from lesions of the cochlea or cochlear
the horizontal or vertical plane.
nerve)
B. NYSTAGMUS AND VOLUNTARY EYE MOVEMENTS
causes the patient to perceive the sound produced by
The patient is asked to turn the eyes in each of thea
carvibrating tuning fork placed at the vertex of the skull
dinal directions of gaze (left, up and left, down andas
left,
coming from the normal ear. With a conductive
right, up and right, down and right; see Chapter 4)(exterto
determine whether gaze paresis (impaired ability to
nal or middle ear) disorder, sound is localized to the
move the two eyes coordinately in any of the cardinal
abdirections of gaze) or gaze-evoked nystagmus is normal ear.
present.
2. The Rinne test may also distinguish between
Nystagmusan abnormal involuntary oscillation ofsenthe eyesis characterized in terms of the positions
of
sorineural
and conductive defects in the affected ear.
gaze in which it occurs, its amplitude, and the
D.
OSITIONAL TESTS
Air Pconduction
(tested by holding the vibrating tuning
direction
When
patients
vertigo
occurs
with a profork next
to theindicate
externalthat
auditory
canal)
normally
of its fast phase. Pendular nystagmus has the same
change
in
position,
the
Nylen-Brny
or
Dix-Hallpike
duces a louder sound than does bone conduction
vemaneuver
is used
to try
to reproduce
(tested by (Figure
placing 36)
the base
of the
tuning
fork overthe
locity in both directions of eye movement; jerk
precipitating
circumstance.
The
head,
turned
to the
the
nystagright,
is rapidly
30 degrees
below
horizontal
mastoid
bone). lowered
This pattern
also occurs
with
acoustic
mus is characterized by both fast (vestibular-induced)
while
gazebut
is maintained
right.of
This process
nerve the
lesions
is reversed to
in the case
and slow (cortical) phases. The direction of jerk is
repeated with the head and eyes turned rst to the
conductive
nystagleft
and then
straight
ahead. The eyes are observed
hearing
loss (Table
34).
mus is dened by the direction of the fast
for
component.
nystagmus, and the patient is asked to note the
Fast voluntary eye movements (saccades) are elicited
onset,
by
severity, and cessation of vertigo.
having
the
patient
rapidly
shift
gaze
from
one
target
Table 34. Assessment of hearing loss.
to
another placed in a different part of the visual eld.
Weber Test
Rinne Test
Slow voluntary eye movements (pursuits) are
assessed
Normal
Sound perceived as coming from midline Air conduction bone conduction
by having the patient track a slowly moving target
Air conduction bone conduction
Sensorineural
hearing loss Sound perceived as coming from normal ear
such
as
the examiners
nger. Sound perceived as coming from affected ear
Bone conduction air conduction on
Conductive
hearing loss
1. Peripheral vestibular disorders produce unidirecaffected side
tional horizontal jerk nystagmus that is maximal on
104 / CHAPTER 3
A
Figure 36. Test for positional vertigo and nystagmus.The patient is seated on a table with the head and
eyes
directed forward (A), and is then quickly lowered to a supine position with the head over the table edge, 45
degrees
below horizontal.The patients eyes are then observed for nystagmus, and the patient is asked to report any
vertigo.
The test is repeated with the patients head and eyes turned 45 degrees to the right (B), and again with the head
and
eyes turned 45 degrees to the left (not shown).
Positional nystagmus and vertigo are usually seconds between assumption of the position and the
associonset of vertigo and nystagmus, a tendency for the
ated with peripheral vestibular lesions and are most
reofsponse to remit spontaneously (fatigue) as the
ten a feature of benign positional vertigo. This is typiposition
cally characterized by severe distress, a latency ofis maintained, and attenuation of the response
several
(habitu-

Table 35. Characteristics of positional nystagmus.toward and the fast phase away from the irrigated
ear.
Warm water irrigation produces the opposite
Feature
Peripheral Lesion
Central Lesion
response.
Vertigo
Severe
Mild
2. In patients with unilateral labyrinthine, vestibular
nerve,
or vestibular nuclear dysfunction, irrigation of
Latency
240 seconds
No
the affected side fails to cause nystagmus or elicits
Fatigability
Yes
No
nystagmus
that is later
in onset or briefer in duration
Other Cranial
Nerves
Habituation
Yes
No
than
Papilledema
associated
with disequilibrium suggests
on the normal
side.
an
ation) as the offending position is repeatedly
intracranial mass lesion, usually in the posterior
assumed
fossa,
(Table 35). Positional vertigo can also occur with centhat is causing increased intracranial pressure. Optic
tral vestibular disease.
neuropathy may be present in multiple sclerosis, neuE. CALORIC TESTING
rosyphilis, or vitamin B12 deciency. A depressed
Disorders of the vestibuloocular pathways can be decorneal reex or facial palsy ipsilateral to the lesion
tected by caloric testing. The patient is placed supine
(and the ataxia) can accompany cerebellopontine
with the head elevated 30 degrees to bring the
angle
superWeakness of the tongue or palate, hoarseness,
Motor System
cially situated lateral semicircular canal into the tumor.
or
upright
Examination
of motor
in the patient
with a
dysphagia results
fromfunction
lower brainstem
disease.
position. Each ear canal is irrigated in turn with cold
disorder of equilibrium should determine the pattern
(33C) or warm (44C) water for 40 seconds, with and
at severity of ataxia and disclose any associated pyleast 5 minutes between tests. Warm water tends ramidal,
to
extrapyramidal, or peripheral nerve involveproduce less discomfort than cold. Caution: Caloricment that might suggest a cause. The clinical
testing should be preceded by careful otoscopic features
examithat help distinguish cerebellar disease from diseases
nation, and should not be undertaken if the tympanic
inmembrane is perforated.
volving these other motor systems are summarized in
1. In the normal awake patient, cold-water caloric
Table 36.
stimulation produces nystagmus with the slow phase
Table 36. Clinical features distinguishing cerebellar from other motor systems disorders.
Cerebellar
Upper Motor Neuron1 Lower Motor Neuron1
Extrapyramidal2
Strength
Normal
Decreased
Decreased
Normal
Tone
Decreased
Increased (spastic)3
Normal
Increased (rigid)3 or
decreased
Tendon reexes
Normal
Increased3
Decreased3
Normal
Plantar responses
Flexor
Extensor3
Flexor
Flexor
Atrophy
Absent
Absent
Present3 or absent
Absent
Fasciculations
Absent
Absent
Present3 or absent
Absent
Tremor
Intention tremor3 or
absent
Absent
Absent
Resting tremor3 or
absent
Chorea or athetosis Absent
Absent
Absent
Present3 or absent
Akinesia
Absent
Absent
Absent
Present3 or absent
Ataxia
Present3
Absent
Absent
Absent
Also see Chapter 5.

Also see Chapter 7.
3 Most helpful diagnostic features.
2
106 / CHAPTER 3
A. ATAXIA AND DISORDERS OF MUSCLE TONE
ditions as asterixis and is a prominent manifestation
Muscle tone is assessed as discussed in Chapter 6.of
TrunCreutzfeldt-Jakob disease. Chorea may be associated
cal stability is assessed with the patient in the sitting
with cerebellar signs in Wilson disease, acquired
position, and the limbs are examined individually. hepa1. Movement of the patients arm is observed asSensory
tocerebralSystem
degeneration, or ataxia-telangiectasia.
his
or her nger tracks back and forth between his or A.
herJOINT POSITION SENSE
In
patients with sensory ataxia, joint position sense is
own nose or chin and the examiners nger. With mild
always
impaired in the legs and may be defective in
cerebellar ataxia, an intention tremor
the
characteristically
appears near the beginning and end of each such arms as well. Testing is accomplished by asking the
pamovement, and the patient may overshoot the target. tient to detect passive movement of the joints, beginning distally and moving proximally, to establish the
2. When the patient is asked to raise the arms rapupper level of decit in each limb. Abnormalities of
idly to a given heightor when the arms, extended
poand outstretched in front of the patient, are displaced
sition sense also can be demonstrated by positioning
by a sudden forcethere may be overshoot
one limb and having the patient, with eyes closed,
(rebound).
B. Vibratory Sense
place
Impaired ability to check the force of muscular
Perception
oflimb
vibratory
is frequently
the opposite
in thesensation
same position.
contracimpaired
tions can also be demonstrated by having the patient
in patients with sensory ataxia. The patient is asked
forcefully ex the arm at the elbow against resistance
to
and then suddenly removing the resistance. If the detect the vibration of a 128-Hz tuning fork placed
over a bony prominence. Again, successively more
limb
is ataxic, continued contraction without resistanceproximal sites are tested to determine the upper level
of
may
the decit in each limb or over the trunk. The
cause the hand to strike the patient at the shoulder
patients
or
threshold for appreciating the vibration is compared
Reexes
in the face.
with the examiners own ability to detect it in the
3. Ataxia of the legs is demonstrated by the supine
Tendon
hand reexes are typically hypoactive, with a
patients inability to run the heel of the foot smoothly
penduthat holds the tuning fork.
up and down the opposite shin.
lar quality, in cerebellar disorders; unilateral
4. Ataxia of any limb is reected by irregularity in
cerebellar
the rate, rhythm, amplitude, and force of rapid
lesions produce ipsilateral hyporeexia. Hyporeexia
succesof
sive tapping movements.
the legs is a prominent manifestation of Friedreich
5. Hypotonia is characteristic of cerebellar
ataxia, tabes dorsalis, and polyneuropathies that
disorders;
cause
with unilateral cerebellar hemispheric lesions, the sensory ataxia. Hyperactive reexes and extensor
B.
WEAKNESS
ipsiplanThe
pattern
any
weakness should be determined.
lateral
limbsof
are
hypotonic.
tar responses may accompany ataxia caused by
Distal
neuropathic weakness
can(rigidity)
be caused
by disorINVESTIGATIVE
STUDIES
6. Extrapyramidal
hypertonia
occurs
with
multiple
ders
that produce
as polyneucerebellar
ataxia insensory
Wilson ataxia,
disease,such
acquired
hepatoBlood
Studies
sclerosis,
vitamin B12 deciency, focal brainstem leropathies
and FriedreichCreutzfeldt-Jakob
ataxia. Paraparesis
may be
cerebral degeneration,
disease,
and
sions, and certain olivopontocerebellar or
sucertain types of olivopontocerebellar degeneration.
Blood
studies may disclose the hematologic
spinocerebelperimposed
on ataxia
in vitamin
B12seen
deciency,
7. Ataxia with
spasticity
may be
in multipleabnormalilar degenerations.
multiple
magnum
lesions, oranomspinal
sclerosis,sclerosis,
posteriorforamen
fossa tumors
or congenital
ties associated with vitamin B12 deciency, the decord
Ataxic quadriparesis,
hemiataxia withcreased levels of thyroid hormones in
alies,tumors.
vertebrobasilar
ischemia or infarction,
contralateral
olivoponto- hemiparesis, or ataxic hemiparesis sughypothyroidism,
gests
a brainstem
lesion. Friedreich and other
cerebellar
degeneration,
the elevated hepatic enzymes and low ceruloplasmin
C.
ABNORMAL INVOLUNTARY MOVEMENTS
hereditary
and copper concentrations in Wilson disease, imAsterixis
may occur in hepatic
encephalopathy,
ataxias, neurosyphilis,
Creutzfeldt-Jakob
disease,acand
munoglobulin deciency and elevated in
quired
vitaminhepatocerebral
B12 deciency. degeneration, or other
ataxia-telangiectasia, antibodies to Purkinje cell antimetabolic
gens in paraneoplastic cerebellar degeneration, or
encephalopathies. Myoclonus occurs in the same congenetic abnormalities associated with hereditary spinocerebellar degenerations.

acoustic nerve lesions, and is impaired less with
disorThe cerebrospinal uid (CSF) shows elevated protein
ders of the labyrinth. Speech discrimination is normal
with cerebellopontine angle tumors (eg, acoustic neuin conductive or brainstem involvement.
roma), brainstem or spinal cord tumors, hypothy- B. ELECTRONYSTAGMOGRAPHY (ENG)
roidism, and some polyneuropathies. Increased This test can be used to detect and characterize
protein
nystagwith pleocytosis is commonly found with infectiousmus,
or including that elicited by caloric stimulation.
C. AUDITORY EVOKED RESPONSE
parainfectious encephalitis, paraneoplastic cerebellar
This test can localize vestibular disease to the
degeneration, and neurosyphilis. Although elevated
pressure and bloody CSF characterize cerebellar peripheral
vestibular pathways.
hemorrhage, lumbar puncture is contraindicated if
cerebellar
hemorrhage is suspected. CSF VDRL is reactive in
tabes dorsalis, and oligoclonal immunoglobulin G PERIPHERAL VESTIBULAR
vertigo occurs upon assuming a particular
(IgG)
bands may be present in multiple sclerosis orPositional
DISORDERS
Imaging
head
position.
It is usually associated with peripheral
other inammatory disorders.
The computed tomography (CT) scan is useful for vestibular lesions but also may be due to central
A list of peripheral vestibular disorders and features
demonstrating posterior fossa tumors or malforma(brainhelpful
the differential
diagnosis is presented in
tions, cerebellar infarction or hemorrhage, and
stem
orincerebellar)
disease.
Table
37. positional vertigo is the most common
cerebelBenign
lar atrophy associated with degenerative disorders.
cause
Magnetic resonance imaging (MRI) provides betterof
vi-vertigoPOSITIONAL
of peripheral origin,
accounting for about
BENIGN
VERTIGO
sualization of posterior fossa lesions, including
30% of cases. The most frequently identied cause is
cerebelhead trauma, but in most instances, no cause can be
lopontine angle tumors, and is superior to CT
determined. The pathophysiologic basis of benign
scanning
posiEvoked Potential Testing
for detecting the lesions of multiple sclerosis.
tional vertigo is thought to be canalolithiasis
Evoked potential testing, especially of optic pathways
stimula(visual evoked potentials), may be helpful in
tion of the semicircular canal by debris oating in the
evaluating
endolymph.
patients with suspected multiple sclerosis. BrainstemThe syndrome is characterized by brief (seconds to
auditory evoked potentials may be abnormal in minutes) episodes of severe vertigo that may be
patients
accomwith cerebellopontine angle tumors even though CT
panied by nausea and vomiting. Symptoms may
scans show
no&abnormality.
Chest
X-Ray
Echocardiography
occur
with any change in head position but are usually
The chest x-ray or echocardiogram may provide evimost
dence of cardiomyopathy associated with Friedreich
severe in the lateral decubitus position with the
ataxia. The chest x-ray may also show a lung tumor
affected
in
ear down. Episodic vertigo typically continues for sevparaneoplastic cerebellar degeneration.
eral weeks and then resolves spontaneously; in some
Special Studies
cases it is recurrent. Hearing loss is not a feature.
In vestibular disorders, three additional special
Peripheral and central causes of positional vertigo
investiusually can be distinguished on physical examination
gations may be of help.
by means of the Nylen-Brny or Dix-Hallpike maneuA. AUDIOMETRY
ver (discussed earlier; see Figure 36). Positional nysThis is useful when vestibular disorders are
tagmus always accompanies vertigo in the benign
associated
disorwith auditory impairment; such testing can
der and is typically unidirectional, rotatory, and
distinguish
delayed in onset by several seconds after assumption
conductive, labyrinthine, acoustic nerve, and
of
brainstem
the precipitating head position. If the position is maindisease.
tained, nystagmus and vertigo resolve within seconds
Tests of pure tone hearing are abnormal when
to
sounds are transmitted through air with conductive
minutes. If the maneuver is repeated successively,
hearing loss and when transmitted through either air
the
or
response is attenuated. In contrast, positional vertigo
bone with labyrinthine or acoustic nerve disorders.
of
Speech discrimination is markedly impaired with
central origin tends to be less severe, and positional
Cerebrospinal Fluid Studies
108 / CHAPTER 3
Table 37. Differential diagnosis of peripheral vestibular disorders.
Hearing Loss
Conductive
Sensorineural
Other Cranial Nerve Palsies
Benign positional vertigo
Mnire disease
Acute peripheral vestibulopathy
Otosclerosis
Head trauma
Cerebellopontine angle tumor
tinnitus and progressive sensorineural hearing loss.

Most cases are
sporadic, but familial
occurrence also
has
been
described,
and
may
show
anticipation, or
ear
generations.
lier onset in successive
Some cases
appear
Acoustic (VIII) neuropathy
to be related to mutations in the cochlin gene on
chro
Basilar meningitis
Hypothyroidism
mosome 14q12q13.
Onset is between
the ages of 20
Diabetes
and 50 years in about three-fourths
of cases, and
Paget disease of the skull (osteitis deformans)
nystagmus may be absent. There is no latency, men

fatigue,
are affected more often than women. The cause is
or habituation in central positional vertigo.
thought to be an increase in the volume of
The mainstay of treatment in most cases of benign
labyrinthine
positional vertigo of peripheral origin (canalolithiasis)
endolymph (endolymphatic hydrops), but the pathois the use of repositioning maneuvers that employgenetic mechanism is unknown.
the
At the time of the rst acute attack, patients
force of gravity to move endolymphatic debris outalready
of
the semicircular canal and into the vestibule, where
may
it have noted the insidious onset of tinnitus,
can be reabsorbed. In one such maneuver (Figure hearing
3
7),
loss, and a sensation of fullness in the ear. Acute
the head is turned 45 degrees in the direction of the
attacks
afare characterized by vertigo, nausea, and vomiting
fected ear (determined clinically, as described
and
above),
recur at intervals ranging from weeks to years.
and the patient reclines to a supine position, with the
Hearing
head (still turned 45 degrees) hanging down over the
deteriorates in a stepwise fashion, with bilateral
end of the examining table. The head, still hanginginvolvedown, is then turned 90 degrees in the opposite ment reported in 1070% of patients. As hearing loss
direcincreases, vertigo tends to become less severe.
tion, to 45 degrees toward the opposite ear. Next, thePhysical examination during an acute episode
patient rolls to a lateral decubitus position with theshows
afspontaneous horizontal or rotatory nystagmus (or
fected ear up, and the head still turned 45 degreesboth)
tothat may change direction. Although spontaneous
ward the unaffected ear and hanging down. Finally,
nysthe
tagmus is characteristically absent between attacks,
patient turns to a prone position and sits up.
caloric testing usually reveals impaired vestibular
VestibulofuncMNIRE DISEASE
suppressant drugs (Table 38) may also be useful in
tion. The hearing decit is not always sufciently adMnire
disease is characterized by repeated
the
vanced to be detectable at the bedside. Audiometry
episodes
of and vestibular rehabilitation, which proacute period,
shows low-frequency pure-tone hearing loss,
vertigo
lasting from minutes
to days,
accompaniedhowever,
by
motes compensation
for vestibular
dysfunction
through
that uctuates in severity as well as impaired speech
the recruitment of other sensory modalities, may be
discrimination and increased sensitivity to loud
helpful as well.
sounds.
Toxic vestibulopathy
Alcohol
Aminoglycosides
Salicylates
Quinine

Table 38. Drugs used in the treatment of vertigo.
Drug
2
Antihistamines
Meclizine
Promethazine
Dimenhydrinate
PSC
4
UT
2, 3
6
1
Dosage1
25 mg PO q46h
2550 mg PO, IM, or PR q46h
50 mg PO or IM q46h or 100 mg
PR q8h
Anticholinergics
Scopolamine
0.5 mg transdermally q3d
Benzodiazepines
Diazepam
510 mg PO or IM q46h
Sympathomimetics
Amphetamine
Ephedrine
510 mg PO q46h
25 mg PO q46h
1PO,
Figure 37. Repositioning treatment for benign posi-
orally; IM, intramuscularly; PR, rectally.

AdaptedfromBalohRW,HonrubiaV:ClinicalNeu
rophysiologyoftheVestibularSystem,2nded.
Vol32ofContemporary
This term is used to describe a spontaneous attack of
vertigo of inapparent cause that resolves
spontaneously
tional vertigo resulting from canalolithiasis. In the
example shown, repositioning maneuvers are used to and is not accompanied by hearing loss or evidence
move endolymphatic debris out of the posterior semi- of
ing, labyrinthectomy, or vestibular nerve section are
circular canal (PSC) of the right ear and into the utricle central
helpful. nervous system dysfunction. It includes disor(UT), the larger of two membranous sacs in the
ders diagnosed as acute labyrinthitis or vestibular
vestibule of the labyrinth, where this debris can be
neureabsorbed.The numbers (16) refer to both the posironitis,
are basedVESTIBULOPATHY
on unveriable inferences
ACUTEwhich
PERIPHERAL
tion of the patient and the corresponding location of
about
the
site
of
disease
and the pathogenetic
debris within the labyrinth.The patient is seated and
the head is turned 45 degrees to the right (1).The head mechais lowered rapidly to below the horizontal (2); the exam-nism. A recent antecedent febrile illness can
iner shifts position (3); and the head is rotated rapidly sometimes
90 degrees in the opposite direction, so it now points be identied, however.
45 degrees to the left, where it remains for 30 seconds
The disorder is characterized by vertigo, nausea,
(4).The patient then rolls onto the left side without
and
turning the head in relation to the body and maintains vomiting of acute onset, typically lasting up to 2
this position for another 30 seconds (5) before sitting
weeks.
up (6).This maneuver may need to be repeated until
Symptoms may recur, and some degree of vestibular
nystagmus is abolished.The patient must then avoid
the supine position for at least 2 days. (Courtesyof dysfunction may be permanent.
During an attack, the patientwho appears ill
Baloh,RW.Reproducedwithpermissionfrom
typically
lies on one side with the affected ear upward
SamuelsMAetal:OfficePracticeofNeurol
and is reluctant to move his or her head. Nystagmus
ogy.ChurchillLivingstone,1995.)
with the fast phase away from the affected ear is
always
present. The vestibular response to caloric testing is
defective in one or both ears with about equal
frequency.
Auditory acuity is normal.
As has been noted, episodes of vertigo tend to re- Acute peripheral vestibulopathy must be distinsolve as hearing loss progresses. Treatment is withguished
difrom central disorders that produce acute
uretics, such as hydrochlorothiazide and triamterene.
verThe drugs listed in Table 38 may also be helpful durtigo, such as stroke in the posterior cerebral
ing acute attacks. In persistent, disabling, drug- circulation.
resistant
Central disease is suggested by vertical nystagmus,
cases, surgical procedures such as endolymphatic alshunttered consciousness, motor or sensory decit, or
dysarthria. Treatment is with a 10- to 14-day course
of
110 / CHAPTER 3
prednisone, 20 mg orally twice daily, the drugs listed
common tumors at this site include meningiomas and
in
primary cholesteatomas (epidermoid cysts).
Table 38, or both.
Symptoms
are produced by compression or displacement of the
OTOSCLEROSIS
cranial nerves, brainstem, and cerebellum and by obOtosclerosis is caused by immobility of the stapes,struction of CSF ow. Because of their anatomic relathe
tionship to the acoustic nerve (see Figure 38), the
ear ossicle that transmits vibration of the tympanic
trigeminal (V) and facial (VII) nerves are often
membrane to the inner ear. Its most distinctive
affected.
feature
Acoustic neuromas occur most often as isolated leis conductive hearing loss, but sensorineural hearing
sions in patients 3060 years old, but they may also
loss and vertigo are also common; tinnitus is infre-be
quent. Auditory symptoms usually begin before 30a manifestation of neurobromatosis.
years of age, and familial occurrence is common. NeurobromatoVestibular dysfunction is most often characterized
sis 1 (von Recklinghausen disease) is a common autoby recurrent episodic vertigowith or without posisomal dominant disorder related to mutations in the
tional vertigoand a sense of positional imbalance.
neurobromin gene on chromosome 17q11.2. In addiMore continuous symptoms may also occur, and the
tion to unilateral acoustic neuromas,
frequency and severity of attacks may increase with
neurobromatosis
time.
1 is associated with caf-au-lait spots on the skin,
Vestibular abnormalities on examination includecutaspontaneous or positional nystagmus of the
neous neurobromas, axillary or inguinal freckles,
peripheral
optic
type and attenuated caloric responses, which are gliomas, iris hamartomas, and dysplastic bony
usually
lesions.
unilateral.
Neurobromatosis
Clinical Findings 2 is a rare autosomal dominant
Hearing loss is always demonstrable by
disaudiometry.
A.
SYMPTOMS
AND
IGNS
order
caused
bySmutations
in the neurobromin 2
It is usually of mixed conductive-sensorineural
Hearing
loss of insidious onset is usually the initial
gene
characsymptom.
Less often,
patients present
with is
on chromosome
22q11.113.1.
Its hallmark
ter, and is bilateral in about two-thirds of patients.headache,
In
bilateral
patients with episodic vertigo, progressive hearingvertigo,
ataxia, which
facial pain,
tinnitus,
a sensation
acousticgait
neuromas,
may be
accompanied
by
loss,
of
other tumors of the central or peripheral nervous sysand tinnitus, otosclerosis must be distinguished from
fullness
in the ear,
or facial weakness.
Although
tem, including
neurobromas,
meningiomas,
gliomas,
Mnire disease. Otosclerosis (rather than Mnirevertigo
and schwannomas.
disultimately develops in 2030% of patients, a nonspeease) is suggested by a positive family history, a tencic feeling of unsteadiness is encountered more
dency toward onset at an earlier age, the presencecomof
HEAD
TRAUMA
conductive
hearing loss, or bilateral symmetric
monly. In contrast to Mnire disease, there is a
auditory
greater
Head
trauma is the most common identiable cause
impairment. Imaging studies also may be
tendency for mild vestibular symptoms to persist beof
diagnostically
benign
positional vertigo. Injury to the labyrinth is tween attacks. Symptoms may be stable or progress
useful. responsible for posttraumatic vertigo;
very slowly for months or years.
usually
Treatment with a combination of sodium uoride, Unilateral hearing loss of the sensorineural type is
however,
calcium gluconate,
and vitamin
D may
be effective.
If most common nding on physical examination.
fractures
of the petrosal
bone may
lacerate
the the
not,
surgical
stapedectomy
should
be
considered.
Other
frequently noted abnormalities are ipsilateral
acoustic
fanerve, producing vertigo and hearing loss. HemotymCEREBELLOPONTINE
ANGLE TUMOR
panum or CSF otorrhea suggests
such a fracture. cial palsy, depression or loss of the corneal reex,
LABORATORY FINDINGS
and
The cerebellopontine angle is a triangular region inB.
Audiometry
a sensorineural
pattern of decit
sensory lossshows
over the
face. Ataxia, spontaneous
the
with
high-frequency
pure-tone
hearing
loss, poor
posterior fossa bordered by the cerebellum, the nystagspeech
discrimination,
and
marked
tone
decay.
CSF
mus, other lower cranial nerve palsies, and
signs
of
lateral
protein
is
elevated
in
about
70%
of
patients,
usually
pons, and the petrous ridge (Figure 38). By far theinin
creased intracranial pressure are less common.
most common tumor in this area is the histologically
the
range of 50200 mg/dL. The most useful diagnosUnilatbenign acoustic neuroma (also termed neurilemoma,
tic
radiologic
is MRI ofcan
theusually
cerebellopontine
aneral
vestibularstudy
dysfunction
be
neurinoma, or schwannoma), which typically arises
gle.
Acoustic
neuromas
sometimes
cause
demonstrated
from the neurilemmal sheath of the vestibular portion
abnormalities
with caloric testing.
of the acoustic nerve in the internal auditory canal.
Less
Acoustic neuroma
Dorsum sellae
Internal auditory canal

VI
VIII
VII
XII
Foramen
magnum
(brainstem
removed)
IX, X, XI
Internal jugular vein
Transverse sinus
1. ALCOHOL
Alcohol causes an acute syndrome of positional
vertigo
because of its differential distribution between the
cupula and endolymph of the inner ear. Alcohol iniFigure 38. Cerebellopontine angle tumor, viewed from above, with the brain removed to permit the cranial
tially diffuses into the cupula, reducing its density
nerves and base of the skull to be seen.The tumor, a neuroma arising from the acoustic (VIII) nerve, may
relacompress
tive(VII)
to the
endolymph.
This difference
in density
adjacent structures, including the trigeminal (V) and facial
nerves,
the brainstem,
and the cerebellum.
makes
the peripheral vestibular apparatus unusually
of the brainstem auditory evoked potentials at a time
sensitive
when radiologic studies show no abnormalities.
to gravity and thus to position. With time, alcohol also
diffuses into the endolymph, and the densities of
cupula and endolymph equalize, eliminating the
graviAcoustic neuroma must be distinguished from other
sensitivity. As the blood alcohol level
cerebellopontine angle tumors, the most common tational
bedeclines,
ing meningioma and cholesteatoma. Meningioma
alcohol leaves the cupula before it leaves the enshould be considered in patients whose initial symptoms indicate more than isolated acoustic nerve dolymph. This produces a second phase of
gravitational
disease.
Cholesteatoma is suggested by conductive hearingsensitivity that persists until the alcohol diffuses out
of
loss,
the endolymph also.
early facial weakness, or facial twitching, with normal
CSF protein. Metastatic carcinoma may also present Alcohol-induced positional vertigo typically occurs
within 2 hours after ingesting ethanol in amounts
as
Treatment
sufa lesion in the cerebellopontine angle.
Treatment is complete surgical excision. In untreated
cient to produce blood levels in excess of 40 mg/dL. It
cases, severe complications may result from
is characterized clinically by vertigo and nystagmus
brainstem
in
compression or hydrocephalus.
the lateral recumbent position and is accentuated
when
TOXIC VESTIBULOPATHIES
the eyes are closed. The syndrome lasts up to about
Several drugs can produce vertigo by their effects 12
on
the peripheral vestibular system.
hours and consists of two symptomatic phases separated by an asymptomatic interval of 12 hours.
Other
signs of alcohol intoxication, such as spontaneous
nysPosterior
fossa
(cerebellum
removed)
112 / CHAPTER 3
tagmus, dysarthria, and gait ataxia, are caused 5. CIS-PLATINUM
primarily
This antineoplastic drug causes ototoxicity in about
by cerebellar dysfunction.
50% of patients. Tinnitus, hearing loss, and vestibular
2. AMINOGLYCOSIDES
dysfunction are most likely to occur with cumulative
Aminoglycoside antibiotics are widely recognized otodoses of 34 mg/kg; they may be reversible if the
toxins that can produce both vestibular and auditory
drug
symptoms. Streptomycin, gentamicin, and
is discontinued.
tobramycin
ACOUSTIC NEUROPATHY
are the agents most likely to cause vestibular toxicity,
and amikacin, kanamycin, and tobramycin are associInvolvement of the acoustic nerve by systemic
ated with hearing loss. Aminoglycosides concentrate
disease is
in
an uncommon cause of vertigo. Basilar meningitis
the perilymph and endolymph and exert their
from bacterial, syphilitic, or tuberculous infection or
ototoxic
sarcoidosis can lead to compression of the acoustic
effects by destroying sensory hair cells. The risk ofand
toxiother cranial nerves, but hearing loss is a more comcity is related to drug dosage, plasma concentration,
mon consequence than vertigo. Metabolic disorders
duration of therapy, conditionssuch as renal fail-asurethat impair drug clearance, preexisting
sociated with acoustic neuropathy include hypothyvestibular
roidism, diabetes, and Paget disease.
or cochlear dysfunction, and concomitant administraCEREBELLAR & CENTRAL
tion of other ototoxic agents.
VESTIBULAR DISORDERS
Symptoms of vertigo, nausea, vomiting, and gait
ataxia may begin acutely; physical ndings include
spontaneous nystagmus and the presence of
Many disorders can produce acute or chronic
Romberg
cerebellar
sign.
The acute phase typically lasts for 1 to 2 weeks
dysfunction (Table 39). Several of these conditions
3.
SALICYLATES
and is followed
byused
a period
of gradual
may also be associated with central vestibular
Salicylates,
when
chronically
andimprovement.
in high doses,
Prolonged
repeated
aminoglycoside
therapyhearing
may
disorders,
can
cause or
vertigo,
tinnitus,
and sensorineural
Table 39. Differential diagnosis
be
lossall
usually reversible when the drug is discontinassociated
with a
chronic
syndrome
progressive
ued.
Symptoms
result
from
cochlear of
and
vestibularof cerebellar ataxia.
vestibular dysfunction.
end-organ
damage. Chronic salicylism is
characterized
Acute
by headache, tinnitus, hearing loss, vertigo, nausea,
Drug intoxications: ethanol, sedative-hypnotics,
vomiting, thirst, hyperventilation, and sometimes a anticonvulsants, hallucinogens
Wernicke encephalopathy1
confusional state. Severe intoxication may be
Vertebrobasilar ischemia or infarction1
associated
Cerebellar hemorrhage
with fever, skin rash, hemorrhage, dehydration,
Inammatory disorders
seizures, psychosis, or coma. The characteristic
laboraChronic
tory ndings are a high plasma salicylate level (about
Multiple sclerosis1,2
or
Alcoholic cerebellar degeneration
above 0.35 mg/mL) and combined metabolic acidosis
Phenytoin-induced cerebellar degeneration
and respiratory alkalosis.
Hypothyroidism
4. QUININE & QUINIDINE
Paraneoplastic cerebellar degeneration
Measures for treating salicylate intoxication include
Both quinine and quinidine can produce the
gastric lavage, administration of activated charcoal,Hereditary spinocerebellar ataxias (SCA17)
syndrome
forced diuresis, peritoneal dialysis or hemodialysis, Friedreich ataxia2
of cinchonism, which resembles salicylate intoxication
Ataxia-telangiectasia
and
in many respects. The principal manifestations are Wilson disease
hemoperfusion.
Acquired hepatolenticular degeneration
tinCreutzfeldt-Jakob disease
nitus, impaired hearing, vertigo, visual decits
Posterior fossa tumor1
(includPosterior
fossa malformations
ing disorders of color vision), nausea, vomiting, abdominal pain, hot ushed skin, and sweating. Fever,
1 May also be associated with central vestibular dysfuncencephalopathy, coma, and death can occur in
tion.
severe
2 May also produce sensory ataxia.
cases. Symptoms result from either overdosage or
idiosyncratic reactions (usually mild) to a single small
dose
of quinine.

particularly Wernicke encephalopathy, vertebrobasilar
acute confusion start to resolve within a few days. Reischemia or infarction, multiple sclerosis, and
covery from ocular palsies is invariably complete, but
posterior
horizontal nystagmus may persist.
fossa tumors.
Ataxia is fully reversible in only about 40% of patients;
where gait returns fully to normal, recovery
ACUTE DISORDERS
typi1. DRUG INTOXICATION
cally takes several weeks to months.
3. VERTEBROBASILAR ISCHEMIA & INFARCTION
Pancerebellar dysfunction manifested by nystagmus,
dysarthria, and limb and gait ataxia is a prominentTransient ischemic attacks and strokes in the vertebrobasilar system are often associated with ataxia or
feature of many drug intoxication syndromes. Agents vertigo.
that
produce such syndromes include ethanol, sedativeInternal Auditory Artery Occlusion
hypVertigo of central vestibular origin with unilateral
notics (eg, barbiturates, benzodiazepines, meprobahearmate, ethchlorvynol, methaqualone), anticonvulsants
(such as phenytoin), and hallucinogens (especiallying loss results from occlusion of the internal auditory
artery (Figure 39), which supplies the acoustic nerve.
phencyclidine). The severity of symptoms is dose reThis vessel may originate from the basilar or anterior
lated; while therapeutic doses of sedatives or
inferior cerebellar artery. Vertigo is accompanied by
anticonnystagmus, with the fast phase directed away from
vulsants commonly produce nystagmus, other
the
cerebelinvolved side. Hearing loss is unilateral and senlar signs imply toxicity.
sorineural.
Lateral
Medullary Infarction
Drug-induced cerebellar ataxia often is associated
with a confusional state, although cognitive function
Lateral medullary infarction produces Wallenberg syn2. WERNICKE ENCEPHALOPATHY
tends to be spared in phenytoin intoxication. The condrome (Figure 310) and is most often caused by
Wernicke encephalopathy (see also Chapter 1) is an
fusional state produced by ethanol and sedative proxacute disorder comprising the clinical triad of ataxia,
drugs is
imal vertebral artery occlusion. Clinical
ophthalmoplegia, and confusion. It is caused by thicharacterized by somnolence, whereas hallucinogens
amine (vitamin B1) deciency and is most commonmanifestations
in
are
vary, depending on the extent of infarction. They
chronic alcoholics, although it may occur as a consemore often associated with agitated delirium. In most
quence of malnutrition from any cause. The major typicases, only general supportive care is necessary. The
cally consist of vertigo, nausea, vomiting, dysphagia,
sites
disof pathologic involvement are the medial thalamichoarseness, and nystagmus in addition to ipsilateral
tinctive features of intoxication with each of these Horner syndrome, limb ataxia, impairment of all sennugroups of drugs are discussed in detail in Chapter sory
1.
Basilar
artery
the
face, and loss of light touch
clei, mammillary bodies, periaqueductal and periven- modalities over
tricular brainstem nuclei (especially those of the
Posterior cerebral artery Internal auditory artery
oculomotor, abducens, and acoustic nerves), and superior
cerebellar vermis. Cerebellar and vestibular involve- Superior
Anterior
ment both contribute to the ataxia.
inferior
cerebellar
cerebellar
artery
Ataxia affects gait primarily or exclusively; the legs
artery
themselves are ataxic in only about one-fth of patients, and the arms in one-tenth. Dysarthria is rare.
Other classic ndings include an amnestic syndrome
or
global confusional state, horizontal or combined horizontal-vertical nystagmus, bilateral lateral rectus
palsies,
and absent ankle jerks. Caloric testing reveals
Vertebral
bilateral
artery
or unilateral vestibular dysfunction. Conjugate gaze
palsies, pupillary abnormalities, and hypothermia can
also occur.
Posterior inferior
The diagnosis is established by the response to adcerebellar artery
ministration of thiamine, which is usually given iniFigure 39. Principal arteries of the posterior fossa.
tially in a dose of 100 mg intravenously. Ocular
palsies
tend to be the earliest decits to improve and
typically
begin to do so within hours. Ataxia, nystagmus, and
114 / CHAPTER 3
Cuneate/gracile nuclei
Nucleus solitarius
Vestibular nuclei
Dorsal motor nucleus

of vagus nerve
Wallenberg syndrome
Inferior cerebellar
peduncle
Spinal tract and nucleus
of trigeminal nerve
Descending
sympathetic tract
Nucleus ambiguus
Spinothalamic tract
Inferior olive
Hypoglossal nerve
Pyramidal tract
Figure 310. Lateral medullary infarction (Wallenberg syndrome) showing the area of infarction (shaded) and
anatomic structures affected.
and position sense in the limbs. There is also impairment of pinprick and temperature appreciation in the
contralateral limbs. Vertigo results from involvement
of
the vestibular nuclei and hemiataxia from
The
cerebellum is supplied by three arteries: the
involvement
supeof the inferior
cerebellar peduncle.
Cerebellar
Infarction
rior cerebellar, anterior inferior cerebellar, and
posterior
inferior cerebellar. The territory supplied by each of
these vessels is highly variable, both from one
individual to another and between the two sides of the
cerebellum in a given patient. The superior, middle, and inferior cerebellar peduncles are typically supplied by the
superior, anterior inferior, and posterior inferior cerebellar arteries, respectively.
Cerebellar infarction results from occlusion of a
cerebellar artery (Figure 311); the clinical syndromes
produced can be distinguished only by the associated
brainstem ndings. In each case, cerebellar signs include ipsilateral limb ataxia and hypotonia. Other
symptoms and signs such as headache, nausea,
Superior cerebellar artery
vomiting, vertigo, nystagmus, dysarthria, ocular or gaze
Anterior inferior cerebellar artery
palsies, facial weakness or sensory loss, and
Posterior inferior cerebellar artery
contralateral
hemiparesis or hemisensory decit may be present.
Brainstem infarction or compression by cerebellar Figure 311. Arterial supply of the cerebellum,
viewed from below.
edema can result in coma and death.
The diagnosis of cerebellar infarction is made by
CT
scan or MRI, which allows differentiation between infarction and hemorrhage; it should be obtained

promptly. When brainstem compression occurs, surgifused, or comatose. In alert patients, nausea and
cal decompression and resection of infarcted tissue
vomitcan
ing are often prominent. The blood pressure is
be lifesaving.
typically
elevated, and nuchal rigidity may be present. The
Paramedian Midbrain Infarction
pupils are often small and sluggishly reactive.
Ipsilateral
Paramedian midbrain infarction caused by occlusion
gaze palsy (with gaze preference away from the side
of
of
the paramedian penetrating branches of the basilar
hemorrhage) and ipsilateral peripheral facial palsy
arare
tery affects the third nerve root bers and red
common. The gaze preference cannot be overcome
nucleus
by
(Figure 312). The resulting clinical picture (Benedikt
caloric stimulation. Nystagmus and ipsilateral depressyndrome) consists of ipsilateral medial rectus palsy
sion of the corneal reex may occur. The patient, if
with a xed dilated pupil and contralateral limb ataxia
(typically affecting only the arm). Cerebellar signs alert,
re- exhibits ataxia of stance and gait; limb ataxia is
sult from involvement of the red nucleus, which re-less common. In the late stage of brainstem compres4.
CEREBELLAR
HEMORRHAGE
ceives
a crossed
projection from the cerebellum insion, the legs are spastic and extensor plantar
Most
cerebellar
hemorrhages are due to hypertensive
responses
the
vascular
disease;
commoncerebellar
causes include
are present.
ascending
limb of less
the superior
peduncle.
anticoagu5. IThe
NFLAMMATORY DISORDERS
CSF is frequently bloody, but lumbar puncture
lation, arteriovenous malformation, blood dyscrasia,
Acute
the cerebellum
medishouldinammatory
be avoided if disorders
cerebellarofhemorrhage
is sustuated
by
infection
or
immune
mechanisms
are
imporpected, because it may lead to a herniation
mor, and trauma. Hypertensive cerebellar
tant
and often reversible causes of ataxia. Cerebellar
syndrome.
hemorrhages
ataxia
by viral
infection
is one is
ofathe
The caused
diagnostic
procedure
of choice
CT principal
scan.
are usually located in the deep white matter of themanifestations
of
St.
Louis
encephalitis.
AIDS
demenTreatment consists of surgical evacuation of the
ceretia
complex
and
meningoencephalitis
associated
hematoma, a procedure that can be lifesaving. with
bellum and commonly extend into the fourth
varicella, mumps, poliomyelitis, infectious
ventricle.
mononucleThe classic clinical picture of hypertensive
osis, and lymphocytic choriomeningitis can also procerebellar
duce cerebellar symptoms. Bacterial infection is a
hemorrhage consists of the sudden onset of
less
headache,
Superior colliculus
Benedikt syndrome
which may be accompanied by nausea, vomiting, and
vertigo, followed by gaitOculomotor
ataxia nucleus
and impaired
consciousness, usually evolving over a period of hours. At the
Medial lemniscus
time of presentation, patients can be fully alert, con-
Red nucleus
Substantia nigra
Cerebral peduncle
Oculomotor nerve (III)
Figure 312. Paramedian midbrain infarction (Benedikt syndrome).The area of infarction is indicated by shading.
116 / CHAPTER 3
common cause of cerebellar ataxia; 1020% of brain
complaint in 1015% of patients. Cerebellar signs are
abscesses are located in the cerebellum, however,present in about one-third of patients on initial
and
examinaataxia may be a feature of Haemophilus inuenzaetion; they ultimately develop in twice that number.
meningitis in children. A cerebellar syndrome has
Nystagmus is one of the most common physical
been
ndings; it can occur with or without other evidence
described in legionnaires disease, usually withoutof
clinicerebellar dysfunction. Dysarthria also occurs frecal evidence of meningitis.
quently. When gait ataxia occurs, it is most often
Several conditions that may occur following an cereacute
illnessAtaxia
or vaccination
produce cerebellar
bellar rather than sensory in origin. Ataxia of the
Acutefebrile
Cerebellar
of Childhood
ataxia that is assumed to be of autoimmune origin.
limbs
Acute cerebellar ataxia of childhood is a syndromeis common; it is usually bilateral and tends to affect
characterized by severe gait ataxia that usually eiresolves
ther both legs or all four limbs.
completely within months. It generally follows an
Evidence that a cerebellar disorder is due to
acute
multiple
viral infection or inoculation. A full discussion of ceresclerosis may be found in a history of remitting and
bellar ataxia in childhood is beyond the scope of this
rechapter.
Acute
Disseminated Encephalomyelitis
lapsing neurologic dysfunction that affects multiple
sites in the central nervous system; from such associThis immune-mediated disorder may cause
ated abnormalities as optic neuritis, internuclear ophdemyelination and inammatory changes in the cerebellar thalmoplegia, or pyramidal signs; or from laboratory
investigations.
CSF analysis
may reveal oligoclonal
white
2. ALCOHOLIC CEREBELLAR
DEGENERATION
bands,
elevated
IgG,
increased
protein,
or develop
a mild lymmatter, producing ataxia that is often associated with
A characteristic cerebellar syndrome
may
in
phocytic
pleocytosis.
Visual,
auditory,
or
somatosenimpaired consciousness, seizures, focal neurological
chronic alcoholics, probably as a result of nutritional
sory
evokedAffected
response
recording
can document
signs,
myelopathy.
deciency.
patients
typically
have a history
Fisheror
Variant
of Guillain-Barr Syndrome
subcliniof
Cerebellar ataxia, external ophthalmoplegia, and arecal
sites
of involvement.
The CT
or MRI
may
daily
or binge
drinking lasting
10scan
or more
years
with
exia constitute this variant of Guillain-Barr syn- show areas of demyelination. It must be emphasized,
associated dietary inadequacy. Most have
drome. Symptoms develop over a few days. Ataxiahowever, that no laboratory nding is itself diagnostic
experienced
priof
multiple
sclerosis,
and the of
history
and neurologic
other
medical
complications
alcoholism:
liver dismarily affects the gait and trunk, with lesser
exease, delirium tremens, Wernicke encephalopathy, or
involvement of the individual limbs; dysarthria is unamination
must be
primarily
relied upon
in arrivingisat
polyneuropathy.
Alcoholic
cerebellar
degeneration
common. CSF protein may be elevated. Respiratory
such
a
diagnosis.
most common in men and usually has its onset beinMultiple
sclerosis
discussed
in more detail in
tween
the ages
of 40isand
60 years.
sufciency occurs rarely, and the usual course is ofChapter 5.
Degenerative changes in the cerebellum are
gradual and often complete recovery over weeks to
largely
months. The ataxia is similar to that of cerebellar disrestricted to the superior vermis (Figure 313);
ease, but it is not yet known whether it arises
because
centrally
CHRONIC DISORDERS
this is also the site of cerebellar involvement in Weror peripherally.
nicke encephalopathy, both disorders may be part of
1. MULTIPLE SCLEROSIS
the same clinical spectrum.
Multiple sclerosis can produce disorders of
Alcoholic cerebellar degeneration is usually
equilibrium
insidious
of cerebellar, vestibular, or sensory origin. Cerebellar
in onset; it is gradually progressive, eventually
signs are associated with demyelinated areas
reaching
(plaques)
a stable level of decit. Progression over weeks to
in the white matter of the cerebellum, cerebellar pemonths is more common than is deterioration over
duncles, or brainstem. As is the case with other maniyears; in occasional cases, ataxia appears abruptly or
festations of multiple sclerosis, these signs may remit
is
and relapse.
mild and stable from the onset.
Involvement of vestibular pathways in the
Gait ataxia is a universal feature and is almost
brainstem
always
produces vertigo, which may be acute in onset and
the problem that initially commands medical
sometimes positional. Vertigo, which is rarely the rst
attention.
symptom of multiple sclerosis, is not uncommon durThe legs are also ataxic on heel-knee-shin testing in
ing the course of the disease.
about 80% of patients. Commonly associated ndings
Gait ataxia from cerebellar involvement is a
are distal sensory decits in the feet and absent
presenting
ankle

mis is relatively spared. Clinical features include
nystagmus, dysarthria, and ataxia affecting the limbs, trunk,
and gait. Polyneuropathy may be present. Symptoms
Posterior
are typically irreversible, but tend to stabilize when
the
4.
HYPOTHYROIDISM
drug
is discontinued.
Among the neurologic disorders associated with hypothyroidism is a subacute or chronically progressive
Anterior
cerebellar syndrome. This condition may complicate
hypothyroidism (of various causes) and is most common in middle-aged or elderly women. Symptoms
evolve over a period of months to years. Systemic
symptoms of myxedema usually precede the
appearance
of the cerebellar disorder, but patients occasionally
present rst with ataxia.
Gait ataxia is the most prominent nding and is
Purkinje cell loss
present in all patients; ataxia of the limbs, which is
also
Figure 313. Distribution of disease in alcoholic cere- common, may be asymmetric. Dysarthria and nystagbellar degeneration. Midsagittal view of the cerebellum mus occur less frequently. Patients may exhibit other
showing loss of Purkinje cells, conned largely to the
neurologic disorders related to hypothyroidism,
superior vermis.
including sensorineural hearing loss, carpal tunnel
syndrome,
reexesfrom polyneuropathyand signs of malnuneuropathy, or myopathy.
trition such as loss of subcutaneous tissue,
generalized
muscle atrophy, or glossitis. Less frequent manifestations include ataxia of the arms, nystagmus,
dysarthria,
hypotonia, and truncal instability.
CT scan or MRI may show cerebellar atrophy (Figure 314), but this is a nonspecic nding that can be
encountered in any degenerative disorder that affects
the cerebellum.
Chronic cerebellar ataxia that begins in adulthood
and primarily affects gait can also occur in hypothyroidism, paraneoplastic syndromes, idiopathic
cerebellar degenerations, and anomalies at the
craniocervical
junction such as Arnold-Chiari malformation. The possibility of hypothyroidism or systemic cancer, which
may be treatable, should be investigated with thyroid
function tests, chest x-ray, and, in women, breast and
pelvic examinations.
No specic treatment is available for alcoholic
cerebellar degeneration. Nonetheless, all patients with
this
3.
PHENYTOIN
-INDUCED
CEREBELLAR
DEGENERATION
diagnosis
should
receive
thiamine
because of the
Chronic
therapy
with
phenytoin,
often with drug Figure 314. CT scan in alcoholic cerebellar degenerapparlevels
ent role of thiamine deciency in the pathogenesisation,
of showing marked atrophy of the cerebellar vermis
in
the
toxic
range,
may
cause
cerebellar
with relative sparing of the cerebellar hemispheres.
Wernicke encephalopathy, a closely related
(CourtesyofAGean.)
degeneration
syndrome.
that
affects from
the cerebellar
hemispheres
inferiornuAbstinence
alcohol, combined
withand
adequate
and
trition, leads to stabilization in most cases.
posterior vermis most severely, while the superior
verSuperior vermis
118 / CHAPTER 3
Laboratory studies show decreased blood levels tected
of
in the blood (Table 310). The CSF may show
thyroid hormones, elevated thyroid-stimulating hora mild lymphocytic pleocytosis or elevated protein.
mone (TSH), and often increased CSF protein.
Treatment may include removal of the underlying
or immunosuppression.
Replacement therapy with levothyroxine, 2550 tumor
The
diagnosis of paraneoplastic cerebellar
increased gradually to 100200 orally, usually
degeneraproduces denite but incomplete improvement.
tion is most difcult when the neurologic symptoms
5. PARANEOPLASTIC CEREBELLAR DEGENERATION
precede the discovery of underlying cancer. The freCerebellar degeneration can also occur as a remote
quent occurrence of dysarthria and dysphagia helps
efto
fect of systemic cancer. Lung cancer (especially distinguish this condition from the cerebellar synsmalldromes produced by chronic alcoholism or hypothycell), ovarian cancer, Hodgkin disease, and breast roidism. Ataxia of the arms also suggests that alcohol
canis
cer are the most commonly associated neoplasms.an unlikely cause. Wernicke encephalopathy should
Paraneoplastic degeneration affects the cerebellar
6.
al-AUTOSOMAL DOMINANT SPINOCEREBELLAR ATAXIAS
vermis and hemispheres diffusely. The pathogenetic
The
spinocerebellar
(Table
wayshereditary
be considered
because ofdegenerations
the susceptibility
of
mechanism in many cases appears to involve
311)
are a group of inherited disorders characterized
paantibodby
slowly
cerebellar ataxia that affects
tients
withprogressive
cancer to malnutrition.
ies to tumor cell antigens that cross-react with
gait
cerebelearly and severely and may eventually conne the
lar Purkinje cells. Cerebellar symptoms may appear
pabetient to bed. These disorders show considerable
fore or after the diagnosis of systemic cancer and clinical
typically develop over months. Although the disorder
variability, even within a given family. Most
usually progresses steadily, it may stabilize;
autosomal
remission
dominant forms, termed spinocerebellar ataxias or
has been described with treatment of the underlying
SCAs, begin in adulthood and show anticipation, in
neoplasm.
which the age at onset decreases, the disease
Gait and limb ataxia are characteristically promiseverity innent, and dysarthria occurs in most cases. The limbs
creases, or both, in successive generations.
may be affected asymmetrically. Nystagmus is rare. Autosomal dominant spinocerebellar ataxia is
Paraneoplastic involvement of other regions of thegenetnervous system may produce associated dysphagia,
ically heterogeneous. The best characterized gene
dementia, memory disturbance, pyramidal signs, or
deTable 310. Antineuronal autoantibodies in paraneoplastic syndromes.
neuropathy. Anti-Purkinje cell antibodies, such as fects are expanded CAG trinucleotide repeats coding
anti-Yo (ovarian and breast cancer), or antinuclear for polyglutamine tracts in proteins without known
Antigen
antibodies, such as anti-Hu (small-cell lung cancer)function
(ataxins), and in the 1A-subunit of the P/Qand
anti-Ri
(breast
cancer),
can
sometimes
be
detype
calcium
channel,
found 2on VGKC
nerve
VGCC1 Amphiphysin
Ma2ismGluR1
3 termiSyndrome
Hu
Yo
Ri
Tr
Ma1which
Limbic encephalitis
Brainstem encephalitis
Cerebellar degeneration
Stiff-person syndrome
Neuromyotonia
Lambert-Eaton syndrome
1
Opsoclonus/myoclonus
Sensory neuronopathy
Voltage-gated calcium channel, P/Q type.

Metabotropic glutamate receptor, type 1.
3 Voltage-gated potassium channel.
AdaptedfromDarnellRB,PosnerJB:Paraneoplasticsyndromesinvolvingthenervoussystem.NEnglJ
Med2003;349:15431554.
2
Table 311. Genetic and clinical features of hereditary spinocerebellar ataxias.

Disease
Gene
Protein
Gene Defect
Syndrome
Autosomal recessive
FA1
FRDA1
Frataxin
GAAn2
Autosomal dominant
SCA 14
SCA1
Ataxin-1
CAGn
ADCA I5
SCA 2
SCA2
Ataxin-2
CAGn
ADCA I
SCA 3/MJD6
SCA3
Ataxin-3
CAGn
ADCA I
SCA 4
SCA4
Unknown
Unknown
ADCA I
SCA 5
SCA5
Unknown
Unknown
ADCA III
SCA 6
CACNL1A4
Ca channel7
CAGn
ADCA III
SCA 7
SCA7
Ataxin-7
CAGn
ADCA II
SCA 8
SCA8
Unknown
CTGn
ADCA I
SCA 10
SCA10
Ataxin-10
ATTCTn
ADCA III
SCA 11
SCA11
Unknown
Unknown
ADCA III
SCA 12
PPP2R2B
PPase28
CAGn
ADCA I
SCA 13
SCA13
Unknown
Unknown
SCA 14
PRKCG
PKC10
Missense
ADCA III
SCA 15
SCA15
Unknown
Unknown
ADCA III
SCA 16
SCA16
Unknown
Unknown
ADCA III
SCA 17
TBP
TATA-binding protein
CAGn
ADCA I
SCA18
SCA18
Unknown
Unknown
11
SCA19
SCA19
Unknown
Unknown
12
SCA20
SCA20
Unknown
Unknown
13
SCA21
SCA21
Unknown
Unknown
14
SCA22
SCA22
Unknown
Unknown
ADCA III
SCA23
SCA23
Unknown
Unknown
15
SCA tremor
FGF14
Fibroblast growth factor-14
Missense
ADCA I
SCA25
SCA25
Unknown
Unknown
16
FA, Friedreich ataxia.

XYZn, expanded XYZ trinucleotide repeat; VWXYZn, expanded VWXYZ pentanucleotide repeat.
3 Childhood onset, ataxia, dysarthria, pyramidal signs, neuropathy, scoliosis, cardiomyopathy, diabetes.
4 SCA, spinocerebellar ataxia.
5 ADCA I includes ataxia, dysarthria, pyramidal signs, extrapyramidal signs, ophthalmoplegia and dementia; ADCA II
includes
ataxia, dysarthria, and pigmentary maculopathy; ADCA III includes ataxia, dysarthria, and sometimes mild pyramidal
signs.
6 MJD, Machado-Joseph disease (same as SCA3).
7 P/Q-type voltage-gated calcium channel, -subunit.1A
8 Protein phosphatase 2, regulatory subunit B,
isoform.
9 Childhood onset, ataxia, and mental retardation.
10 Protein kinase C, gamma subunit.
11 Ataxia, muscle atrophy, sensory decit.
12 Ataxia, mild cognitive defect.
13 Ataxia, dysphonia, palatal tremor.
14 Ataxia, extrapyramidal signs.
15 Ataxia, tremor, dyskinesia.
16 Ataxia, sensory neuropathy.
Adaptedfromwww.neuro.wustl.edu
119
2
120 / CHAPTER 3
nals. Other types of mutations include expanded CTG
7. FRIEDREICH ATAXIA
trinucleotide (SCA8) and ATTCT pentanucleotide Among the idiopathic degenerative disorders that
(SCA10) repeats. In many cases, the size of these proexpansions correlates with disease severity and
duce cerebellar ataxia, Friedreich ataxia merits
inversely
separate
with age at onset.
consideration because it is the most common, and
The gain-of-function mutations seen in SCAs ap-bepear to alter the properties of the mutated protein,cause of its unique clinical and pathologic features.
which cannot be processed normally. The abnormally
Unprocessed fragments are conjugated with ubiquitin,
like
a most of the late-onset autosomal dominant spinprotein involved in nonlysosomal degradation of ocerebellar ataxias discussed above, Friedreich ataxia
defecbegins in childhood. It is transmitted by autosomal retive proteins, with which they are transported to the
cessive inheritance and is due to an expanded GAA
nucleus in a complex called a proteasome. The
trinucleotide repeat in a noncoding region of the
precise
frataxin gene on chromosome 9 (see Table 311). The
relationship of this accumulation to the neurotoxicity
recessive inheritance of Friedreich ataxia suggests a
that results from these mutations is uncertain, butlossintranuclear protein aggregates may interfere with of-function mutation. Most affected patients are honuclear
mozygous for the trinucleotide repeat expansion in
function.
the
Detailed clinical evaluation of relatively large
Atrophy of the cerebellum and sometimes also of
Friedreich
numbers ataxia gene, but some are heterozygous,
the brainstem may be apparent on CT or MRI scans
with
of patients has allowed certain diagnostic criteria to
(Figure 315). However, denitive diagnosis is by the
be repeat affecting one allele and a point mutation
demonstrating one of the known SCA gene defectson
on
established
(see Table 311). Clinical manifestations
genetic testing. There is no specic treatment for the
al- other allele.
spinocerebellar ataxias, but occupational and
Thealways
pathologic
ndings
are localized,
forbefore
the most
most
appear
after age
4 years and
the
physical
part,
to
the
spinal
cord.
These
include
degeneration
end
Findings
therapy and devices to assist ambulation may be Clinical
of
of puberty, with more expanded repeats correlating
helpthe
withspinocerebellar
earlier onset. tracts, posterior columns, and
ful, and genetic counseling may be indicated.
dorsal
The initial symptom is progressive gait ataxia, folDentatorubral pallidoluysian atrophy (DRPLA) also
roots
as depletion
ofwithin
the neurons
in During
Clarke collowedas
bywell
ataxia
of all limbs
2 years.
the
produces autosomal dominant cerebellar ataxia and
umn
that
are
the
cells
of
origin
of
the
dorsal
same early period, knee and ankle tendon reexes
respinocereare
sults from a polyglutamine expansion. Because ex-bellar
tracts.
Large dysarthria
myelinatedappears;
axons ofreexes
peripheral
lost and
cerebellar
in the
trapyramidal features are prominent, this disordernerves
is
and
cell
bodies
of
primary
sensory
in
arms and in some cases at the knees may neurons
be
discussed in Chapter 7.
dorsal
root
ganglia
are
also
involved.
preserved.
Figure 315. CT scan in spinocerebellar atrophy,

showing an atrophic cerebellum and brainstem.
(CourtesyofAGean.)
Joint position and vibration sense are impaired in the

legs, typically adding a sensory component to the
gait
ataxia. Abnormalities of light touch, pain, and
temperature sensation occur less frequently. Weakness of the
legsand less often the armsis a later development
and may be of the upper or lower motor neuron
variety
(or both).
Extensor plantar responses usually appear during
the
rst 5 years of symptomatic disease. Pes cavus (higharched feet with clawing of the toes caused by
weakness
and wasting of the intrinsic foot muscles) is a widely
recognized sign, but it also may be an isolated nding
in otherwise unaffected family members. It is also a
classic feature of other neurologic disorders, notably
certain hereditary peripheral neuropathies (eg,
CharcotMarie-Tooth disease). Severe progressive
kyphoscoliosis
contributes to functional disability and may lead to

chronic restrictive lung disease. While
teen years. The bulbar conjunctivae are typically afcardiomyopathy
fected rst, followed by sun-exposed areas of the
is sometimes detectable only by echocardiographyskin,
or
vectorcardiography, it may result in congestive heart
including the ears, nose, face, and antecubital and
failure and is a major cause of morbidity and death.
popliteal fossae. The vascular lesions, which rarely
Other abnormalities include visual impairment bleed, spare the central nervous system.
(usually from optic atrophy), nystagmus,
Immunologic
paresthesias,
impairment (decreased circulating IgA and IgE) usutremor, hearing loss, vertigo, spasticity, leg pains, ally becomes evident later in childhood and is maniand
fested by recurrent sinopulmonary infections in more
diabetes mellitus.
than 80% of patients.
Friedreich ataxia can usually be differentiated from Other common clinical ndings are progeric
other cerebellar and spinocerebellar degenerationschanges of the skin and hair, hypogonadism, and in(see
sulin resistance. The characteristic laboratory abnorabove) by its early onset and the presence of
malities include those related to immunologic deprominent
ciency and elevation of and
sensory impairment, areexia, skeletal abnormalities,
carcinoembryonic antigen levels.
and cardiomyopathy. A somewhat similar disorder
Because the vascular and immunologic manifestamay
tions of ataxia-telangiectasia occur later than the
result from vitamin E deciency. Cerebellar ataxia
neurothat
logic symptoms, the condition may be confused with
begins in childhood can also be caused by ataxiaPrognosis
Friedreich ataxia, which also manifests in childhood
telang(see above). Ataxia-telangiectasia can be
No
treatment
is available,
butthat
orthopedic
procedures
iectasia;
the clinical
features
distinguish
distinguished
such
as tenotomy may help to correct foot
Friedreich
by its earlier onset (before age 4 years), associated
deformities.
ataxia from ataxia-telangiectasia are discussed
choreoathetosis, and the absence of such skeletal
Advances
in
antimicrobial
therapy
have
altered
the
below.
abnorultimalities as kyphoscoliosis.
mate course of the disorder, so that cardiomyopathy
There is no specic treatment for ataxiahas
telangiectabecome more frequent and infection less frequent9.
asWILSON DISEASE
Cerebellar
symptoms
occur
in Wilson
disease,
sia, but antibiotics
aremay
useful
in the
management
ofa
a
disorder
of
copper
metabolism
characterized
by
cause of death. Neurologic dysfunction typically incopper
fections and x-rays should be avoided because of the
results
deposition
in a variety
of tissues.
Wilsonradiation
disease is
abnormal cellular
sensitivity
to ionizing
in an
in
the
inability
to
walk
unaided
within
5
years
after
8. ATAXIA-TELANGIECTASIA
inherited
autosomal
recessive
disorder
due
to
the
Ataxia-telangiectasia (also known as Louis-Bar syn-this
10.
Cdisorder.
REUTZFELDT-JAKOB DISEASE
mutations
onset
of
symptoms
and
in
a
bedridden
state
within
drome) is an inherited autosomal recessive disorder
Creutzfeldt-Jakob
is described
in Chapter 1 as
in the ATP7B genedisease
on chromosome
13q14.3q21.1,
1020
average
duration
ofresults
symptomatic
with itsyears.
onsetThe
in infancy.
The
disease
from mua
which codes for the polypeptide of a copper-transilltations
in the ATM gene, which has been localized prion
to
disease that causes dementia. Cerebellar signs
porting ATPase. Wilson disease is discussed in more
ness is about 11q22.3.
25 years,Deletions,
with deathinsertions,
occurring and
at a subchromosome
are
demean
stitutions
all have been described and are presumed
present in about 60% of patients, and the patients
tail in Chapter 7.
age of about 35 years.
to
presrepresent loss-of-function mutations, consistent with
ent with ataxia in about 10% of cases. Cerebellar inthe autosomal recessive inheritance of ataxiavolvement is diffuse, but the vermis is often most setelangiecverely affected. In contrast to most other cerebellar
tasia. Although the abnormal gene product has notdisorders, depletion of granule cells is frequently
been identied, a defect in DNA repair is thought to
more
be involved in pathogenesis. Ataxia-telangiectasiastriking
is
than Purkinje cell loss.
characterized by progressive cerebellar ataxia,
Patients with cerebellar manifestations of
oculocuCreutzfeldt-Jakob disease usually complain rst of
taneous telangiectasia, and immunologic deciency.
gait
All patients suffer from progressive pancerebellar deataxia. Dementia is usually evident at this time, and
generationcharacterized by nystagmus, dysarthria,
cognitive dysfunction always develops eventually.
and gait, limb, and trunk ataxiathat begins in in-Nysfancy. Choreoathetosis, loss of vibration and position
tagmus, dysarthria, truncal ataxia, and limb ataxia
sense in the legs, areexia, and disorders of
are
voluntary
all present initially in about half the patients with the
eye movement are almost universal ndings. Mental
ataxic form of Creutzfeldt-Jakob disease. The course
deciency is commonly observed in the second is
decade;
characterized by progressive dementia, myoclonus,
oculocutaneous telangiectasia usually appears in the
and
breasts and skin, chest x-ray, urinalysis, and tests for

the
presence of occult blood in the stool may lead to a
diag122 / CHAPTER 3
nosis. The prognosis for patients with cerebellar
metasextrapyramidal and pyramidal dysfunction. Death
tases is usually worse than for patients with
typisupratentorcally occurs within 1 year after onset.
ial lesions. Patients with carcinoma of the breast tend
11. POSTERIOR FOSSA TUMORS
to
Tumors of the posterior fossa cause cerebellar sympsurvive longer than those with primary lung tumors.
toms when they arise in the cerebellum or compress
Cerebellar astrocytomas usually occur between the
it
from without. The most common cerebellar tumorsages
of of 2 and 20 years, but older patients can also be
afchildhood are astrocytomas and medulloblastomas.
Metastases from primary sites outside the nervousfected. These tumors are often histologically benign
and cystic in appearance. Symptoms of increased insystracranial pressure, including headache and vomiting,
tem predominate in adults (Table 312).
typically precede the onset of cerebellar dysfunction
Patients with cerebellar tumors present with
headache from the increased intracranial pressureby
or
several months. If complete surgical resection is
with ataxia. Nausea, vomiting, vertigo, cranial nerve
possipalsies, and hydrocephalus are common. The nature
ble, cerebellar astrocytoma is potentially curable.
of
the clinical ndings varies with the location of the tu-Medulloblastoma is common in children but rare in
mor. Most metastases are located in the cerebellaradults. It is believed to originate from
hemispheres, causing asymmetric cerebellar signs.neuroectodermal
rather than glial cells. In contrast to astrocytomas,
Medulloblastomas and ependymomas, on the other
medulloblastomas tend to be highly malignant. They
hand, tend to arise in the midline, with early involveoften spread through the subarachnoid space and
ment of the vermis and hydrocephalus.
As in the case of most brain tumors, the CT scanventricles and may metastasize outside the nervous
orespeciallyMRI is extremely useful in diagnoses
system.
but biopsy may be required for histologic
Whereas most childhood medulloblastomas are
characterizalocated
tion. Methods of treatment include surgical resection
in the midline, adult-onset tumors usually arise laterand irradiation. Corticosteroids are useful in controlally. Headache, vomiting, ataxia, and visual deterioraling the associated edema.
Metastasesfrom the lung and breast and less tion are common presenting symptoms. Hemiataxia
is
often
frequent nding in adults because of the
from other sitesare the most common tumors of athe
hemispheric
cerebellum, especially in adults. The site of the
location of most tumors. Gait ataxia, papilledema,
primary
Table
312.
Tumors
of
the
cerebellum.
nystumor may or may not be evident at the time the patagmus, facial palsy, and neck stiffness are also comtient presents with central nervous system
Percentage of
mon. Without treatment, medulloblastoma causes
involvement.
Cerebellar
Percentage
of
death within a few months after presentation. TreatIf the site is not evident,
careful
examination
of the
Tumors in
All Cerebellar
ment with partial surgical resection, decompression,
Adults (20 years) and craniospinal irradiation may prolong survival for
Tumors
Type
years. Developing the tumors in adulthood and being
Metastasis
36
56
female are favorable prognostic factors.
Acoustic neuromas have been discussed previously
Astrocytoma
28
10
as a cause of vestibular nerve dysfunction. Growth of
Medulloblastoma
16
9
these or other less common tumors of the cerebellopontine angle may result in compression of the
Schwannoma
4
7
ipsilatHemangioblastoma
4
5
eral cerebellar hemisphere, causing hemiataxia in
addiMeningioma
4
5
tion to the earlier symptoms of vertigo and hearing
Ependymoma
2
1
loss. These tumors are histologically benign and often
fully resectable. Unilateral acoustic neuromas can
Other
6
7
occur
DatafromGilmanS,BloedelJR,LechtenbergR:
in neurobromatosis 1 (von Recklinghausen disease),
Page334in:DisordersoftheCerebellum.Vol21 whereas bilateral acoustic neuromas are
oContemporaryNeurologySeries.Davis,1981.f
characteristic of
neurobromatosis 2. These disorders are discussed in
more detail in the section on cerebellopontine angle
tumors (above).

arachnoidal cap cells, and involve the cerebellum Table 313. Causes of sensory ataxia.
indirectly by compression. The locations of posterior
Polyneuropathy1
fossa
Autosomal dominant sensory ataxic neuropathy
meningiomas (in decreasing order of frequency)
Cisplatin (cis-platinum)
include
Dejerine-Sottas disease (HMSN2 type III)
the posterior surface of the petrous bone, the
Diabetes
Diphtheria
tentorium
cerebelli, the clivus, the cerebellar convexities, andHypothyroidism
Immune-mediated neuropathies (GALOP syndrome, antithe
foramen magnum. Meningiomas grow slowly and usu-MAG antibody syndrome, Miller Fisher syndrome, antiGD1b antibody syndrome)
ally present with headache, although tumors of the
Isoniazid
cereParaneoplastic sensory neuronopathy (anti-Hu
bellopontine angle or clivus may come to attentionantibodies)
when
Pyridoxine
they give rise to cranial nerve or brainstem
Refsum disease
Taxol
symptoms.
Where possible, complete surgical resection is
Myelopathy3
curative.
Acute transverse myelitis
Ependymomas most commonly arise from the AIDS (vacuolar myelopathy)
walls
Multiple sclerosis
Tumor or cord compression
or choroid plexus of the fourth ventricle. Like medul12.
POSTERIOR F
OSSA MALFORMATIONS
loblastomas,
they
are malignant tumors that seed Vascular malformations
Developmental
anomalies
affecting
the cerebellum
through the ventricular
system
and usually
occur in
Polyneuropathy or myelopathy
and
children. Because of their location they produce early
Friedreich ataxia
brainstem
may
present
with
vestibular
or
cerebellar
hydrocephalus; cerebellar signs caused by
Neurosyphilis (tabes dorsalis)
symptoms
in
adulthood.
This
occurs
most
commonly
compression
Nitrous oxide
with
type
(adult)manifestations.
Arnold-Chiari malformation,
which
are late
orI minor
Surgical resection,
consists
of downward
displacement
ofprocedures
the cerebellar
craniospinal
irradiation,
and shunting
toVitamin E deciency
tonresils
the foramen
The clinical
1 Involving large, myelinated sensory bers.
lievethrough
hydrocephalus
may magnum.
prolong survival,
but widemanifes2 Hereditary motor and sensory neuropathy.
spread dissemination of the tumors and
tations
of
this
malformation
are
related
to
cerebellar
3 Involving posterior columns.
postoperative
inrecurrences are common.
volvement, obstructive hydrocephalus, brainstem
compression, and syringomyelia. Type II Arnold-Chiari
malformation is associated with meningomyelocele
Compression of the brainstem by herniated cerebellar
(protissue may be associated with vertigo, nystagmus,
trusion of the spinal cord, nerve roots, and meninges
and
through a fusion defect in the vertebral column) and
lower cranial nerve palsies. Syringomyelia typically
has
proits onset
in childhood.
Dorsal
root
Dorsal spinocerebellar tract
Cerebellar
ataxia in the type I malformation
usually
Posterior column
Lateral corticospinal tract
affects the gait and is bilateral; in some cases it is
asymmetric. Hydrocephalus leads to headache and
vomiting.
Vitamin B12 deficiency

(subacute combined degeneration)
Tabes dorsalis
Friedreich ataxia
Figure 316. Principal sites of spinal cord disease (shading) in disorders producing sensory ataxia.
124 / CHAPTER 3
duces a capelike distribution of defective pain andGutmann DH et al: The diagnostic evaluation and multidisciplinary management of neurobromatosis 1 and neurobrotemmatosis 2. JAMA 1997;278:5157.
perature sensation.
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pression of the posterior fossa may be of therapeutic
Nadol FB: Hearing loss. N Engl J Med 1993;329:10921102.
benet.
Parnes LS et al: Diagnosis and management of benign paroxysmal
SENSORY ATAXIAS
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Sensory ataxia results from impaired proprioceptive

sensation at the level of peripheral nerves or roots,
posterior columns of the spinal cord, or sensory
Cerebellar & central vestibular disorders
pathways
in the brain. Clinical ndings include defective jointAlbin RL: Dominant ataxias and Friedreich ataxia: an update. Curr
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af-J et al: Clinical spectrum of episodic ataxia type 2. Neurology
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KEY CONCEPTS

Disorders of consciousness include disorders in

Certain causes of acute confusional state must be

An acute confusional state can be most readily

The most common causes of dementia are

Consciousness is awareness of the internal or

DISORDERS OF COGNITIVE FUNCTION / 3

its ascending projections to the thalamus and cerebral

A history of epilepsy suggests ongoing seizures, a

Acute to subacute; uctuating

Not impaired, except occasionally late in

Head trauma, meningitis, subarachnoidTetany

DISORDERS OF COGNITIVE FUNCTION / 5

Multiinfarct dementia, progressive supranuclear palsy

Acquired hepatocerebral degeneration

Creutzfeldt-Jakob disease, AIDS dementia complex

Dementia with Lewy bodies, corticobasal ganglionic degeneration,

Huntington disease,Wilson disease

Argyll Robertson Neurosyphilis

Normal pressure hydrocephalus

sure to cold, ethanol or sedative drug intoxication,Head & Neck

Table 15. Minimental status examination.

Evaluation of mental status (Table 14) helps to

1Atotal score of should generally lead to more detailed

and it may be difcult or impossible to conduct the

DISORDERS OF COGNITIVE FUNCTION / 7

Figure 12. Anatomic basis and clinical features of aphasias.

DISORDERS OF COGNITIVE FUNCTION / 9

Meningitis, encephalitis, subarachnoid hemorrhage

India ink stain

Alcohol intoxication, hyperglycemia Glutamine

HIV antibody titer AIDS and related disorders

Polymerase chain Bacterial meningitis, tuberculous

Complex partial seizures, herpes

DISORDERS OF COGNITIVE FUNCTION / 11

Opening Red Blood

Protein Glutamine Smears Cultures

Lumbar cerebrospinal uid.

with these syndromes should be given thiamine, 100

DISORDERS OF COGNITIVE FUNCTION / 13

Infectious and Noninfectious Meningitis/Encephalitis

also Table 111.

monia and pulmonary edema caused by uid

Like ethanol, sedative drugs can produce confusional

DISORDERS OF COGNITIVE FUNCTION / 15

Table 112. Features of hyperglycemic

Early signs of hypoglycemia include tachycardia,

DISORDERS OF COGNITIVE FUNCTION / 17

VITAMIN B12 DEFICIENCY

The presenting symptoms are usually due to anemia

DISORDERS OF COGNITIVE FUNCTION / 19

istration of lactulose, 2030 g three or four times

declined dramatically in recent years, at least partly

DISORDERS OF COGNITIVE FUNCTION / 21

Less than 3 months S agalactiae

Ampicillin, 100 mg/kg intravenously every 8 hours

cefotaxime, 50 mg/kg intravenously every 6 hours

vancomycin, 15 mg/kg intravenously every 6 hours, to maximum of

vancomycin, 15 mg/kg intravenously every 6 hours, to maximum of

Gram-negative bacilli cefotaxime, 2 g intravenously every 6 hours

ceftazidime, 50100 mg/kg intravenously every 8 hours, to

ceftazidime, 50100 mg/kg intravenously every 8 hours, to

Bacteria typically gain access to the central nervous