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THE HYPERKINETIC syndromes

The patient who presents with a hyperkinetic movement disorder experiences excessive movement. The
patient may state that it interferes with the activities of daily living, or the patient may be unaware of the problem
and the family may prompt the evaluation. The correct diagnosis depends on the character of the movement, that
is, when it occurs, its speed, its location, and contributing factors. The more common disorders include dystonia,
tremor, chorea, tics, myoclonus, and tardive dyskinesia.

I. Dystonia
A. Definition. Dystonia is a disorder consisting of intermittent or sustained, often painful, twisting,
repetitive muscle spasms that may occur in one part of the body (focal dystonia) or throughout the entire body
(generalized dystonia).
1. Initially, the movements may be triggered by a specific act, such as writing, and are made worse by
movement of other parts of the body.
2. There may be superimposed tremor or myoclonic jerks.
3. The patient may use a "sensory trick" - a tactile stimulus - that can decrease the muscle contractions.
4. The movements may be painful.
B. Classification
1. Dystonia is classified by the part of the body affected (focal versus generalized dystonia), by the age
of onset (adult-onset versus childhood-onset dystonia), and by contributing factors (idiopathic versus secondary
dystonia).
2. Psychogenic dystonia. Dystonia was once diagnosed as hysteria or malingering, and patients were
often referred to a psychiatrist for evaluation. Psychogenic dystonia can be differentiated from idiopathic or
secondary dystonia only with a detailed history and physical examination. Sensory tricks and variations in
weakness are common in idiopathic dystonia, and referral to a specialist may be needed to discern idiopathic
dystonia from the psychogenic form. Clues to psychogenic dystonia include inconsistent movements and
postures, false weakness and sensory symptoms, and overt psychiatric disease.

C. Pathophysiology
1. Idiopathic dystonia is not associated with any particular brain lesion. Secondary dystonia is most
often observed in patients with lesions in the basal ganglia, such as the putamen, and their connections with the
thalamus and cortex.

D. Generalized dystonia. The spasms of generalized dystonia affect most of the body. They can manifest
in one part of the body, particularly the foot, but rapidly spread to contiguous parts and usually involve the limbs,
trunk, and neck. Generalized dystonia more commonly manifests among children and young adults. Onset is
typically in the legs and spreads to contiguous body parts.

E. Focal dystonia is isolated to one part of the body

F. Etiology. Dystonia can be idiopathic (primary) or have a known cause (Secondary

1. Idiopathic (primary) dystonia


a. Idiopathic dystonia has no known cause.
b. Birth history is normal, and the examination findings are normal exifor dystonia. Ceruloplasmin and
brain imaging are normal.
c. Types of idiopathic dystonia include focal and generalized forms. Regardless of a focal or generalized
presentation, dystonia can be genetic, such as autosomal dominant (DYT1), X-linked (Lubag syndrome), or
sporadic.

2. Secondary dystonia. The most common known metabolic defect causing secondary dystonia is
Wilson's disease.

3. Acquired dystonia occurs as a result of an injury, treatment, or other disease process. These can include
a. Prenatal injury resulting in an ischemic event manifesting as dystonia.
b. Exposure to toxins (carbon monoxide, manganese) resulting in structural changes to the basal
ganglia.
c. Anoxic injury to the cerebral cortex or basal ganglia resulting in dystonic posturing.
d. Tardive syndrome from dopamine blockers (phenothiazine, metoclopramide). Tardive dystonia
generally occurs during treatment or within 3 months of discontinuation of therapy.
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e. Focal brain lesions (stroke, tumor, demyelinating, postinfectious, posttraumatic), regardless of the
cause, can manifest as dystonia.
f. Peripheral nerve injury to the neck or limbs can result in dystonic posturing of that body part.
Why this causes dystonia has not been determined.
g. Psychogenic dystonia remains a diagnosis of exclusion. Irregular spasms, unusual triggers, and bizarre
postures may be clues.

G. Clinical manifestations of dystonia


1. Focal dystonia
a. Blepharospasm is a disorder that consists of uncontrollable involuntary spasms of the eyelids
causing spontaneous closure. It often interferes with vision, resulting in functional blindness. It may be
worsened by bright light or stress.
b. Oromandibular dystonia consists of grimacing of the lower part of the face, usually involving the
mouth, jaw, and platysma muscle. If associated with blepharospasm, it is called Meige's syndrome.
c. Spasmodic torticollis or cervical dystonia consists of intermittent, uncontrollable spasms of the
neck muscles, often associated with severe pain. The neck may involuntarily turn, tilt, or rotate forward, sideways,
or backward.
d. Spasmodic dysphonia involves only the vocal cords. There are two types of spasmodic dysphonia.
With adductor-type spasmodic dysphonia, hyperadduction of the cords produces an intermittent strain and
strangle quality to the voice. Often patients also report tightness in the throat during the spasms. With the more
rare abductor type of spasmodic dysphonia, there is a whispering quality to the voice, similar to the movie star
Marilyn Monroe's voice.
e. Occupational dystonia. Writer's cramp is the most common and most underdiagnosed form of limb
dystonia. Dystonic posturing may be noticed in the hand or foot. Early in the course of the disease, the movement
may be brought out by performing a specific task such as writing, typing, or playing a musical instrument.
Examples of this include an auctioneer who has jaw dystonia only during an auction, a secretary who has
dystonic hand cramps while typing, and a violinist who has finger spasms only while playing.
2. Hemidystonia involves one side of the body and almost always results from a focal lesion (vascular,
neoplastic, or traumatic).
3. Generalized dystonia. Spasms occur in two or more limbs, and usually also in the trunk and neck.
Symptoms usually begin in the legs and progressively involve other parts of the body.

II. Tremor
A. Definition. Tremor consists of rhythmic, oscillating movements of agonist and antagonist muscles. The
movements are equal in amplitude and frequency. Symptoms are made worse by anxiety and disappear with sleep.
B. Classification
1. Physiologic tremor is a low-amplitude (8 to 12 Hz) tremor that is most prominent in
outstretched hands and that under certain circumstances is present in all persons.
2. Essential tremor is a postural or action-involved tremor that rarely is present at rest. The frequency
usually is 4 to 12 Hz but may decrease with age. Data suggest that different anatomic locations (arm tremor only
versus head and arm tremor versus isolated head tremor) may have clinically different presentations. Most
subjects progressed slowly, but a small subgroup had a more rapid progression. The more rapid progression
appeared to be associated with a higher age at onset and the presence of concomitant head and arm tremor.
3. Cerebellar tremor is most prominent in voluntary movements and has a frequency of 3 to 4 Hz.
Patients perform poorly on finger-to-nose and heel-to-shin testing. The tremor may involve only the trunk in
some patients.
4. Rest tremor (parkinsonian tremor) occurs at 3 to 7 Hz and is most obvious when the limb is fully
supported and at rest. Rest tremor is reduced by action and intention.
C. Etiology
1. Physiologic tremor is exacerbated by excited mental states, metabolic endocrine derangements,
fever, drugs (thyroid, lithium, (3-agonists, phylline, and sodium valproate), alcohol withdrawal, and caffeine
use
2. Essential tremor
a. The cause of essential tremor is unclear.
b. Most patients have strong family histories.
c. An association with Parkinson's disease and dystonia has been su|
d. The diagnosis can be confirmed by means of suppression of the t:
through ingestion of a small amount of alcohol. Lack of response does exclude the diagnosis.
3. Cerebellar tremor is typically observed with a lack of feedback of the bellum to the motor cortex.
The cause of a Cerebellar tremor include demnating disease (such as multiple sclerosis), a space-occupying lesion, or
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an ischemic, toxic, or infectious disorder.
4. Rest tremor is part of the clinical features of Parkinson's disease. However, some patients come to medical
attention with this type of tremor and may not have other symptoms of Parkinson's disease, such as bradykinesia,
postural instability, and cogwheel rigidity. The cause of a resting tremor is generally considered to be in the central
nervous system (CNS), but the exact anatomic lesion is unknown.

III. Chorea
A. Definition. Chorea is hyperactive, fast, arrhythmic, often semipurposeful movement. It can affect the limbs,
face, or trunk.
B. Classification
1. Adult-onset chorea
a. Positive family history
(1) Huntington's disease
(a) Huntington's disease is a progressive neurodegenerative disease with autosomal dominant
inheritance localized to chromosome 4.
(b) Patients with positive family histories often come to medical attention with chorea. The mean
age at onset is 40 years, but the onset can be any time from childhood to old age. Some patients may notice problems
with control of fine movement, dropping of objects, or incoordination before the onset of chorea.
(c) Cognitive deficits manifest as problems of concentration, attention, and coordination of
spatial motor acts rather than problems of memory. Subtle findings, such as changes in job performance or interests,
may be revealed when the patient visits the physician. Memory problems often are short-term problems, and unlike
patients with Alzheimer's disease, patients with end-stage Huntington's disease may retain recognition of
family and familiar surroundings.
(2) Wilson's disease.
b. No family history. A focal brain lesion, such as a mass, infection, or vascular lesion can cause chorea
in someone without a family history of chorea.
c. Other causes of chorea
(1) Pregnancy. Chorea gravidarum or chorea caused by hormone replacement in a pregnant patient
should be investigated.
(2) Encephalitis
(3) Drugs. Levodopa, oral contraceptives, anticonvulsants, lithium
(4) Metabolic and autoimmune disorders. Consider systemic lupus erythematosus, antiphospholipid
antibody syndrome, or lupus anticoagulant, thyrotoxicosis Sydenham's chorea, polycythemia rubra vera, and
hypoparathyroidism.
(5) Infection. Lesions due to toxoplasmosis have been reported.

2. Childhood-onset chorea
a. Positive family history
(1) Wilson's disease.
(2) Huntington's disease can occur among children whose fathers have Huntington's
disease.
(3) A history of rheumatic fever suggests a diagnosis of Sydenham's chorea.
(4) A history of progressive cerebellar ataxia, choreoathetosis, ocular motor apraxia, and
telangiectasias of the conjunctiva and skin in child or adolescent suggests a diagnosis of ataxia
telangiectas (Louis—Barr syndrome).
b. History of birth trauma or CNS infection. Childhood-onset chor can develop in children
with a history of birth injury or as a result of encephalitis.

IV. Hemiballismus
A. Definition. Hemiballismus is a rare disorder involving violent flinging of arm or leg on one side of
the body.
B. Etiology. Caused by destruction of part of the contralateral subthalamic nucle that results in
disinhibition of the output of the globus pallidus. The cause I ally is hemorrhagic or ischemic infarction but
also can be previous surgery or undiagnosed tumor.

V. Tics
A. Definition. Tics are sudden, brief movements or vocalizations that appear ir
ularly in a group of muscles. A tic can be a simple movement, such as a head je
or shoulder shrug, or a complicated task that appears to mimic a voluntary г
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such as an obscene gesture.
B. Types of tic disorders
1. Motor tics are abrupt, simple motor tasks, such as rapid head jerks.
2. Vocal tics are repetitive vocalizations, such as grunting and throat cle
3. Complicated motor and vocal tics
a. Complicated motor tics are semipurposeful movements.
b. Complicated vocal tics are repeated words or sentences. They can made-up or obscene words.
4. Tourette's syndrome (TS)
a. Patients with TS have multiple motor tics with one or more vocal tic
b. Onset of symptoms occurs before 21 years of age.
c. The estimated prevalence of TS is 1 to 10 cases per 10,000 persons. However, because the diagnosis of
TS can be missed in the mildest form, this may be a gross underestimation.
d.Symptoms persist for at least 12 months.
e. Behavioral disturbances
(1) Obsessive-compulsive disorder is characterized by repetitive, stereotyped behaviors or
thoughts.
(2) Attention-deficit hyperactivity disorder (with or without hyperactivity) manifests as poor
attention span, restlessness, poor concentration, and low impulse control.
f. Learning disabilities. In addition to obsessive-compulsive disorder and attention-deficit hyperactivity
disorder, some patients with TS have problems with classroom learning and academics.
g. Sleep disturbances include somnambulism, nightmares, insomnia, and restlessness. These disturbances
may be related to treatment, environment, or superimposed psychiatric disease.
C. Etiology
1. Tics involve inherited changes in synaptic transmission.
2. The dopamine hypothesis involves both presynaptic and postsynaptic function. It has been proposed
that TS is caused by supersensitivity of the postsynaptic dopamine receptors, dopamine hyperinnervation, abnormal
presynaptic function, or excessive phasic release of dopamine.
3. TS is generally hereditary. The gene and the biochemical defect are unknown. There is strong evidence that
monozygotic twins have a 86% concordance rate of TS compared with a 20% rate among dizygotic twins. A gene has not
been identified.
4. Other causes
a. Tics may be observed after head trauma, toxin exposure, and encephalitis.
b. Tics can occur in association with other primary neurologic disorders, such as Huntington's
disease, Parkinson's disease, dystonia, and side effects of medications such as methylphenidate.

VI. Myoclonus
A. Definition. Myoclonus is defined as sudden, brief, involuntary jerks or contractions, either rhythmic or
irregular, of single muscles or groups of muscles. It can occur at rest or in response to touch, auditory, or visual
stimulation.
B. Types of myoclonic disorders. Myoclonus can be divided into epileptic, nonepileptic, and inherited types.
1. Epileptic myoclonus comprises generally progressive degenerative disorders affecting the nervous system.
Myoclonus can occur in association with ataxia, dementia, or other seizure types.
a. Progressive myoclonic epilepsy. Myoclonic and tonic-clonic seizures occur among patients with
progressive neurologic decline.
(1) Progressive myoclonic epilepsy is associated with ataxia and dementia.
(2) Neuropathologic studies can help differentiate the subgroups of neurologic syndromes associated
with myoclonus.
(a) Myoclonic epilepsy with ragged red fibers (MERRF) manifests in the second decade
with myoclonic seizures and possibly hearing loss, optic atrophy, neuropathy, or hypoventilation. The
diagnosis is triggered by detection of ragged red fibers during muscle biopsy.
(b) Lafora's myoclonic epilepsy (Lafora's bodies) is an autosomal recessive storage disease
diagnosed by means of skin biopsy. Dementia always is present and is accompanied by myoclonus
and seizures. The mean age at presentation is 14 years, and the disorder can manifest as a behavioral
change or school problem.
(c) Baltic myoclonus (Unverricht-Lundborg disease) has
autosomal recessive inheritance, and the mean age at presentation is 10 years. Myoclonus always is
present, can be provoked by sound or touch, and can provoke a generalized seizure. There is no test for
this disorder. Gait ataxia, dysarthria, tremor, and mild dementia eventually develop.

b. Infection of the CNS


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(1) Creutzfeldt-Jakob disease manifests a rapid onset of dementia and associated neurologic
findings of myoclonic jerks,
(2) Subacute sclerosing panencephalitis. Myoclonus is preceded by intellectual decline,
personality changes, ataxia, and hyperactive reflexes.
c. Drug-related conditions. Myoclonus has been found among patients treated with levodopa,
bromocriptine, tricyclic antidepressants, and narcotics.
d. Toxic and metabolic conditions. Myoclonus can occur in a confused patient as either large
rhythmic movements or small irregular jerks and may be stimulus induced. Myoclonic movements can be
confused with seizures, particularly if the patient is acutely ill, and ruling out seizures may necessitate an EEG.
The most common cause is severe renal or hepatic disease. Systemic infection or drug intoxication also can
cause myoclonic jerks. In rare instances, heavy metal intoxication can cause myoclonus.

2. Nonepileptic myoclonus. Nonepileptic myoclonic disorders are nonprogressive. EEG correlation is


found in some cases of epilepsia partialis continua and juvenile myoclonic epilepsy.
a. Action myoclonus is induced by a voluntary movement or stimulus, such as a loud noise, and
is common after hypoxic injury.
b. Palatal myoclonus consists of regular, rhythmic movement of the palate that can spread to
the throat, face, and diaphragm. Movement persists during sleep. The neuropathologic lesion involves the
red nucleus, the inferior olive, and the dentate nucleus. This lesion often is ischemic, but it can be neoplastic,
inflammatory, or degenerative.
c. Segmental myoclonus may arise in an arm or leg secondary to peripheral nervous system or
CNS trauma, infection, or inflammation. It also can accompany renal failure, neuropathy, or acquired
immunodeficiency syndrome.
d. Sleep myoclonus occurs soon after going to or arousing from sleep. It can be confused with
seizure, particularly among infants. This benign form of myoclonus can be difficult to differentiate from
infantile spasms EEG findings are normal.
e. Epilepsia partialis continua manifests as regular myoclonic jerking associated with a cortical
discharge and no change in level of consciousness.
f. Juvenile myoclonic epilepsy. Among children, jerks can precede seizure. A family history
and abnormal EEG findings establish the diagnosis.

g. Opsoclonus-myoclonus among children


(1) Neural crest tumors may be seen on chest radiograph, or chest CT may be needed.
Elevated levels catecholamine metabolites are present in the urine.
(2) Opsoclonus-myoclonus also can occur in postinfectious syndromes.

3. Inherited myoclonus-dystonia is a new term used to describe cases of myoclonus that begin in
the first two decades of life, are autosomal dominant with variable penetrance and little or no progression,
are responsive to alco hol ingestion, and are associated with dystonia. This disorder has been linked to the
site of the dopamine D2 receptor gene on chromosome 11 in some fam ilies, but the gene has not been
located. In addition, other families with this syndrome do not link to this region of chromosome 11. Eight
families have been linked to a region on chromosome 7q. The likelihood is that inherited myoclonus-
dystonia is a phenotype with several genotypes depending on the family studied.

П. Tardive dyskinesia
A. Definition. Tardive dyskinesia is a disorder that manifests as involuntary move ments among some
patients after they receive prolonged neuroleptic drug therapy.
B. Classification
1. Classic tardive dyskinesia manifests as choreoathetoid movements of the face, limbs, and trunk.
2. Variable forms
a. Tardive dystonia manifests as spasms similar to those observed in torticollis, blepharospasm, or
Meige's syndrome.
b. Tardive akathisia manifests as persistent motor restlessness.
C. Etiology
1. Tardive dyskinesia must be differentiated from other drug-induced syndromes.
a. Acute extrapyramidal syndrome. Anticholinergic drugs relieve acute extrapyramidal
syndrome but leave a tardive syndrome unchanged or worse.
b. Dopamine agonists and levodopa can cause hyperkinetic dyskinesia.
2. Risk factors for tardive dyskinesia
a. Age older than 65 years
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b. Severity may be greater in affective disorders than in schizophrenia.
c. Long-term use of antiemetic drugs, such as prochlorperazine and meto clopramide
d. The relation between total dosage and duration is unclear.

HYPOKINETIC SYNDROMES

Hypookinesia is defined as a decrease in the normal amount, amplitude, or speed of automatic or volitional
movements. The term bradykinesia often is used when the predominant movement abnormality is slowness. The
term akinesia sometimes is used to imply a severe reduction in the amount or amplitude of movement. In truth, it
is rare for any of the three pameters of movement to be affected in isolation. Thus, a patient with bradykinesia
typically manifests a decreased amount and amplitude of movement. The movement of patients with
hypokinesia often is referred to as parkinsonian because bradykinesia is so common in Parkinson's disease.
However, bradykinesia is only one of four cardinal features of Parkinson's disease, the others being rigidity,
tremor, and postural imbalance. Bradykinesia in the absence of the other features is not suficient to make a
diagnosis of Parkinson's disease. The term parkinsonism is used to condition characterized by one or more of
these cardinal signs that clinically resembles idiopathic Parkinson's disease (IPD) but is histologically different and
often accompanied by aditional neurologic signs and symptoms.
Hypokinesia can be used to describe both slowed volitional movements, such as reaching for object, and
automatic movements, such as eye blinking or arm swing while walking. Surrisingly, when hypokinesia develops
over a period of several months or longer, the patient and family members may be relatively unaware of the problem.
A striking and remarkable decrease blink frequency often goes unnoticed until brought to the attention of the
patient or family members. When hypokinesia begins to result in functional disability, patients become aware of
problem in motor function, but rather than attribute it to the speed or amplitude of their movement, they more
commonly describe the difficulty as "weakness." Through careful questing, the clinician can discern a history of
weakness from that of hypokinesia. It is important to determine whether slowness or lack of movement is due to
extrapyramidal system disorder (e.g., Parkinson's disease) or to certain psychiatric disoders (catatonia or severe
depression). One final differentiation must be made from neurotlar disorders producing severe stiffness with
associated slowness of movement. Hypokinesia related to abnormalities of the motor system is seldom life
threatening except extreme form, in which severe immobilization can result in serious complications such as
pneumonia or pulmonary embolism. Yet hypokinesia always merits serious attention because it often results in
considerable functional and social disability.
I. Etiology
A. Basal ganglia abnormalities.
1. Degenerative disorders of the basal ganglia.
2. Pharmacologic agents.
3. Vascular disorders.
4. Trauma.
5. Toxins.
6. Central nervous system infection.

B. Psychiatric syndromes can result in marked slowness or reduction in motor activity.


1. Depression is classically associated with psychomotor retardation in which spontaneous movement
may be both reduced and slowed.
2. Catatonia is characterized by severe reduction in spontaneous movement and a tendency to
remain unmoving in a single position for a protracted period even when passively placed in that position by
the examiner. This phenomenon is known as waxy flexibility.
C. Metabolic disorders, notably hypothyroidism, can result in global slowing of motor function.
D. Neuromuscular disorders that result in extreme muscle rigidity or stiffness retard the speed of
movement, especially of axial and appendicular muscles but seldom of facial muscles.

II. The clinical manifestations of hypokinesia result from different combinations of reduction in the
speed, frequency, and amplitude of spontaneous or automatic movement.
A. Hypomimia is a decrease in facial expression. The diminished range of facial response to emotional
stimuli gives rise to the term expressionless facies. The reduced eye blink rate results in an appearance
resembling a constant stare.
B. Diminished automatic movement is noticeable as a decrease in gesticulation and head movement
during conversation, a reduction in the automatic repositioning of limbs while sitting in a chair or reclining in
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bed, and as a decrease the amplitude of arm swing while walking. In severe hypokinesia, affected arms may not
swing at all but be held in a semiflexed posture across the front of the trunk. Among patients with asymmetric
hypokinesia, as is often the case Parkinson's disease, reduction in arm swing is greatest on the more involved side.
C. Impairment of repetitive movements is particularly prominent among patients with
hypokinesia. The patient may state that activities such as hand writing or buttoning a shirt are particularly difficult.
Not only are repetitive movements performed slowly, but also the amplitude of each successive movement
typically becomes progressively smaller. This may account for the progressively smaller letters (micrographia)
seen when a hypokinetic patient is asked to write a long sentence or for increasing difficulty with the successive
fine movements required to successfully place a button through a button hole.
D. Impaired initiation of movement manifests as difficulty in arising or hesitancy in taking the first
step while attempting to walk. Many pat: with Parkinson's disease have difficulty initiating two motor acts
simultaneously such as standing up and shaking hands.
E. Freezing is a sudden involuntary cessation of a motor act, usually walking, WD other functions remain
intact. This phenomenon is confined to basal disorders. Freezing can occur spontaneously or be provoked by
external circum stances, such as attempting to turn in mid gait or pass through a narrow space such as a
doorway. Emotional stimuli, including anger or fear, can provoke freez ing, as can the prospect of entering a
room filled with people. A variety of sensory or motor tricks such as marching to a cadence are effective in
overcoming freezing.
F. Hypophonia is characterized by diminished amplitude and inflection of speech. In its most severe
form, it results in a muffled pattern of articulation.
Tachy phemia is an excessively rapid speech pattern that is a common accompaniment of hypophonia,
making such speech even more unintelligible.

IV. Physical examination


A. Clinical findings of parkinsonism
1. Gait and posture should be evaluated by having the patient walk a dis tance of at least
20 feet (6 m) in an area free of obstacles. Patients with parkinsonism have a reduced length of
stride. The arms do not swing and may be held flexed across the front of the trunk. The upright
posture is com monly flexed in IPD. There may be difficulty in initiating gait, and turns may be
accomplished with several small steps or with the body moving as a sin gle unit (en bloc turning).
The gait in IPD occasionally is characterized by progressively more rapid, small steps as the
body leans forward (festina tion). On the other hand, the patient's feet may "freeze" in mid gait.
2. Rising from a chair is tested by asking the patient to rise with arms crossed in front of
the body to prevent pushing off. A patient with hypokinesia may need several attempts to
succeed or may be totally unable to rise without using the arms. If the patient is unable to rise
without assis tance, a judgment must be made whether the cause is weakness (which can be tested
independently) or bradykinesia.
3. Postural reflexes are evaluated by asking the patient to establish a comfortable base, with
feet slightly apart. While standing behind the patient, the examiner applies a brisk backward
sternal perturbation. A normal response is to take a corrective step backward to prevent falling.
When pos tural reflexes are impaired, more than one step is needed before balance is
reestablished. When postural reflexes are absent, the patient continues to reel backward and falls
if not stopped by the examiner.
4. Rigidity. If rigidity is present, it must be determined whether it is pre dominant in axial
muscles (neck or trunk), in the limbs, or equally severe both. Increased resistance to passive
movement of the involved body part is easily appreciated when rigidity is severe. When subtle,
rigidity can be rein forced by asking the patient to alternately open and close the fist of the hand on
the side opposite of the arm or leg being tested. The presence of tremor in the limb demonstrating
rigidity gives rise to a ratchet-like sensation referred to as cogwheel rigidity.
5. Tremor may appear in one or more forms among patients with parkinsonism.
a. Resting tremor, the hallmark of IPD and also present in some other forms of
parkinsonism, is most common in the hands and occurs to a slightly lesser extent in the lower
extremities and mandible. Rest tremor rarely involves the head and never affects the voice. It
appears at a fre quency of 4 to 5 Hz and often is at least temporarily extinguished by voli tional
movement. Because it is well known that rest tremor is enhanced by stress or anxiety, a subtle
tremor can be uncovered by asking the patient to perform difficult mental arithmetic, a
mildly stressful task. Rest tremor is the hallmark of IPD, and its absence casts doubt on the
diagnosis but certainly does not rule it out.
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b. Action tremor can be present in Parkinson's disease as well as in other parkinsonian
syndromes, especially those associated with cerebellar dys function. It can be present as a
postural tremor while the arms are out stretched in front of the patient or as a kinetic tremor
while the patient is performing a task such as the finger-to-nose test. Postural tremor alone,
in the absence of parkinsonian signs, suggests a diagnosis of essen tial tremor.
c. Positional tremor. Some tremors are particularly prominent when the involved body part
is placed in a specific position. The wingbeating tremor of Wilson's disease is an example
of this phenomenon. This tremor is noticed when the arms are abducted at the shoulders
while flexed at the elbow.
6. Bradykinesia can be documented by simply observing the speed, amplitude, and amount of
ordinary movements made by the patient, such as gestures or shifting of body position. Specific
tasks such as the finger-to-nose test also provide an opportunity to observe the speed of movement.
Repetitive motion tasks such as tapping the index finger against the thumb demonstrate slowness
of movement and a progressive loss of amplitude as the movement is repeated.
7. Facial expression. The diminished facial expression typical of IPD is characterized by
a constant neutral countenance with infrequent eye blink ing. A fixed facial expression, often
present in progressive supranuclear palsy, consists of an unchanging expression, such as surprise
in which the forehead may be furrowed, the eyelids retracted, and the nasolabial folds deepened.
Myerson's sign is present in Parkinson's disease and a variety of other basal ganglia disorders. It
consists of persistent reflex blinking to repetitive finger taps applied to the glabella just superior to
the bridge of the nose. Among healthy persons, there is rapid habituation to this stimulus, so that
no blinking occurs after the fourth or fifth tap.

B. Secondary parkinsonism. Parkinsonism can be induced by a wide spectrum of disease processes that
affect the brain, especially the basal ganglia. These include infection, cerebrovascular disorders, exposure to
toxins, metabolic disorders, trauma, neoplasm, drug effects, hypoxemia, and hydrocephalus. Selected causes are as
follows.
1. Drug-induced parkinsonism. Neuroleptics and metoclopramide block striatal D2 dopamine
receptors, and reserpine depletes dopamine from presynaptic vesicles. Each of these drugs can
produce motor symptoms indistinguishable from those of IPD. The "atypical" neuroleptic
clozapine mainly blocks extrastriatal (D4) receptors and does not cause parkinsonism. Another
atypical agent, quetiapine, also seems to have low potential to cause this adverse effect. Other
atypical neuroleptics, such as risperidone and olanzapine, can cause parkinsonism, especially when
high dosages are used. An underlying predisposition to Parkinson's disease may be responsible in
part for the emergence of this syndrome. The resolution of drug-induced parkinsonism can take
several months after discontinuation of the offending medication.
2. Normal pressure hydrocephalus (NPH)
3. Hemiatrophy-hemiparkinsonism. Patients with this disorder come to medical attention
at a relatively early age with markedly asymmetric parkin sonism affecting the side of the body
that manifests hemiatrophy. The patients may have a history of abnormal birth and
contralateral hemisphere hemiatrophy, both of which raise the possibility of an early childhood
brain insult that later in life manifests as delayed-onset parkinsonism. The slow progression of
this disorder, its occasional association with dystonia, and the striking asymmetry form the basis
of its distinction from IPD.
4. Toxins
a. MPTP .
b. Carbon monoxide .
c. Manganese intoxication.
d. Cyanide and methanol intoxication .

5. Cerebrovascular disease. Either a lacunar state with multiple small infarcts of the
basal ganglia or subacute arteriosclerotic encephalopathy affecting basal ganglia connections
can lead to parkinsonism. In either condi tion, dementia is common. Resting tremor usually is
absent in these patients.. Gait disorder can be prominent and occasionally constitutes the only
neuro logic symptom, giving rise to the term lower body parkinsonism. The response to levodopa
is limited.
6. Trauma . Pugilistic encephalopathy is a progressive neurologic syndrome characterized by
parkinsonism, dementia, and ataxia. It occurs among box ers with a history of repeated head
trauma. Treatment usually is unsatis factory. Focal acute injury to the midbrain and substantia
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nigra and subdural hematoma are two other possible causes of posttraumatic parkinsonism.
7. Aftermath of encephalitis. Fifty percent of the survivors of the encephalitis lethargica
epidemic of 1917 to 1925 eventually had parkinsonism, often as long as decades after the acute
infection. This form of encephalitis has not reappeared in epidemic form. Accordingly, new
cases of postencephalitic parkinsonism are rare in the modern era.

C. Parkinson's-plus syndromes. This is a group of parkinsonian syndromes dif ferentiated from IPD
by the presence of additional prominent neurologic abnor malities. In these conditions, there can be
cerebellar, autonomic, pyramidal, oculomotor, cortical sensory, bulbar, cognitive, and psychiatric
dysfunction as well as apraxia and movement disorders not typical in unmanaged IPD, such as myoclonus,
dystonia, or chorea. Any of these neurologic or psychiatric abnormali ties can appear early in the course of the
illness. Early falls with gait disturbance or postural instability, absence of resting tremor, early dementia and
supranuclear gaze palsy are signs that always should prompt consideration of a Parkinson's-plus syndrome.
The parkinsonian components of these disorders, such as akinesia and rigidity, are usually not responsive to
levodopa, although early transient responsiveness can be observed. The onset of these diseases is generally
in the fifth or sixth decade of life with an average survival period of 5 to 15 years. The cause of death usually
is pneumonia, other intercurrent infections, or sepsis. The etio- pathogenesis of this entire group of
disorders is largely unknown.
Despite the apparent clinical differences between IPD and the Parkinson's- plus syndromes,
differentiation between the two can be difficult. In a clinico- pathologic study, 24% of patients given the
clinical diagnosis of IPD were found to have a different type of parkinsonism at autopsy. In Parkinson's-
plus syn dromes, the findings at head CT or brain MRI can be unremarkable, can show generalized
cerebral or cerebellar atrophy, or occasionally reveal focal changes in structures such as the caudate,
putamen, cerebellum, or midbrain. Blood cell count, blood chemistry, serology, electromyography (EMG),
and evoked poten tials usually are not helpful. Electroencephalography may show nonspecific abnormality,
such as slowing of the background activity. The specific features of individual Parkinson's-plus syndromes
are as follows. Although each of these conditions has characteristic clinical findings, it is important to
remember that there is considerable overlap in signs and symptoms.

1. Progressive supranuclear palsy (PSP)


a. Clinical features. Early onset of gait difficulty, loss of postural reflexes resulting in
backward falls, and freezing of gait, coupled with supranu clear gaze palsy (initially downgaze) are
suggestive of PSP. Axial rigid ity and nuchal dystonia with extensor posture of the neck, generalized
bradykinesia, "apraxia" of eyelid opening and closing, blepharospasm, a furrowed forehead leading to a fixed
facial expression, and a monotonous but not hypophonic voice are additional features suggesting the
diagno sis. There is variable, but often mild, cognitive decline, especially in exec utive functions. The presence
of prominent bradykinesia in association with the typical fixed facial expression raises the possible
diagnosis of Parkinson's disease for these patients, but the ocular motility abnor malities, the frequent
absence of tremor, and the absence or loss of levodopa response suggest the correct diagnosis.
b. Neuropathologic examination. Globose neurofibrillary tangles are present and affect
mainly the cholinergic neurons of the basal ganglia and brainstem nuclei with apparent sparing of the cortex.
Cytoplasmic neuronal inclusions consisting of aggregated hyperphosphorylated tau protein are present.
2. Cortical-basal ganglionic degeneration
a. Clinical features. This syndrome can manifest as a strikingly asymmetric or unilateral akinetic-rigid
syndrome associated with limb apraxia, alien limb phenomenon, cortical sensory signs, stimulus sensitive
myoclonus, dystonia, and postural or action tremor. Supranuclear gaze palsy, cognitive impairment, and
pyramidal tract signs also can be present.
b. Neuroimaging. Findings at MRI or CT of the brain are abnormal in some cases and reveal
asymmetric frontoparietal atrophy.
c. Neuropathologic examination. Neuronal loss and gliosis are found in the frontoparietal regions
and substantia nigra pars compacta. Swollen achromatic neurons and basophilic nigral inclusions, which
represent an overlap with Pick's disease, are characteristic. Abundant cytoplasmic inclusions consisting of
aggregated hyperphosphorylated tau protein are found.
3. Multiple system atrophy (MSA)
a. Clinical features. This degenerative disorder consists of three component syndromes that can occur
individually or in various combinations.
(1) Striatonigral degeneration. In this syndrome, akinetic-rigid parkinsonism is predominant, but
tremor is seldom present. It usually is not responsive to levodopa because the degenerative process
involves the postsynaptic dopamine receptors.
(2) Sporadic olivopontocerebellar atrophy. Cerebellar signs, especially ataxia and dysarthria, are
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the prominent findings in this syndrome, although they seldom exist in isolation. Other associated
signs include gaze palsy, hyperreflexia, an extensor plantar response, and most important, features of
parkinsonism.
(3) Shy-Drager syndrome. In this syndrome, dysfunction of the autonomic nervous system results in
symptoms such as disabling orthostatic hypotension, bowel and bladder dysfunction, and impotence.
It is not clear whether these three disorders are distinct entities or represent different clinical
presentations of the same basic condition, but they commonly occur together and share the pathologic
features described in c. From a diagnostic point of view, the syndrome of MSA always should be
suspected when a patient with hypokinesia has little response to levodopa and has prominent
autonomic or cerebellar dysfunction.
b. Neuroimaging. MRI of the brain shows putaminal hypointensity in striatonigral degeneration,
probably caused by excessive iron deposition in this structure. Cerebellar atrophy can be seen in sporadic
olivoponto-cerebellar atrophy.
c. Neuropathologic examination. Common to all the MSA syndromes is the presence of
characteristic glial cytoplasmic inclusions. Like Lewy bodies in IPD, these inclusions stain for the protein a-
synuclein. Especially in Shy-Drager syndrome, additional neuronal loss and gliosis are seen in the
structures responsible for autonomic functions, such as the intermediolateral cell column of the spinal cord
and the dorsal motor nucleus of the vagus.
4. Dementia syndromes. Alzheimer's disease, Pick's disease, and dementia with Lewy bodies are degenerative
CNS diseases the predominant manifestation of which is dementia. Familial frontotemporal dementia and
parkinsonism linked to chromosome 17 are associated with mutations in the taugene. Although the degenerative
process in these disorders has a predilection for certain cortical regions, subcortical structures also may be involved. This
involvement leads to extrapyramidal manifestations, including parkinsonism. The key to identifying a primary
dementia disorder as a cause of parkinsonism is the early appearance of dementia, which often antedates the onset of
hypokinesia or rigidity.

D. Heredodegenerative diseases
1. Wilson's disease, an autosomal recessive condition associated with impairment of copper excretion,
results in copper accumulation in different organ systems, including the CNS, liver (cirrhosis), cornea (Kayser-
Fleischer ring), heart, and kidney.
a. Clinical features. The age at onset ranges from 5 to 50 years, peaking between 8 and 16 years.
Neurologic symptoms are present at the onset of the disease in about 40% of patients. Extrapyramidal
symptoms such as dystonia, rigidity, and bradykinesia are more common among children whereas
tremor and dysarthria are more likely to appear amongadults. A variety of psychiatric symptoms can be
seen in Wilson's disease. An especially important clue to the diagnosis is the presence of liver
dysfunction such as cirrhosis or chronic active hepatitis, especially in a young patient. The combination of
bradykinesia and tremor in these patients can suggest Parkinson's disease, but the very young age at
onset and the presence of psychiatric symptoms, liver dysfunction, or dystonia should prompt a search
for laboratory signs of Wilson's disease. Because the consequences of Wilson's disease are preventable,
and the neurologic symptoms are reversible with early treatment with copper chelating drugs, this
condition should always be kept in the differential diagnosis of atypical parkinsonism, especially that
appearing before the age of 50 years.
b. Neuroimagitig. MRI of the brain shows ventricular dilatation as well as cortical and brainstem
atrophy. The basal ganglia, especially the putamen, can appear either hypointense or hyperintense on T2-
weighted studies and hypodense on CT scans. Occasionally there is the characteristic "face of the giant
panda" appearance of the midbrain on MR images.
c. Neuropathologic examination. There is generalized brain atrophy. The putamen, globus
pallidus, and caudate are cavitated and display a brown pigmentation that reflects copper deposition.
d. Other tests. Measurement of ceruloplasmin in the plasma is the most useful screening test.
The results usually is less than 20 mg/dL (normal, 25 to 45 mg/dL). Plasma copper level is decreased, and
24-hour urinary _;copper excretion is increased. Slit-lamp examination of the cornea reveal
a Kayser-Fleischer ring in almost all patients with neurologic symptom and represents a highly specific
but not pathognomonic finding. If one о more of these test results are normal and the diagnosis is in
doubt, the diagnosis is confirmed with liver biopsy results that show increased cop per content.
2. Huntington's disease is a relentlessly progressive autosomal dominant disorder characterized by
dementia, psychiatric disturbance, and a variet; of movement disorders.
a. Clinical features. The major clinical components of Huntington's dis ease are cognitive decline,
various psychiatric abnormalities (personal ity changes, depression, mania, psychosis), and movement
disorder Although chorea is the most common motor symptom, bradykinesia usu ally coexists with
chorea and may explain the occasional exacerbation a motor impairment when control of chorea is
11
attempted with antidopamin ergic medications. An abnormality of saccadic eye movement, particularlj
slow saccades, is often one of the earliest neurologic signs of this disorder The typical age at onset is in the
fourth or fifth decade, but 10% of patients have symptoms before 20 years of age (juvenile Huntington's).
Successive generations may have symptoms at a progressively earlier age, especially if they have
inherited the disease from their father, reflecting genetic phenomenon of anticipation. The juvenile
form manifests as combination of a progressive akinetic-rigid syndrome (the Westphal variant),
dementia, ataxia, and seizures. These akinetic-rigid patient are most likely to be confused with those
with IPD, but the autosoffll dominant inheritance pattern, the early age at onset, and the presem of
seizures should suggest the correct diagnosis. There is a general inverse correlation between the age at
onset and the rapidity of progression. The duration of illness from onset to death is approximately 15 years
for adult-onset Huntington's disease and 8 to 10 years for those with onset in childhood.
b. Neuroimaging. Atrophy of the head of the caudate is the principal finding at neuroimaging. It can be
appreciated on either MRI or CT.
c. Neuropathologic examination. There is loss of medium spiny striatal neurons as well as gliosis in
cortex and striatum, particularly the caudate. This striatal neuronal loss accounts for the drastic decrease in
the two neurotransmitters associated with these cells, y-aminobutyric acid, and enkephalin.
d. Other tests. Huntington's disease can be diagnosed, and presymptomatic cases can be identified with
great certainty by means of DNA testing. The genetic abnormality has been localized to chromosome 4 and
consists of an expansion of the usual number of repeats of the trinucleotide sequence CAG. The presence
of 40 or more CAG repeats confirms the diagnosis of Huntington's disease. The age at onset usually is
inversely proportional to the number of CAG repeats. Because of the ethical, legal, and psychologic
implications of presymptomatic predictive testing, it should be performed only by a team of clinicians and
geneticists fully sensitive to these issues and aware of published guidelines.
3. Other neurologic conditions occasionally associated with parkinsonism include neuroacanthocytosis,
Hallervorden-Spatz disease, Machado-Joseph disease, and familial calcification of the basal ganglia.

Signs of Cerebellar Dysfunction


The following findings can be expected with cerebellar disease:,
1. Ataxia: This ataxia involves the limbs, particularly the distal extremities, and is associated with
deviations of gait and stance toward the side of the lesion.
2. Dysmetria: The inability to gauge distance correctly, resulting in premature arrest of movement or
overshooting (past pointing or hypermetria).
3. Asynergia: Loss of coordination in the in nervation of muscle groups needed for the performance of
precise movements. Individual muscle groups function independently and are incapable of complex movement
patterns.
4. Dysdiadochokinesia: (adiadochokinesia): Rapid alternating movements of agonist antagonist muscles
cannot be performed. Alternating movements, such as rapid pronation and supination of the hands, are slow,
hesitating, and arrhythmic.
5. Intention tremor: An action tremor that is evident when an object is pointed at. It becomes more severe
as the finger or toe approaches the object. This tremor is usually associated with damage to the dentate nucleus or
superior cerebellar peduncle.
6. Rebound phenomenon: Caused by an in ability to adjust promptly to changes in muscle tension. For
example, a patient pressed against the hand of the examiner cannot immediately relax when the examiner
withdraws his hand but follows the hand with an uncontrolled hitting motion.
7. Hypotonia: Flabbiness and rapid exhaustion of the ipsilateral musculature as a result of alterations in
tonic innervation. The deep tendon reflexes tend to be sluggish and to have a reverberating quality.
8. Scanning speech: Asynergia of the muscles of speech results in slow, hesitant, and poorly articulated
speech with in appropriate emphasis on individual syllables that cause some words to be uttered explosively.
9. Inability to discriminate weight: An object whose weight is being judged is always believed to be lighter
when held in the harid ipsilateral to the cerebellar lesion. This phenomenon is probably related to ipsilateral
hypotonia and asthenia. It has been shown in animal experiments that specific functional deficits can be correlated
with damage to certain precise cerebellar areas. In disease states of the cerebellum, however, correlations are
unusual. The cerebellum must always act in its entirety to maintain equilibrium and muscle tone during each
movement or for sustaining a posture and to assure smoothness, coordination, and precision in each voluntary and
involuntary movement.