Cerebelo y Ataxias Continum

Review Article
Cerebellar and Afferent

Address correspondence to
Dr Massimo Pandolfo,
Department of Neurology,
Hôpital Erasme, Route de
Lennik 808, 1070
Brussels, Belgium,
massimo.pandolfo@ulb.ac.be.
Ataxias
Relationship Disclosure: Massimo Pandolfo, MD; Mario Manto, MD, PhD
Dr Pandolfo receives
unrestricted support for
conferences from Santhera
Pharmaceuticals and royalty ABSTRACT
payments from Athena
Diagnostics, Inc, for Methods Purpose of Review: Ataxia is the predominant manifestation of many acquired
to Diagnose Friedreich Ataxia. and inherited neurologic disorders affecting the cerebellum, its connections, and
Dr Pandolfo serves on the the afferent proprioceptive pathways. This article reviews the phenomenology and
drug safety monitoring board
of and receives research etiologies of cerebellar and afferent ataxias and provides indications for a rational
support from Repligen approach to diagnosis and management.
Corporation. Dr Manto Recent Findings: The pathophysiology of ataxia is being progressively understood
receives honoraria from
Cambridge University and linked to the functional organization of the cerebellum. The impact of cere-
Press and Springer bellar diseases on different neurologic functions has been better defined and
Science+Business Media, and shown not to be limited to loss of motor coordination. The role of autoimmunity is
receives research grants from
the Communauté Fran0aise, increasingly recognized as a cause of sporadic cases of ataxia. Large collaborative
the European Commission, studies of long duration are providing crucial information on the clinical spectrum
and the Fonds de la and natural history of both sporadic ataxias (such as the cerebellar form of multiple
Recherche Scientifique
Belgium. Dr Manto serves system atrophy) and inherited ataxias. New dominant and recessive ataxia genes
as editor-in-chief of have been identified. On the therapeutic front, progress mostly concerns the de-
The Cerebellum and as velopment of treatments for Friedreich ataxia.
associate editor of the Journal
of NeuroEngineering and Summary: Ataxia is the clinical manifestation of a wide range of disorders. In
Rehabilitation. addition to accurate clinical assessment, MRI plays a major role in the diagnostic
Unlabeled Use of workup, allowing us to distinguish degenerative conditions from those due to other
Products/Investigational
Use Disclosure: Dr Pandolfo
types of structural damage to the cerebellar or proprioceptive systems. Diagnostic
discusses experimental algorithms based on clinical features, imaging, and neurophysiologic and biochem-
therapeutics for the treatment ical parameters can be used to guide genetic testing for hereditary ataxias, the
of inherited ataxias and
immunomodulatory treatments
diagnosis of which is likely to be greatly improved by the introduction of new-
for immune-mediated ataxias. generation DNA-sequencing approaches. Some rare forms of ataxia can be treated,
Dr Manto reports no disclosure. so their diagnosis should not be missed. Proven symptomatic treatments for ataxia
* 2013, American Academy are still lacking, but intensive physical therapy appears to be helpful.
of Neurology.
Continuum (Minneap Minn) 2013;19(5):1312–1343.
PHENOMENOLOGY tion of muscle spindles.1 Pathology in

The word ataxia comes from Greek afferent ataxia may be found in the
and means ‘‘lack of order.’’ Ataxia peripheral nerves, dorsal root ganglia,
Supplemental digital content: designates the jerky or irregular char- and spinal cord.
Videos accompanying this ar- acter of movement or posture. Cere-
ticle are cited in the text as Cerebellar Ataxia
Supplemental Digital Content. bellar ataxia results from a genuine
Videos may be accessed by cerebellar disorder or from a com- Patients with cerebellar ataxia are
clicking on links provided in
the HTML, PDF, and iPad
bined involvement of cerebellar and typically clumsy, as the cerebellum is
versions of this article; the extracerebellar structures, especially involved in limb coordination and
URLs are provided in the print the brainstem. Afferent ataxia is attrib- control of balance. The cerebellum is
version. Video legends begin
on page 1338. uted to a loss of proprioceptive sen- functionally asymmetrical, for motor
sory feedback during movement and as well as cognitive operations. Cere-
stance, probably due to loss of func- bellar signs are currently considered
1312 www.ContinuumJournal.com October 2013
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

KEY POINTS
to fall into one of the following six gaze holding, as well as vestibulo- h Flocculus/paraflocculus
categories: (1) oculomotor distur- ocular responses. The dorsal oculo- and nodulus/uvula play
bances, (2) speech deficits, (3) distur- motor vermis and the fastigial nuclei key roles in sustained
bances in limb movements, (4) are critically involved in saccades and pursuit eye movements
deficits of posture and gait, (5) deficits pursuit initiation. and gaze holding, as
of cognitive operations, and (6) subtle Speech deficits. Speech deficits well as vestibulo-ocular
autonomic signs. include dysarthria and mutism. responses. The dorsal
Oculomotor disturbances. The oc- Speech is typically slow, with slurring, oculomotor vermis and
ulomotor disturbances encountered and may evolve into an explosive and the fastigial nuclei are
in cerebellar patients are summarized scanning speech, often having a nasal critically involved in
saccades and pursuit
in Table 7-1.2 Cerebellar circuitry fine- character. Cerebellar mutism desig-
initiation.
tunes each subtype of ocular move- nates an absence of speech occurring
ment.3 Flocculus/paraflocculus and after posterior fossa surgery in chil- h Cerebellar mutism
nodulus/uvula play key roles in sus- dren. Paroxysmal attacks of dysarthria designates an absence
of speech occurring
tained pursuit eye movements and and limb ataxia have been reported
after posterior fossa
after midbrain infarction involving the
surgery in children.
cerebellothalamocortical pathway.4
TABLE 7-1 Most Common Disturbances in limb movements. h Contrary to apraxia,
Oculomotor Deficits ataxic movements have
in Cerebellar Contrary to apraxia, ataxic movements
a correct motor plan
Ataxiasa,b have a correct motor plan and involve
and involve the correct
the correct body parts but show body parts, but they
b Deficits of Fixation irregularity of speed and acceleration show irregularity of
Instability of gaze and delayed timing of some compo- speed and acceleration
Flutter nents, as already recognized by and delayed timing of
Macrosaccadic oscillations Holmes.5 These basic abnormalities some components.
translate into a number of disturbances, h Hypotonia is not
b Impaired Pursuit
including dysmetria (hypermetria, invariably present in
Saccadic pursuit
hypometria), kinetic tremor, action ataxic patients, many of
b Nystagmus tremor, impaired muscle tone, dys- whom have normal
Gaze-evoked diadochokinesia, decomposition of muscle tone. Muscle
Rebound movement/asynergia, dysrhythmo- tone may be increased
Upbeat kinesis, and impaired check and re- in multiple system
bound. Holmes5 also described the atrophy (rigidity) and in
Downbeat
occurrence of hypotonia, particularly spastic ataxia.
Periodic alternating
after acute cerebellar lesions, and h Ataxic patients complain
b Deficits of Saccades of easy fatigability,
thought that it contributed to the move-
Hypermetric which resolves after
ment abnormality. Hypotonia, how-
Hypometric ever, is not invariably present in ataxic acute lesions but
remains a problem in
b Misalignment patients, many of whom have normal
individuals with chronic
Skew deviation muscle tone. It is most common in
cerebellar pathology.
b Deficits of Reflexes
children. In some specific conditions,
such as the inherited spastic ataxias and
Impaired vestibuloocular responses
multiple system atrophy, ataxic patients
Impaired optokinetic reflex
may instead have spasticity or extrapy-
a
Adapted from Manto MU, Cambridge ramidal rigidity.
University Press.2 B with permission of
Cambridge University Press. Although weakness is not a direct
b
Apraxia of gaze and ophthalmoparesis consequence of cerebellar disease,
not listed.
many patients report easy fatigability,
which resolves after acute lesions but
Continuum (Minneap Minn) 2013;19(5):1312–1343 www.ContinuumJournal.com 1313

Cerebellar and Afferent Ataxias
KEY POINT
h The main features of the remains a problem in individuals with agrammatism, and inappropriate be-
cerebellar cognitive chronic cerebellar pathology. havior have been reported in patients
affective syndrome are ‘‘Cerebellar fits’’ are episodes of with cerebellar impairment.7,8 The
impaired executive alteration of consciousness and exten- most common neuropsychiatric symp-
functions, impaired sor posturing, which may progress to toms reported in cerebellar patients
visuospatial skills, respiratory compromise and death, are distractibility, perseveration, diffi-
agrammatism, and associated with different posterior culty in shifting attention, impulsive-
inappropriate behavior. fossa pathologies. Their physiopathol- ness, anhedonia, and passivity. The
ogy remains unclear. Ganglioglioma of dysregulation of affect occurs mainly
the cerebellum and hamartoma of the in lesions affecting the so-called ‘‘lim-
floor of the fourth ventricle may cause bic cerebellum’’ which includes the
paroxysmal facial contractions.6 vermis and the fastigial nuclei.
Deficits of posture and gait. Ataxia Autonomic disturbances. The cer-
of posture/gait is very common in cerebellum tunes the activity of autonomic
ebellar disorders and is the most dis- centers in the brain.9 A minority of
abling deficit during activities of daily cerebellar patients shows abnormal
living. Ataxia of posture/gait needs to be vasomotor responses to voluntary
distinguished from psychogenic ataxia, movements, such as pupil dilatation
a common presentation of psychogenic and flushing of the face, hyperventila-
movement disorders, and primary or- tion, or bradycardia. These usually
thostatic tremor (Figure 7-1), where overlooked signs of distorted auto-
the perception of upright unsteadiness nomic control are subtle as compared
is reduced by walking. to the dysautonomia associated with
Cognitive deficits. Impaired execu- multiple system atrophy (MSA) or
tive and visuospatial functions, spinocerebellar ataxia type 3 (SCA3).
FIGURE 7-1 Surface EMG recordings in right lower limbs in a patient reporting unsteadiness while standing. Typical
primary orthostatic tremor confirmed by fast Fourier transform analysis demonstrating a 19-Hz orthostatic
tremor.

KEY POINTS
Afferent Ataxia logic signs and symptoms (such as h ‘‘Pure’’ afferent ataxia
Clinically, afferent ataxia is often dis- myoclonus, seizures, intellectual dis- differs from cerebellar
tinguished from a genuine cerebellar ability, paresis, visual loss, deafness, ataxia by (1) the heavy
ataxia by (1) the heavy dependence on and myopathy) and by systemic in- dependence on visual
visual guidance, (2) the minor degree volvement. Point mutations of mtDNA guidance, (2) the minor
of oculomotor deficits, and (3) the are maternally transmitted; single de- degree of oculomotor
absence of dysarthria. In most cases, letions of mtDNA are usually sporadic, deficits, and (3) the
afferent ataxia is associated with im- while multiple mtDNA deletions and absence of dysarthria.
paired tendon reflexes and sensory mtDNA depletion may be due to h Clues for psychogenic
deficits.10 dominant or recessive nuclear DNA ataxia are abrupt onset,
mutations. history of spontaneous
Psychogenic Ataxia Congenital ataxias are developmen- remissions, search for
Like other psychogenic movement distal disorders of the cerebellum, which compensation, context
may be associated with other neuro- of litigation,
orders, psychogenic ataxia should be
somatizations, and
suspected in the presence of unusual, logic or systemic involvement. Inheri-
response to placebo.
bizarre clinical features, which may tance is autosomal or X-linked
correct when attention is manipulated. recessive. Some ataxias are paroxysmal h Ethnic differences in the
disorders (episodic ataxias), which may prevalence of hereditary
Onset is often abrupt and spontaneous
ataxias should be taken
remissions may occur. In some cases, in some cases be associated with a
into account in the
particularly in onset after minor trauma, slowly progressive degenerative com-
diagnostic workup.
ongoing litigation with search for component. Episodic ataxias are dominant
pensation may be a factor. disorders.
Presentation Autosomal Dominant

Presentation may be acute, subacute, Progressive Degenerative
or slowly progressive in both children Ataxias
and adults. In addition, there are The current nomenclature for the
congenital and episodic ataxias. Etiol- dominantly inherited degenerative
ogies include hereditary and acquired ataxias uses the acronym SCA (for
conditions (summarized below). spinocerebellar ataxia) followed by
a progressive number. Even after
HEREDITARY ATAXIAS excluding some inappropriate desig-
The hereditary ataxias are a large and nations (SCA9, a reserved but never
complex group of diseases affecting assigned SCA designation; SCA24, an
the cerebellum or its connections. Al- autosomal recessive ataxia; SCA29, a
though they are all characterized by congenital nonprogressive ataxia; and
ataxia as an early and prominent SCA15/16 and 19/22, allelic disorders
feature, the genetic, clinical, patho- [ie, due to mutations in the same
physiologic, pathogenic, and neuro- gene]), more than 30 SCA genetic sub-
pathologic characteristics of these types exist, with ethnic differences in
diseases are quite diverse. their prevalence (Table 7-2) (Supple-
Most hereditary ataxias are trans- mental Digital Content 7-1, links.lww.
mitted as autosomal dominant or com/CONT/A84) that should be taken
autosomal recessive traits. X-linked into account in the diagnostic workup.
ataxias are rare, with fragile X tremor- Several SCAs, including the most
ataxia syndrome (FXTAS) being the common ones, are due to CAG repeat
most prominent. Mitochondrial DNA expansions in the coding regions of
(mtDNA) mutations may cause ataxia, the respective genes (SCA1, 2, 3, 6,
usually accompanied by other neuro- 7, and 17), resulting in expanded

KEY POINT
h Anticipation occurs TABLE 7-2 Geographical Distribution of the Most Common
in polyglutamine Autosomal Dominant Spinocerebellar Ataxias
spinocerebellar ataxias
(SCAs) and may be Spinocerebellar Ataxia
extreme in the case of (SCA) Type Most Common Countries
SCA7 and SCA2, with SCA1 Australia, Japan, India, Italy, South Africa
infantile cases
SCA2 India, Italy, Mexico, Spain, United States
occasionally occurring
in the offspring of a SCA3 Brazil, France, Germany, Japan, Portugal, Spain,
United States (very rare in Italy)
still-asymptomatic
mutation-carrying SCA6 Australia, Germany, Taiwan, United States
parent. SCA7 Finland, Mexico, South Africa
SCA10 Brazil, Mexico (very rare in the rest of the world)
SCA12 India
SCA13 France, Philippines
SCA14 Australia, France, Japan, Netherlands,
United Kingdom, United States
SCA28 France, Italy, United Kingdom
SCA31 Japan (Nagano prefecture)
SCA36 Japan
Dentatorubral-pallidoluysian Caribbean, Japan, United States (in African
atrophy (DRPLA) Americans)
glutamine tracts known as poly- tein,17,18 data suggest that polyQ-

glutamine (polyQ) in the encoded containing microaggregates may inter-
proteins. Pathogenic mechanisms vary fere with various cellular components
depending on the normal function and sequester transcription factors,
and interactions of the mutated pro- contributing to altered gene expres-
tein, which are affected by the pres- sion.19,20 Expanded CAG repeat muta-
ence of the polyQ tract.11 However, tions have some common properties,
changes in gene expression appear to including intergenerational instability.
be a common mechanism, because all The resulting variation in repeat
mutated proteins in polyQ SCAs regu- length correlates with variable age of
late gene expression, either directly at onset, with longer repeats causing
the level of transcription (SCA1, 3, 7, earlier onset. Accordingly, the phe-
and 17, and possibly SCA6), or by nomenon of anticipation (ie, earlier
modulating RNA processing (SCA1 onset of the disease in successive
and 2) and micro-RNA pathways generations), is largely due to prog-
(SCA2). In addition, polyQ proteins ressive repeat expansion at every
(or fragments) have an intrinsic ten- parent-child transmission. Anticipa-
dency to aggregate and are found in tion may be extreme, particularly in
inclusion bodies, mostly intranuclear, SCA7 and SCA2, with infantile cases
that are a pathologic hallmark of occasionally occurring in the offspring
polyQ diseases.12Y15 While the forma- of a still-asymptomatic mutation-
tion of such inclusion bodies may be carrying parent.21 Additional genetic
dissociated from pathogenicity in ani- (and perhaps nongenetic) modifiers
mal models,16 and even be protective also affect age of onset and clinical
by sequestration of the toxic pro- presentation.

SCA10, 12, 31, and 36 are due to SCA8 is linked to an expanded CTG
noncoding repeat expansions. The most repeat, whose pathogenicity has been
recently discovered SCA of this group questioned because of its occasional
is SCA36, a type of spinocerebellar presence in control subjects and in
ataxia accompanied by motor neuron patients with other subtypes of ataxia.24
involvement that is more common in A possible explanation of these contra-
Japan and caused by an intronic dictory findings is that the expression
GGCCTG hexanucleotide repeat ex- of an antisense CAG-containing, polyQ-
pansion in the NOP56 gene. In the encoding transcript may be critical for
presence of an expanded GGCCTG the SCA8 repeat to be pathogenic.25
repeat, the RNA transcribed from this The remaining SCAs are due to
gene forms nuclear aggregates, called point mutations or deletions in the
nuclear foci, in which specific RNA- respective genes. Clinical variability in
binding proteins remain sequestered, these conditions may be related to the
resulting in altered expression of many specific mutation and also to modi-
genes.22 A similar pathogenic mecha- fiers. Mutated genes encode proteins
nism of RNA toxicity is shared by other whose functions are relevant for the
diseases due to noncoding repeat cerebellar system (Table 7-3), includ-
expansions, such as myotonic dystro- ing calcium homeostasis, intracellular
phy and FXTAS (see below). RNA signaling, cytoskeleton, mitochondria,
metabolism appears to be primarily neuropeptides, and membrane ion
affected in SCA31 as well.22,23 These channels. Some recently discovered
noncoding repeats have a much lower genes include the voltage-gated potas-
tendency to cause anticipation than sium channel Kv4.3-encoding gene
the coding CAG repeats. KCND3, mutated in SCA19/22,27,28
TABLE 7-3 Autosomal Dominant Spinocerebellar Ataxias Due

to Non-Expansion Mutations
Spinocerebellar
Ataxia (SCA) Type Mutated Gene Protein, Function
SCA5 SPTBN2 Beta 3 spectrin, cytoskeletal protein
SCA11 TTBK2 Tau tubulin kinase 2, involved in
ciliogenesis26
SCA13 KCNC3 Voltage-gated potassium channel
SCA14 PRKCG Protein kinase C gamma, intracellular
signaling
SCA15/16 ITPR1 Inositol 1,4,5-trisphosphate receptor
type 1, calcium homeostasis
SCA19/22 KCND3 Voltage-gated potassium channel
SCA20 250 Kb dupl. Unknown
SCA23 PDYN Prodynorphin, neuropeptide precursor
SCA27 FGF14 Fibroblast growth factor 14
SCA28 AFG3L2 Adenosine triphosphatase family
gene 3-like 2, mitochondrial protease
SCA35 TGM6 Transglutaminase 6

KEY POINT
h SCAs may present and the vesicle-associated membrane have had diplopia, episodic vertigo,
with a ‘‘pure’’ cerebellar protein 1 (VAMP1) gene, mutated in a dysarthria, and impaired handwriting
syndrome or with dominantly inherited spastic ataxia29 for years before the frank appearance
associated weakness, not included in the SCA classification, of the gait disorder.31 In most cases,
pyramidal signs, sensory but also causing prominent cerebellar symptoms appear in the third to fifth
loss, cranial nerve symptoms. decade, but age of onset is variable,
involvement, other SCAs may present with a ‘‘pure’’ particularly for the SCAs that are due
movement disorders, cerebellar syndrome with few, if any, to CAG repeat expansion mutations,
dementia, epilepsy, additional neurologic signs and symp- which may have infantile (SCA2 and
peripheral neuropathy, toms, or with associated weakness, SCA7 in particular) to late adult onset
optic atrophy, and, in
pyramidal signs, sensory loss, cranial (the rule for SCA6).
the case of SCA7,
nerve involvement, other movement Table 7-4 summarizes the non-
retinal macular
degeneration.
disorders, dementia, epilepsy, periph- cerebellar signs and symptoms that
eral neuropathy, optic atrophy, and, in suggest specific genetic subtypes of
the case of SCA7, retinal macular de- SCA. It should be kept in mind,
generation (Case 7-1) (Supplemental however, that none of these is sensi-
Digital Content 7-2, links.lww.com/ tive or specific enough to allow a
CONT/A85). Gait imbalance is usually clinical diagnosis of SCA subtype,
the first manifestation of disease, except for macular degeneration,
followed by progressive limb ataxia, which is systematically and exclusively
dysarthria, dysphagia, and oculomotor found in SCA7. Furthermore, some
disturbances.30 However, patients may patients carrying SCA mutations may
Case 7-1
This 46-year-old woman presented with a family history of ataxia and
visual loss. A niece, the daughter of the patient’s younger brother, had
died at age 18 months of a multisystem disorder with severe cerebellar
atrophy, cardiomyopathy, and renal failure. This brother showed loss of
balance and clumsiness, accompanied by loss of visual acuity, at age 32, a
few years after the death of his daughter. Two years later, the patient’s
father developed gait instability at age 60, but his vision remained normal.
The patient’s first symptom was an alteration of color vision on the
yellow-blue axis, which became evident when she was 40 years old. At age
42, she could not tandem walk and had a very mild loss of visual acuity but
could continue working as a nurse. At age 43, her gait had become frankly
abnormal, some clumsiness of the hands had appeared, and her visual
acuity was 6/10 bilaterally with correction. The patient could not continue
working. At age 45, the combination of ataxia of gait and visual loss
prevented her from driving and even going out alone. She needed help for
all activities of daily living. Neurologic examination revealed, in addition to
gait and limb ataxia, the presence of diffuse hyperreflexia and a marked
slowing of saccades. MRI showed marked cerebellar and pontine atrophy.
Funduscopic examination confirmed the presence of a retinal macular
dystrophy. Genetic testing confirmed a pathologic CAG repeat expansion
(44 triplets) in the spinocerebellar ataxia type 7 (SCA7) gene.
Comment. This is a typical case of SCA7, in which the patient’s family
history clearly illustrates the great variability in severity and the marked
anticipation that may occur in this disease.

KEY POINT
TABLE 7-4 Non-Ataxia Signs and Symptoms Suggesting Specific h Some patients carrying
Genetic Subtypes of Autosomal Dominant SCA mutations may
Spinocerebellar Ataxia present only with
noncerebellar clinical
Sign or Symptom Spinocerebellar Ataxia (SCA) Type features.
Pyramidal features SCA1, SCA3, SCA 23, SCA28
Motor neuron involvement SCA2, SCA3, SCA36
Peripheral neuropathy SCA1, SCA2, SCA3, SCA4, SCA12, SCA18, SCA25
Slow saccades SCA2, SCA7
Ophthalmoparesis SCA1, SCA28
Retinal macular degeneration SCA7
Eyelid retraction SCA3
Tremor SCA12, SCA15/16, SCA27
Parkinsonian features SCA2, SCA3, SCA12, SCA17, SCA21
Dystonia SCA14, SCA15/16, SCA27 (orofacial), SCA31
(torticollis)
Myoclonus SCA2, SCA14, SCA19/22
Chorea SCA17
Dementia SCA2, SCA7, SCA17, SCA19 (executive dysfunction)
Intellectual disability SCA13
Seizures SCA10
present only with noncerebellar clin- neuropathologic heterogeneity of

ical features. Examples include SCA2 SCAs. Cerebellar atrophy tends to be
patients carrying CAG repeats in the more progressive in SCAs due to
low pathologic range who present with repeat expansions than in SCAs due
levodopa-responsive parkinsonism32 or to point mutations.36 Atrophy follows
motor neuron disease,33 SCA3 patients genotype-specific patterns, which have
with peripheral neuropathy and rest- been investigated in detail for SCA1, 2,
less legs syndrome,34 and SCA14 pa- 3 and 6.37 Recent work indicates that
tients who may develop prominent atrophy of specific extracerebellar
action myoclonus well before the ap- structures (pontine volume in SCA1,
pearance of ataxia.35 striatal volume in SCA3, caudate vol-
Some autosomal dominant diseases ume in SCA6), as assessed by MRI
not included in the SCA classifica- volumetric analysis, is more sensitive
tion can also present with ataxia as to progression than measures of clini-
a prominent clinical feature. These cal decline, suggesting that it may be
include dentatorubral-pallidoluysian used as a biomarker in clinical trials.38
atrophy (DRPLA), neuroferritinopathy,
prion diseases (in particular, Gerstmann- Autosomal Recessive
Str.ussler-Schenker syndrome), Alexander Degenerative Ataxias
disease, and adult-onset leukodystrophy. Degenerative recessive ataxias are pro-
Neuroimaging studies show cere- gressive, severe, disabling diseases of
bellar atrophy with variable brainstem, complex etiology characterized by
supratentorial, and spinal cord in- progressive alterations of either the
volvement, reflecting the clinical and cerebellum, the spinocerebellar tracts,

KEY POINTS
h Among white patients, or the posterior columns of the spinal intron of the gene encoding frataxin, a
Friedreich ataxia cord. 39 Different combinations of small mitochondrial protein participat-
accounts for at least these pathologic sites, and therefore ing in the biogenesis of iron-sulfur
one-third of the cases of of cerebellar and afferent ataxia, are (Fe-S) clusters,46 important cofactors
recessive ataxia. often observed. Ataxia may occur in for many proteins with different func-
h A proportion of combination with other neurologic tion (energy production, iron, amino-
recessive ataxias appear and extraneurologic alterations (eg, acid and purine metabolism, DNA
to be mild variants of peripheral nerves; pyramidal and ex- repair) and cellular localization. The
metabolic diseases. trapyramidal systems; cortical, ocular, expanded GAA repeat induces a con-
auditory, or visceral dysfunction). In densed chromatin conformation that
most cases, onset of the disease is in is not permissive for gene transcrip-
childhood or before the third decade tion,47 so frataxin is not produced in
of life, but late-onset cases are known sufficient amounts. Rare FRDA patients
for several of these conditions. Dis- are compound heterozygotes for the
ease progression is variable but often GAA repeat expansion, including a loss-
leads to severe disability. of-function point mutation or deletion
Friedreich ataxia (FRDA) accounts in frataxin.48
for at least one-third of the cases The most common pathogenic
of recessive ataxia in white popula- mechanism in recessive ataxias involve
tions (Supplemental Content 7-3, altered mitochondrial function (FRDA,
links.lww.com/CONT/A86), while in vitamin E deficiency, possibly auto-
Japan the most common recessive somal recessive spastic ataxia of
ataxia is ataxia with oculomotor apraxia Charlevoix-Saguenay [ARSACS]), DNA
type 1 (AOA1). A growing list of mo- repair defects (ataxia telangiectasia,
lecular defects accounts for another AOA1 and 2), and altered protein
20% of cases. Nearly 50% of the cases quality control (Marinesco-Sjögren syn-
remain without a diagnosis.40 Table 7-5 drome, ARSACS), but as new causative
summarizes the clinical and genetic genes are discovered, it is clear that
characteristics of the major non- other cellular functions may be altered,
Friedreich autosomal recessive ataxias such as lipid metabolism, cannabi-
(Case 7-2). noid metabolism, and ion channels.
The number of recessive ataxia Oxidative stress may have a causative
genes has grown to more than 30. role in many of these disorders, par-
Some recent discoveries include mu- ticularly when mitochondria are pri-
tations in "-glucosidase 2 (GBA2) in a marily altered or DNA lesions (which
form of recessive spastic ataxia,41,42 in in neurons are mostly due to oxi-
the metabotropic glutamate receptor dative damage) cannot be properly
1 in a recessive congenital ataxia in repaired.49
Roma people,43 and in synaptotagmin A proportion of recessive ataxias
14 (SYT14) (a protein involved in appear to be mild variants of metabolic
vesicle exocytosis highly expressed in diseases, including leukodystrophies
the cerebellum) in an adult-onset (metachromatic leukodystrophy,
recessive spinocerebellar ataxia with Krabbe disease, adrenoleukodystro-
psychomotor retardation.44 phy), variants of Tay-Sachs disease,
FRDA is due to a GAA repeat Sandhoff disease, cerebrotendinous
expansion, which is present in homo- xanthomatosis, carbohydrate glycopro-
zygosis in affected individuals, since tein deficiency type 1a, and Niemann-
the disease is recessive.45 The FRDA Pick disease type C. The atypical
GAA expansion mutation occurs in an presentation of these patients, often

KEY POINTS
associated with mild metabolic alter- affects men older than 50 years and is h In recessive or sporadic
ations, often makes early diagnosis characterized by ataxia and action cases of degenerative
difficult. tremor (Supplemental Digital Content ataxia with mild or
Most degenerative recessive ataxias 7-4, links.lww.com/CONT/A87). Typi- absent cerebellar
have symptom onset in childhood or cal MRI findings are fluid-attenuated atrophy, a genetic test
adolescence, but variability is consid- inversion recovery (FLAIR) middle for Friedreich ataxia is
erable. In the case of FRDA, the cerebellar peduncle and cerebral indicated even if onset
instability of the causative repeat ex- periventricular white matter hyper- has been unusually late
pansion mutation explains part of the intensities. A recent study pointed out and the clinical picture
variability in onset and severity, with that the clinical picture may be more is atypical.
larger expansions associated with ear- complex than previously thought.52 h Fragile X tremor-ataxia
lier onset and more severe disease.50,51 Main findings were as follows: (1) syndrome mostly affects
However, diseases due to ‘‘classical’’ tremor may be essential-like, cerebel- men over 50 years of
mutations may also show substantial lar, or parkinsonian; (2) peripheral neu- age and is characterized
by ataxia and action
clinical variability, including in age of ropathy is very common and may be
tremor. Typical MRI
symptom onset, often without any length-dependent or not; and (3) 60%
findings are fluid-
clear genotype-phenotype correlation. of patients have parkinsonism. The attenuated inversion
As in the case of SCAs, the first symp- same study found no family history of recovery (FLAIR) middle
tom is usually gait imbalance, followed fragile X syndrome in almost half cerebellar peduncle and
by limb ataxia and dysarthria. The type (46%) of the cases. FXTAS also occurs cerebral periventricular
of ataxiaVafferent, cerebellar, or mixedV in women, although the characteristic white matter
and the additional (including extra-ataxic clinical manifestation of fragile X pre- hyperintensities.
and systemic) clinical features, if pres- mutation in females is premature ovar-
ent, may guide the diagnosis, although ian failure.
confirmation by genetic or biochemical
testing is necessary. A useful distinction Congenital Ataxias
is between cases with marked cerebel- This group of disorders includes cere-
lar atrophy and those with mild or bellar malformations that cause im-
absent cerebellar atrophy. In the latter paired motor development with usually
case, a genetic test for FRDA is indi- nonprogressive ataxia. Other malfor-
cated even if onset has been unusually mations affecting the CNS or other
late and the clinical picture is atypical. organs may coexist. MRI is a very useful
In addition to late onset, up to the tool to guide diagnosis. Joubert syn-
seventh decade (Case 7-3), atypical drome and related disorders are the
FRDA cases may present with retained most common genetic congenital
reflexes, spasticity, mild or absent ataxias. These recessive conditions are
limb ataxia, lack of dysarthria, and no characterized by vermis hypoplasia and
cardiomyopathy. Conversely, FRDA is large, horizontal superior cerebellar pe-
virtually excluded in the presence of duncles, which, in axial MRI images,
prominent cerebellar atrophy. generate the pathognomonic ‘‘molar
tooth sign.’’ Clinically, nonprogressive
X-Linked Degenerative Ataxias ataxia is accompanied by hypotonia,
The major X-linked ataxia is FXTAS, a oculomotor apraxia, episodes of apnea/
condition occurring in carriers of hyperpnea in infancy, and variable
intermediate length (premutation) al- intellectual disability. Eyes, liver, and
leles (50 to 200 triplets) of the CGG kidneys may be variably affected in a
repeat whose full expansion (9200 group of diseases related to Joubert
triplets) causes the fragile X syndrome syndrome, collectively called cilio-
of mental retardation. FXTAS mostly pathies.53 These diseases are all due to

TABLE 7-5 Major Non-Friedreich Autosomal Recessive Ataxias
Significant Developmental Peripheral Other Movement

Condition Onset Age Delay/ Intellectual Disability Neuropathy Disorders
Ataxia with Vitamin E Late childhood, j + +/j
deficiency (AVED) adolescence
Ataxia-telangiectasia Early childhood j +/j +
Ataxia with oculomotor Childhood +/j + +

apraxia type 1
Ataxia with oculomotor Late childhood to j + +
apraxia type 2 early adulthood
Autosomal recessive Childhood j + j

spastic ataxia of
Charlevoix-Saguenay
Cholestanolosis Childhood to + + +/j
adulthood
Marinesco-Sjögren Childhood + j j
syndrome
Spinocerebellar ataxia Adolescence j + j

with neuropathy 1
Giant axonal Early to + + j
neuropathy mid-childhood
Coenzyme Q10 deficiency Childhood to + + j
(various diseases) adulthood
Late-onset GM2 Childhood to + j +

gangliosidosis adulthood
Abetalipoproteinemia Infancy and j + j

childhood
Refsum disease Childhood to j + j

young adulthood
Congenital disorder of Infancy to +/j + +

glycosylation 1a adulthood
Wilson disease Childhood to j j +

adulthood
, = decreased; j = increased; + = present; j = absent.

a
The Leuko screen offers combined determination of Arylsulfatase A, Hexosaminidase A+B, and Galactocerebrosidase in leukocytes.

Ophthalmic Other Clinical Early Cerebellar Other MRI Diagnostic Tests
Abnormalities Features Atrophy Features and Results
, acuity, retinitis Prominent posterior j j ,vitamin E, TTPA genetic
pigmentosa column loss, pyramidal testing
signs, cardiomyopathy
Oculomotor apraxia Telangiectasia, j j j !-fetoprotein, low
immunodeficiency immunoglobulins, ATM
genetic testing
Oculomotor apraxia Hypoalbuminemia, + j APTX genetic testing
hypercholesterolemia
Oculomotor apraxia Moderately elevated + j SETX genetic testing
!-fetoprotein, raised
creatine kinase in some
j Marked spasticity, + Linear pontine SACS genetic testing
hypermyelinated hypointensities
retinal fibers
Cataracts Tendon xanthomas, chronic + Cerebral atrophy, white j cholestanol, CYP27A1
diarrhea, seizures matter abnormalities genetic testing
Cataracts Myopathy, + Cerebellar cortical Electron dense structures
hypogonadism, short T2 abnormalities on muscle biopsy, SIL1
stature, skeletal anomalies genetic testing
j Hypoalbuminemia, + j TDP1 genetic testing
hypercholesterolemia
j Kinky hair, pyramidal j White matter signal Giant axons on nerve biopsy,
signs abnormalities GAN genetic testing
+/j Seizures, myopathy, + j Coenzyme Q10 deficiency
pyramidal signs in muscle/fibroblasts,
genetic testing (various genes)
Optic atrophy, retinitis Seizures, cognitive + j "-Hexosaminidase A
pigmentosa regression, psychiatric enzymatic testinga, HEXA
disturbance genetic testing
Retinitis pigmentosa Diarrhea, fat malabsorption j j Extremely low cholesterol
(including vitamin E levels, abnormal lipoprotein
deficiency), red blood profile, MTP genetic testing
cell acanthocytosis
Retinitis pigmentosa Deafness, anosmia, j j j Phytanic acid, deficiency
ichthyosis of phytanoyl-CoA hydroxy-
lase enzyme activity, genetic
testing of PHYH, PEX7
Retinitis pigmentosa, Seizures, hypogonadism, + White matter Abnormal transferrin isoform
strabismus skeletal abnormalities abnormalities pattern, deficient
phosphomannomutase
activity, PMM2 genetic testing
Kayser-Fleischer rings Liver disease, psychiatric j Basal ganglia, thalamic, , Serum copper and
disturbance and brainstem ceruloplasmin, j urinary
abnormalities copper excretion, ATP7B
genetic testing

KEY POINT
h Episodic ataxias are a
group of disorders,
Case 7-2
A 35-year-old woman had a history of ataxia since the age of 13. First
caused by mutations
symptoms were loss of balance and falls. Gait instability progressed
of ion channel genes,
relentlessly until, at age 20, she was entirely wheelchair dependent. Limb
that are characterized
ataxia developed later but became severe enough to make her dependent
by attacks of ataxia of
on others for most activities of daily living. At examination, the patient
variable duration,
was unable to stand without strong support and unable to walk. Her
which may be
speech was slurred and irregular; occasionally, she needed to repeat
accompanied by other
words. Cognitive function appeared to be preserved. Eye movements were
neurologic symptoms.
very abnormal, with saccadic pursuit and slow saccades. Saccades tended
to be hypometric, followed by a hypermetric correction. No nystagmus or
typical oculomotor apraxia was evident, as the patient was able to direct
her gaze to a lateral target without turning her head. Mild distal weakness
and amyotrophy were present in all four limbs. Discrimination of two
points was impaired on the patient’s fingertips, and she demonstrated a
marked loss of vibration sense below the knees. She executed the
finger-to-nose test slowly, with decomposition of movement and
dysmetria but no intention tremor. The patient was unable to perform
the heel-to-knee test. No tendon reflex could be elicited. Plantar responses
were mute. EMG and nerve conduction studies demonstrated a severe
sensorimotor neuropathy. Slow conduction velocities and temporal
dispersion indicated a demyelinating component, while markedly
decreased amplitudes of motor and sensory potentials and fibrillations
revealed axonal involvement. MRI showed severe atrophy of the
cerebellum, with no other evident abnormality. Blood test revealed a
moderately increased !-fetoprotein (26 ng/mL, with normal values being
less than 15 ng/mL).
Comment. The clinical picture of progressive ataxia starting in the
second decade, accompanied by sensorimotor neuropathy, slow saccades,
severe cerebellar atrophy, and moderately elevated !-fetoprotein is
strongly suggestive of ataxia with oculomotor apraxia type 2 (AOA2).
Genetic analysis of the SETX gene confirmed the diagnosis by the
identification of a homozygous nonsense mutation.
mutations in genes encoding proteins 6. Episodic ataxia type 1 (EA1), caused

of the primary cilium, a microtubule- by mutations in the potassium chan-
containing extension of the cell mem- nel gene KCNA1, gives short (seconds
brane essential for the development of to minutes) attacks of ataxia, with
many tissues. interictal myokymia and, in some
cases, seizures and neuromyotonia.
Episodic Ataxias EA2 is due to (mostly nonsense) muta-
Episodic ataxias are a group of disor- tions in the calcium channel gene
ders, caused by mutations of ion CACNA1A, so it is allelic to SCA6 and
channel genes, that are characterized to a form of familial hemiplegic mi-
by attacks of ataxia of variable dura- graine. Attacks in EA2 are of longer
tion, which may be accompanied by duration (hours to days) and are ac-
other neurologic symptoms. Eight companied by interictal nystagmus and
genetic subtypes have been identified. slowly progressive ataxia with cerebel-
The causative gene is known in four of lar atrophy. EA5 is clinically similar to
them: episodic ataxia types 1, 2, 5, and EA2 and caused by mutations in the

Case 7-3
A 61-year-old woman had poor balance since age 55. The patient
considered herself ‘‘clumsy’’ since childhood but had no obvious symptom
of ataxia until the age of 56, when she stopped running because of
instability and risk of falling. More recently, her gait became unstable,
although she needed no support, and mild dysarthria and limb ataxia had
developed. On neurologic examination, she showed a wide-based gait
with polydirectional sway and inability to tandem walk. She could stand
with feet close together, but only with sway. Mild dysarthria was evident,
but all words were easy to understand. Her eye movements were
abnormal, with occasional square-wave jerks and dysmetria of saccades.
Finger-to-nose and heel-to-knee tests showed mild dysmetria and terminal
oscillations, and she demonstrated mild loss of vibration sense at the
ankles and toes. Tendon reflexes were normal and symmetric, but plantar
responses were extensor bilaterally. Nerve conduction studies revealed a
sensory neuropathy affecting the lower limbs, with reduced sensory nerve
action potentials at the peroneal nerves (1.6 HV on the right, 4.5 HV on
the left), and normal conduction velocities. Central conduction time after
cortical magnetic stimulation was bilaterally increased. MRI of the
patient’s brain showed mild atrophy of the superior vermis and a few
nonspecific white matter T2 hyperintensities. CSF was normal, and all
tested paraneoplastic antibodies were negative (Hu, Ri, Yo). Tests for
autoimmunity were also negative, including antibodies directed against
myelin-associated glycoprotein, neutrophil cytoplasm, nuclear antigens,
phospholipids, and gliadin. Vitamin E levels were normal. A genetic test
for Friedreich ataxia (FRDA) showed a homozygous GAA repeat expansion
in the frataxin gene, establishing the diagnosis of late-onset FRDA.
Comment. This case illustrates how a recessive ataxia that mostly affects
the young may have unusually late onset. FRDA was the first candidate for
genetic testing because of some suggestive clinical features, including the
presence of square-wave jerks, the distal loss of vibration sense, the
extensor plantar responses, and the sensory axonal neuropathy. MRI only
revealed very mild cerebellar atrophy, which is compatible with a diagnosis
of FRDA, while a more severe atrophy would have made the diagnosis
very unlikely. In this case, concerns about an inflammatory, paraneoplastic,
or autoimmune cause prompted many investigations, including CSF
analyses, some of which could have been avoided by performing the FRDA
genetic test sooner. This patient subsequently underwent a detailed
cardiologic evaluation that showed no sign of cardiomyopathy, as is often
the case in late-onset FRDA. She had no skeletal abnormality. At age 71,
she was still able to walk without support; remained independent,
although slow, in performing all activities of daily life; and had not
developed diabetes mellitus, despite the association between FRDA
and diabetes mellitus.
related CACNB4 gene. In EA6, due to Hereditary Afferent Ataxias

mutations in a glial glutamate trans- Several hereditary ataxias have an afferent
porter gene (SLC1A3), alternating component. FRDA is the main example,
hemiplegia and seizures may occur in as it is characterized by proprioceptive
addition to episodic ataxia. loss and prominent pathology in the

KEY POINTS
h The main causes of dorsal root ganglia and dorsal columns. be considered. Table 7-72 lists some
acute ataxia in adults Other conditions with an afferent con- complementary investigations that may
are vascular lesions, tribution to ataxia include ataxia with guide the diagnosis in adults.
cranial trauma, vitamin E deficiency (AVED), ataxia
infections, intoxications, telangiectasia, AOA1 and 2, abetalipo- Sporadic Cerebellar Ataxias
immune ataxias, proteinemia, and some SCAs (SCA18 is The main causes of acute cerebellar ataxia
vestibular disorders, and a pure afferent ataxia). in adults are vascular lesions, cranial
psychogenic causes. Hereditary neuropathies may cause trauma, infections, intoxications, immune
h Alcohol is the most afferent ataxia, in particular Charcot- ataxias, vestibular disorders, and psycho-
common cerebellotoxic Marie-Tooth disease (CMT) type 2B, an genic causes. The clinical presentations of
agent. Chronic axonal form with mutations in the RAB7 ischemic cerebellar strokes are summa-
consumption causes gene; Dejerine-Sottas disease (due to rized in Table 7-8.2 A representative MRI
cerebellar atrophy mutations in PMP22 [CMT1E] or of vascular lesions in the cerebellum is
predominating in the periaxin genes [CMT4F]; Refsum dis- shown in Figure 7-2.
anterior vermis and gait
ease; the hereditary sensory and auto- Paraneoplastic cerebellar degenera-
more than limb ataxia.
nomic neuropathies (HSAN IYV).10,54 tion often presents as a subacute cere-
Rare recessive afferent ataxia disor- bellar syndrome and may occur before
ders include posterior column ataxia the identification of an underlying can-
and retinitis pigmentosa, due to FLVCR cer, usually a small cell lung cancer, a
mutations; and sensory ataxia, neurop- breast or ovarian cancer, or a lym-
athy, dysarthria, and ophthalmoparesis phoma. A profound cerebellar atrophy
(SANDO), due to POLG1 mutations. of rapid progression characterizes most
Whereas posterior column ataxia and of these syndromes (Figure 7-3).
retinitis pigmentosa presents with af- Posterior fossa trauma should not
ferent ataxia, night blindness, and be overlooked for obvious anatomic
areflexia in infancy, with further pro- reasons, and the possibility of a dis-
gression in the second decade,55 section of neck vessels should be kept
SANDO is of late onset.56 Mitochon- in mind. Figure 7-4 shows recordings
drial recessive ataxia syndrome is a re- of a severe action tremor following
cessive ataxia due to a specific POLG1 cerebellar trauma. Cerebellar contusion,
mutation that differs from SANDO be- cerebellar hematoma and subarach-
cause of juvenile onset, cerebellar in- noid hemorrhage, diffuse axonal in-
volvement, mild cognitive impairment, jury, and subdural/epidural hematoma
involuntary movements, psychiatric represent the various forms of cere-
symptoms, and epilepsy.57 bellar lesions associated with head
trauma.
DIAGNOSIS OF ATAXIAS IN Alcohol is the most common cerebello-
DAILY PRACTICE toxic agent (Table 7-9). Chronic con-
Table 7-6 provides the main differen- sumption causes cerebellar atrophy
tial diagnoses of ataxia in children. predominating in the anterior vermis
Blood studies, genetic tests, and brain (Figure 7-5)58 and gait more than limb
imaging play a determinant role in the ataxia. In these patients, ataxia of gait is
diagnosis. To fully delineate the phe- also more severe than limb ataxia.
notype, nerve conduction studies/ Wernicke encephalopathy, which oc-
EMG (presence versus absence of pe- curs due to thiamine (vitamin B1) defi-
ripheral neuropathy, axonal versus ciency, combines a mental confusional
demyelinating) and referral to an oph- state, oculomotor deficits (most often
thalmologist (retinitis pigmentosa, cat- nystagmus and various degrees of paral-
aract, and cherry red spot, etc) should ysis of external rectus muscles), and gait

TABLE 7-6 Differential Diagnosis of Ataxias in Children
b Congenital Ataxia
Metabolic
Congenital disorder of glycosylation
Glucose transporter 1 deficiency
Hydroxyglutaric aciduria
Malformation
Hypoplasia
Agenesis
Joubert syndrome
Dandy-Walker syndrome
Progressive ataxia of infantile onset
Infantile-onset spinocerebellar ataxia (IOSCA)
Marinesco-Sjögren syndrome
Ataxia-telangiectasia
Rett syndrome
Angelman syndrome
b Acquired Progressive Ataxia
Ataxia with vitamin E deficiency (AVED)
Ataxia and oculomotor apraxia types 1 and 2 (AOA1, AOA2)
Friedreich ataxia
Mitochondrial diseases
Leukodystrophies
Neuronal ceroid lipofuscinosis
b Intermittent Ataxia
Metabolic
Maple syrup urine disease
Hartnup disease
Glucose transporter 1 deficiency
Mitochondrial disease
Infectious
Recurrent ataxia of viral origin
Immune
Multiple sclerosis
Neurovascular
Migraine
Stroke
Intoxication
Psychogenic
b Acute-Onset Ataxia
Infection (cerebellitis)
Paraneoplastic
Continued on next page

KEY POINT
h Some cases of cerebellar TABLE 7-6 Differential Diagnosis of Ataxias in Children (continued )
and afferent ataxia are
due to autoimmune Immune
causes. Although
Multiple sclerosis
some entities remain
Acute disseminated encephalomyelitis (ADEM)
controversial, an
autoimmune cause Miller Fisher syndrome
must be considered Bickerstaff encephalitis
in the differential Vestibular
diagnosis. Benign paroxysmal positional vertigo (BPPV)
Ménière syndrome
Neuronitis
Intoxication
Ethanol
Trauma
Psychogenic
b Spastic Ataxia
Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS)
(Supplemental Digital Content 7-5, links.lww.com/CONT/A88)
Krabbe disease
GM2 gangliosidosis
Spinocerebellar ataxia 3 and 7, dentatorubral-pallidoluysian atrophy (DRPLA)
Spastic paraplegia (in particular SPG5 and SPG7)
Pelizaeus-Merzbacher disease
Portneuf spastic ataxia
ataxia. The main conditions associated mellitus). Experimental evidence63

with Wernicke encephalopathy are al- supports the concept that antibodies
coholism, hyperemesis gravidarum, directly cause stiff-person syndrome
gastroplasty/intestinal surgery, prolonged and cerebellar ataxia, but it remains to
parenteral nutrition, long stay in critical be determined whether the antiY
care units, dialysis, chemotherapy or glutamic acid decarboxylase autoanti-
immunosuppressive drugs, thyrotoxico- bodies or other autoantibodies made
sis, and food refusal (psychogenic).59 by these patients are responsible. Glu-
In addition to multiple sclerosis, in ten ataxia is a type of autoimmune
which lesions commonly affect the ataxia described to occur in genetically
cerebellum and its afferent and efferent susceptible patients (the human leuko-
connections, several immune ataxias cyte antigen class II type DQ2 is
have been recognized.60,61 Antibodies overrepresented) who produce circu-
to glutamic acid decarboxylase are lating antigliadin antibodies following
found in the serum of most patients exposure to gliadin in food.64 Ataxia
with type 1 diabetes mellitus as well as may develop in the absence of enterop-
those with immune-mediated syn- athy and may have an insidious course.
dromes affecting the CNS, including Neurophysiologic investigations show
stiff-person syndrome, and in a few pa- evidence of a sensorimotor axonal neu-
tients with cerebellar ataxia62 (mostly ropathy in half of the patients. However,
women also affected with diabetes this entity remains controversial, as

antigliadin antibodies are found in
TABLE 7-7 Laboratory asymptomatic individuals and have
Investigations
in Adult-Onset been reported in subjects with other
Cerebellar Ataxiasa forms of degenerative ataxia, including
hereditary diseases.65 Ataxia can occur
b Blood Studies in the context of Hashimoto encepha-
Sedimentation rate lopathy, but, rarely, subacute or chronic
C-reactive protein progressive ataxia has been reported
Serum electrolytes to be the main neurologic symptom in
Glucose, glycosylated hemoglobin individuals with antithyroid antibodies,
Renal and liver function tests
in most of whom cerebellar atrophy
was shown on MRI.66,67 Case reports of
Cholesterol, triglycerides,
low-density lipoprotein, improvement with IV immunoglobulin
very-low-density lipoprotein suggest a role of autoimmunity in these
Vitamin E patients, but again, it remains uncertain
Vitamin B12, homocysteine, whether the antithyroid antibodies
folic acid are directly involved or whether other
Copper and ceruloplasmin immune mechanisms are responsible.
Protein electropheresis Ataxia may also occur in the context of
Acanthocytes
a systemic autoimmune disease, such as
systemic lupus erythematosus and
Lactate/pyruvate
Sjögren syndrome. In these conditions,
Heavy metals
a role for autoantibodies directed against
Antinuclear antibodies
cellular components of the nervous
Thyroid stimulating hormone, system has been postulated, but patho-
antithyroid peroxidase and
antithyroglobulin antibodies
genic mechanisms have not yet been
fully elucidated. In the case of Sjögren
Antigliadin/endomysium
antibodies syndrome, an autoimmune sensory neu-
Antiglutamic acid decarboxylase
ronopathy may cause afferent ataxia.10
antibodies Multiple system atrophy (MSA)
Anticerebellar antibodies combines symptoms of dysautonomia,
b CSF Studies
parkinsonism, and cerebellar ataxia
and corticospinal signs at various de-
Cell count and cytology
grees (Case 7-4).68 Pathologically, glial
Protein, glucose, lactate
cytoplasmic !-synuclein inclusions are
Immunoglobulin G index,
the hallmark of the disease. Predomi-
oligoclonal bands
nant parkinsonian features that re-
14-3-3 protein
spond poorly to levodopa treatment
Anticerebellar antibodies
characterize the parkinsonian variant
Cultures of MSA (MSA-P), whereas the group of
b Urine Studies MSA-C refers to patients who exhibit
Metabolic screening predominant cerebellar deficits (Sup-
Protein electrophoresis plemental Digital Content 7-6,
Heavy metals links.lww.com/CONT/A89 ). Symp-
Bile alcohols toms of autonomic impairment may
a
Adapted from Manto MU, Cambridge appear before motor symptoms. They
University Press.2 B with permission of consist of urinary tract dysfunction (in-
Cambridge University Press.
continence, urinary urgency or re-
tention), orthostatic hypotension,

a
TABLE 7-8 Main Presentations of Territorial Cerebellar Infarctions
Territory and Specific Infarction Presentation

Posterior inferior cerebellar artery (PICA)
Wallenberg syndrome Vertigo, nystagmus, ipsilateral Horner
sign, limbs ataxia, cranial nerve palsies
(V, IX, X), contralateral thermalgic
dissociation, lateropulsion
PICA infarction without brainstem Vertigo, headache, nystagmus, limbs
involvement ataxia, gait ataxia, lateropulsion
Medial PICA infarction Vertigo, lateropulsion, limbs dysmetria
(+ Wallenberg syndrome)
Lateral PICA infarction Vertigo, limbs dysmetria
Multiple cerebellar infarctions Vertigo, headache, impaired consciousness
Anterior inferior cerebellar artery
Classic syndrome Vertigo, tinnitus, hearing loss, dysarthria,
facial palsy/sensory loss, ipsilateral Horner
syndrome, limbs dysmetria, gaze palsy,
motor weakness (ipsilateral)
Isolated vertigo (labyrinthitis-like) No additional features
Massive infarction Impaired consciousness, tetraplegia,
ophthalmoplegia
Superior cerebellar artery
Lateral syndrome Limbs dysmetria, kinetic tremor,
lateropulsion, dysarthria, nystagmus,
contrapulsion of ocular saccades
Medial syndrome Gait ataxia, limbs ataxia, dysarthria
Rostral basilar artery Dizziness, diplopia, drowsiness,
syndrome thalamo-mesencephalic signs, Balint
syndrome, brainstem syndrome
(Benedikt, Claude, Weber), paresthesia,
hemiballism
Classic infarct Limbs dysmetria, ipsilateral Horner sign,
contralateral thermalgic dissociation,
slow involuntary movements, sleep
disorders, palatal/jaw myoclonus,
contralateral palsy of nerve IV
‘‘Vestibular form’’ Headache dizziness, unsteadiness,
dysarthria, nystagmus, dysmetria
Concomitant infarction of the
anterior circulation
a
Adapted from Manto MU, Cambridge University Press.2 B with permission of Cambridge
University Press.
digestive tract dysfunction (constipa- sleep apnea, and stridor may also
tion or diarrhea), erectile dysfunction, predate the onset of motor symp-
and dyshydrosis. Sleep disorders such toms.68 MSA represents the most
as REM sleep behavior disorder, central common nonhereditary degenerative

KEY POINT
h Multiple system atrophy
represents the most
common nonhereditary
degenerative ataxia. The
disorder usually starts
around 55 years of age.
Several signs are not
suggestive of multiple
system atrophy: classical
‘‘pill rolling’’ tremor,
marked dementia,
good/long-standing
response to levodopa,
gaze palsy, slowing of
saccades.
FIGURE 7-2 Axial T2-weighted MRI showing multiple vascular lesions in the posterior fossa
(arrows).
ataxia. The disorder typically starts sical ‘‘pill rolling’’ tremor, marked
around 55 years of age. MSA is a dementia, good/long-standing re-
progressive, eventually fatal disease sponse to levodopa, gaze palsy, or
with a median survival of around 10 slowing of saccades.69 In MSA, MRI
years after symptom onset.68 Several shows progressive cerebellar and pon-
signs not suggestive of MSA should tine atrophy. Atrophy of pontocerebellar
prompt reconsideration of the diag- fibers gives a characteristic appear-
nosis, such as the presence of clas- ance on axial T2-weighted images of
FIGURE 7-3 Magnetic resonance sagittal T1-weighted images showing severe cerebellar
atrophy associated with a paraneoplastic cerebellar syndrome induced by a
thymic carcinoma.

FIGURE 7-4 Severe action tremor of the right upper limb following brain trauma. Surface EMG recordings of the
brachioradialis muscle, biceps muscle, flexor carpi radialis muscle, and extensor carpi radialis muscle, and
bi-axial accelerometry recordings of the hand while the patient is attempting to draw. Bottom right shows fast
Fourier transform of accelerometric recordings.
the pons, called the ‘‘cross sign’’ Acquired Afferent Ataxias

(Figure 7-670). Acquired afferent ataxias may be
Idiopathic late-onset cerebellar immune-mediated (including paraneo-
ataxia (ILOCA) often starts between plastic), toxic (including iatrogenic),
40 and 55 years of age and presents vitamin-related, or of unknown
with a slowly progressive cerebellar cause.10 Acquired peripheral sensory
syndrome for which known causes neuropathies that may cause afferent
have been excluded. In some cases, a ataxia are listed in Table 7-10.
follow-up of several years may be nec- Paraneoplastic afferent ataxia has a
essary to differentiate ILOCA from an subacute to chronic course and may
early case of MSA-C that has not yet be associated with bronchogenic carci-
developed overt autonomic failure. noma, small cell lung cancer, breast
Figure 7-7 shows computed posturo- cancer, ovarian cancer, sarcoma, and
graphies illustrating the gait and bal- Hodgkin’s lymphoma. It is due to T-cellY
ance abnormalities in ILOCA and mediated sensory ganglionopathy.
other acquired and inherited ataxias. Onconeural antibodies such as anti-Hu

and antiYcollapsin response mediator
TABLE 7-9 Toxins Causing protein-5 can be found in most cases,
Cerebellar Ataxia
but not invariably.
b Ethanol Other immune-mediated sensory
b Heavy metals
ganglionopathies causing afferent
ataxia also have a subacute to chronic
b Drugs
course and may be associated with
Lithium salts
Sjögren syndrome, unclassified auto-
Phenytoin
immune disorders, chronic auto-
Metronidazole and other azoles immune hepatitis, or monoclonal
Calcineurin inhibitors gammopathy of unknown signifi-
Amiodarone cance. The specific serology findings
b Chemotherapy for each of these conditions assist in
b Drug abuse (cocaine, heroin, the diagnosis.
methadone, phencyclidine, Toxic and vitamin-related afferent
herbs) ataxias tend to have a slower, subacute to
b Solvents chronic course. In addition to the well-
known myelopathy and neuropathy
FIGURE 7-5 Magnetic resonance sagittal T1-weighted images showing marked atrophy of the
vermis in a patient with history of chronic alcohol intake.

KEY POINT
h When an inherited
condition is suspected,
Case 7-4
A 70-year-old man started to lose his balance 6 years ago. Family history
family history should be
was negative for ataxia. At age 66, neurologic examination had demonstrated
the first criterion used to
a clearly abnormal gait with polydirectional sway and enlarged base,
direct testing.
mild dysarthria, saccadic ocular pursuit, some terminal oscillations at
the finger-to-nose and heel-to-knee tests, mild cogwheel rigidity at both
wrists, and mild generalized bradykinesia. Through questioning of the
patient and his wife, it emerged that a possible REM sleep behavior
disorder had been present for several years, antedating the appearance
of ataxia. The patient also reported episodes of dizziness and fainting,
suggesting postural hypotension, and of urinary urgency. MRI revealed
moderate cerebellar and brainstem atrophy. At age 68, the patient’s gait
ataxia had progressed, causing frequent falls and the need for constant
support. A gaze-evoked nystagmus and dysmetria of saccades had
appeared. Dysarthria was severe enough to make many of his words
unintelligible, and mild dysphagia had appeared. Limb ataxia, rigidity,
and bradykinesia had become worse. His blood pressure fell from
110/70 mm Hg when sitting to 90/60 after standing for 3 minutes, without
a compensating increase in heart frequency. A therapeutic trial with
levodopa was not beneficial. Fludrocortisone was prescribed for postural
hypotension, with benefit. Repeat brain MRI showed progression of
cerebellar and brainstem atrophy, with a typical ‘‘cross sign’’ in axial
T2-weighted images of the pons.
Comment. The combination of cerebellar, autonomic, and extrapyramidal
involvement as well as the lack of response to levodopa and the typical
MRI findings confirm the clinical diagnosis of multiple system atrophy
in this patient. Further disease progression is expected to lead to major
motor disability, worsening of dysphagia, and severe autonomic impairment,
with shortened life expectancy.
caused by vitamin B12 deficiency, intellectual disability, or myoclonus.

afferent ataxia may also be a symp- Evidence of dominant inheritance
tom of copper-deficient myelopathy71 should initially prompt testing for the
and nitrous oxide toxicity (through most common SCAs due to CAG expan-
vitamin B12 deficiency).72 Sensory sion mutations (ie, SCA1, 2, 3, 6, 7, and
neuronopathies causing ataxia may be 17), which is often offered as a panel.
associated with deficiencies of ribofla- Patients of Asian and African origin
vin, nicotinic acid, or vitamin E (also should also be screened for DRPLA. If
found in genetic forms), and with these genetic investigations are negative,
pyridoxine intoxication. the patient should be referred to a
specialized center for testing of less
Hereditary Ataxias common SCAs, which should be priori-
When an inherited condition is sus- tized based on clinical and epidemiologic
pected, family history should be the considerations. Clinical features should
first criterion used to direct testing. also guide genetic testing for the autoso-
Also, it is important to document family mal dominant episodic ataxias.
history of neurologic conditions other When family history supports re-
than ataxia because some SCAs may cessive inheritance (ie, when multiple
present with parkinsonism, neuropa- siblings are affected and parents are
thy, motor neuron disease, spasticity, unaffected), patients should be first

KEY POINT
h Sporadic cases may
represent instances of
recessive disorders
with only one affected
sibling. Considering
the variability of clinical
presentation and age
of onset of recessive
ataxias, consensus is
emerging that a genetic
recessive etiology
should be considered
for sporadic cases of
degenerative ataxia with
no identifiable acquired
cause, even when onset
is after age 40.
FIGURE 7-6 Magnetic resonance axial T2-weighted images showing a ‘‘cross sign’’ in the
pons (arrows) in a patient presenting with the sporadic form of multiple system
atrophy, cerebellar type.
Reprinted from Manto MU, Habas C, Springer.70 B 2013 with permission from Springer Science +
Business Media.
tested for FRDA, except when cere- Sporadic cases may represent in-
bellar atrophy is prominent. Further stances of recessive disorders with
testing should be guided by clinical only one affected sibling. Considering
and biochemical findings whose alter- the variability of clinical presentation
ation indicates or suggests a specific and age of onset of recessive ataxias,
diagnosis, such as high cholestanol consensus is emerging that a genetic
(cholestanolosis), low vitamin E recessive etiology should be consid-
(AVED), high cholesterol and low ered for sporadic cases of degenerative
albumin (AOA1), or high !-fetoprotein ataxia with no identifiable acquired
(AOA2 and AT). As a further step, cause even when onset is after age 40.
mutation analysis of the SACS, POLG, In addition to atypical cases of diseases
APTX, and SPG7 genes (taking into usually presenting earlier in life, in
account specific phenotypes) and bio- some recently discovered recessive
chemical testing for white blood cell ataxias (such as the form due to muta-
enzymes for metachromatic leukodys- tions in ANO10), symptoms usually
trophy and Krabbe disease, phytanic begin after the age of 40.73 Dominant
acid for Refsum disease, and long-chain diseases may also appear as sporadic
fatty acids for adrenoleukodystrophy when family history is unknown or a
may be requested. If still no diagnosis potentially affected parent died before
can be established, referral to a spe- developing symptoms, or, rarely, be-
cialized center is recommended in cause of reduced penetrance or de
order to perform skin or muscle biopsy novo mutations. In SCA2 and SCA7,
targeted at diagnoses such as Niemann- large repeat expansions may cause
Pick disease type C, recessive ataxia extreme anticipation, so a child may
with coenzyme Q deficiency (ADCK3/ become affected before the parent who
SCAR9), and mitochondrial disorders. transmitted the mutation. Testing for

FIGURE 7-7 Computerized posturography showing impaired balance while standing with feet
together in a patient with idiopathic late-onset cerebellar ataxia (A), in a patient
with multiple system atrophy, cerebellar type (B), in a patient with chronic alcohol
intake (C), spinocerebellar ataxia type 2 (D), and abnormal tandem gait in patient
with immune ataxia (E).
the fragile X premutation should be relatives include children with full-

considered in the presence of a sugges- blown fragile X syndrome or women
tive family history, for example, when with premature ovarian failure, but also
TABLE 7-10 Acquired Sensory Neuropathies Causing Afferent Ataxia
b Miller Fisher syndrome

b Chronic inflammatory demyelinating polyneuropathy
b Diabetic polyneuropathy
b CANOMAD (chronic ataxic neuropathy, ophthalmoplegia, monoclonal IgM
protein, cold agglutinins and disialosyl antibodies) syndrome
b AntiYmyelin-associated glycoprotein (MAG) antibodies
b Vitamin E deficiency
b Chemotherapy-induced polyneuropathies (cisplatin, carboplatin, oxaliplatin,
doxorubicin)

KEY POINTS
in sporadic cases when clinical and resis has also been proposed to remove h Acquired ataxias should
imaging features are suggestive of this phytanic acid. In Niemann-Pick type C be treated according to
diagnosis. disease, treatment with miglustat, a their specific etiology.
All of the above recommendations molecule that inhibits glycolipid synthe- This may include
for genetic testing may soon become sis, at the dose of 200 mg 3 times a day, treatment of strokes,
surpassed by the progressive introduc- has resulted in partial improvement and tumors, multiple
tion of next-generation sequencing in slowed disease progression.77 The ob- sclerosis, avoidance
the diagnostic arena. While exome and servation that ataxia telangiectasia pa- of toxic agents,
whole-genome sequencing still remain tients treated with steroids (originally and vitamin
research tools, several laboratories are for lymphoma) showed improvement of supplementation.
already developing targeted next- ataxic symptoms prompted further con- h Some evidence
generation sequencing approaches to sideration of glucocorticoids for this has shown that
sequence all known ataxia genes. The condition.78 Glucocorticoids may be immunomodulatory
benefits of such increased diagnostic beneficial because they penetrate the treatments, like IV
immunoglobulin, may
power may be great if it is considered a CNS, where they act as anti-inflammatory
be effective for some
complement rather than a replacement and antioxidant drugs. However, their
immune-mediated
of careful clinical assessment. side effects, particularly an increased risk ataxias, but no
of infection in the already immunocom- controlled randomized
TREATMENT promised ataxia telangiectasia patients, trials have been
Acquired ataxias should be treated impose caution before this treatment conducted.
according to their specific etiology. can be recommended. h Specific treatment exists
This may include treatment of strokes, At least 12 drugs are in the devel- for only a few hereditary
tumors, multiple sclerosis, avoidance opment pipeline for the treatment of ataxias: ataxia with
of toxic agents, and vitamin supple- FRDA.79 These include lipid-soluble vitamin E deficiency,
mentation. Some evidence has shown antioxidants such as the short-chain coenzyme Q10
that immunomodulatory treatments, coenzyme Q analog idebenone and deficiency,
like IV immunoglobulin, may be effec- compound A0001 (!-tocopheryl qui- cerebrotendinous
tive for some immune-mediated none), related to both coenzyme Q xanthomatosis
ataxias, but there have been no con- and vitamin E. Despite some promis- (cholestanolosis), and
trolled randomized trials.74 Results ing results in a phase 2 study,80 no Niemann-Pick disease
type C.
depend on the cause of ataxia and efficacy of idebenone in improving
the extent of neuronal damage. ataxia or cardiomyopathy could be h Corticosteroids may
Specific treatment exists for only a few demonstrated in two phase 3 stud- improve symptoms of
hereditary ataxias. AVED responds to ies.81 A phase 2A trial with A0001 ataxia-telangiectasia,
but their use is not
high-dose vitamin E supplementation showed signs of efficacy on ataxia,82
recommended until
(800 mg/d to 1500 mg/d).49 Vitamin E but the short duration of the study (4
supported by evidence
supplementation should also be pre- weeks) imposes caution. Deferiprone from controlled trials.
scribed for abetalipoproteinemia, in ad- is an orally administered, membrane-
dition to a low-fat diet. Recessive ataxias permeable iron chelator, thought to h At least 12 drugs are
in the development
with coenzyme Q deficiency should be be useful in FRDA by removing excess
pipeline for the
treated with coenzyme Q10 supplemen- redox-active iron from mitochon- treatment of Friedreich
tation, 150 mg/d to 300 mg/d. 75 dria.83 Despite an encouraging open- ataxia, but none has yet
Cerebrotendinous xanthomatosis label pilot study,84 a 6-month phase 2 been proven effective in
should be treated with cheno- randomized controlled trial in FRDA, phase 3 randomized
deoxycholic acid, which suppresses however, was inconclusive (unpub- controlled trials.
cholestanol synthesis, at the dose of lished data). Human recombinant
750 mg/d.76 For Refsum disease, the erythropoietin has been shown to
basic treatment is avoidance of phytanic increase frataxin levels in cultured
acid and a high-calorie diet; plasmaphe- cells,85 providing the rationale for

KEY POINTS
h Attempts to develop a clinical testing in FRDA. However, the Finally, some evidence indicates
symptomatic treatment only randomized controlled trial that that intensive coordinative training
for ataxia have so far used human recombinant erythropoi- (at least 3 times a week for 4 weeks)
met with limited success etin was negative.86 Results from a may help improve motor performance
and only in specific controlled trial with a similar mole- and reduce ataxia symptoms in pa-
conditions. cule, carbamylated erythropoietin, tients affected with cerebellar ataxia,
h Some evidence which does not induce erythropoiesis with less effect on afferent ataxia.94
suggests that intensive but preserves the ability to upregulate
coordinative training frataxin in vitro, are not yet available. CONCLUSION
(at least 3 times a week Robust induction of frataxin expres- Ataxias are characterized by quite di-
for 4 weeks) may sion has been obtained in cultured verse genetic, clinical, pathophysiolog-
help improve motor cells and animal models using a family ic, pathogenetic, and neuropathologic
performance and of histone deacetylase inhibitors acting features. Although in some cases a
reduce ataxia symptoms on the chromatin changes triggered by complete diagnostic workup may even-
in patients affected
GAA repeat expansions.48,87Y89 Early tually require referral to a specialized
with cerebellar ataxia,
clinical development of these mole- center, the general neurologist can
with less effect on
afferent ataxia.
cules has been initiated. identify and manage the most common
Attempts to develop a symptomatic conditions causing ataxia. The diagnos-
treatment for ataxia have so far met tic process must consider the age of the
with limited success, with a few excep- patient; the mode of presentation and
tions. The potassium channel blocker the rate of progression of the disease;
4-aminopyridine has been shown to the associated signs and symptoms; the
shorten attacks, decrease nystagmus, presence of a history of alcohol abuse
and improve quality of life in patients or exposure to toxic substances (includ-
with episodic ataxia.90 Some episodic ing drugs), of previous or concurrent
ataxias, in particular EA2, may respond infection, of neoplasia, or of a family
to acetazolamide, and a limited re- history of a similar disorder.
sponse to the same drug has also been Progress in research and the pro-
reported for SCA6.91 Varenicline, a gressive availability of advanced diag-
nicotinic acetylcholine receptor agonist nostic technologies is rapidly
used to help smoking cessation, at the increasing our power to specifically
dose of 1 mg twice a day has im- diagnose even the rarest forms of
proved gait and stance in SCA3 pa- ataxia, but similar progress in therapy
tients in a randomized controlled still has to come. However, many pa-
trial.92 A single randomized controlled tients presenting with ataxia have a
trial of riluzole at the dose of 100 mg/d, condition that can be treated, if not
involving a very heterogeneous group cured, such as vascular disease, tumor,
of patients with ataxia of varied etiolo- multiple sclerosis or another inflamma-
gies showed an improvement of the tory disease, infection, autoimmune
International Cooperative Ataxia Rating disease, or drug toxicity. Even for some
Scale score after 8 weeks.93 Several of the rare genetic diseases, progress is
drugs that act on serotonin receptors being made toward the development
(5-hydroxytryptophan, buspirone, of treatments, making the quest for a
tandospirone), as well as amantadine, diagnosis even more important.
thyrotropin-releasing hormone, and
zinc supplementation, have been test- VIDEO LEGENDS
ed for a symptomatic effect in ataxia, Supplemental Digital Content 7-1
mostly in open-label trials, but results Spinocerebellar ataxia type 12. Video shows a
remain inconclusive. 68-year-old woman with onset of postural and

action hand tremor at age 48, progressing slowly Supplemental Digital Content 7-5
to include gait ataxia at age 58, then dementia at Autosomal recessive spastic ataxia of
age 65. She had a family history of severe tremor Charlevoix-Saguenay. Video shows a 28-year-
in three of her four siblings, her mother (also old woman with early-onset (at 2 years of age)
rigidity and falls), two maternal uncles, and her spasticity of lower limbs, followed by progres-
maternal grandfather. Her examination also sive trunk and limb ataxia, dysarthria, and
revealed appendicular and gait ataxia, titubation, neuropathy. She had been using a wheelchair
apraxia, paratonia, and dementia. SCA12, a type for 7 years. A baclofen pump placed 3 years
of dominant ataxia common in India but rare before the video markedly improved the dis-
elsewhere, was confirmed by genetic testing. comfort caused by her severe lower limb
links.lww.com/CONT/A84 spasticity. Note the relatively mild upper limb
Video courtesy of Andrew P. Duker, MD. ataxia compared to the severe involvement of
B 2013 American Academy of Neurology. her lower limbs. Eye movement abnormalities
include gaze-evoked nystagmus, saccadic pur-
Supplemental Digital Content 7-2 suit, and dysmetria of saccades.
Spinocerebellar ataxia type 2. Video shows a links.lww.com/CONT/A88
32-year-old woman with 49 CAG repeat expan- B 2013 American Academy of Neurology.
sions in ataxin-2 who had onset of gait impair-
ment in her late teens, with slowly progressive Supplemental Digital Content 7-6
ataxia. The slowness of saccades is the diagnos- Cerebellar variant of multiple system atro-
tic feature on examination. phy. Video shows a 59-year-old woman with
links.lww.com/CONT/A85 an 8-year history of progressive difficulty with
Video courtesy of Alberto J. Espay, MD, MSc, FAAN. walking, balance, and speech. The earliest
B 2013 American Academy of Neurology. reported difficulty was stiffness in her legs
and staggering while walking, followed by
Supplemental Digital Content 7-3 slurring of speech and trouble with fine motor
Friedreich ataxia. Video shows a 25-year-old skills (eating and getting dressed) within 1 year
man with Friedreich ataxia since childhood, who of symptom onset. She then developed a left
has been in wheelchair for 3 years. Note the hand resting tremor and dystonia. Response to
evident proximal weakness of the upper limbs, levodopa was poor. She died from her illness
slowness of movement, and lack of an obvious shortly after this video was taken. Neuropatho-
kinetic tremor. The video also shows the charac- logic examination demonstrated classical oligo-
teristic eye movement abnormality of Friedreich dendroglial inclusions typical of multiple
ataxia, and fixation instability with square-wave system atrophy, cerebellar type.
jerks. Note the absence of nystagmus. links.lww.com/CONT/A89
links.lww.com/CONT/A86 Video courtesy of Alberto J. Espay, MD, MSc, FAAN.
B 2013 American Academy of Neurology. B 2013 American Academy of Neurology.
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Review Article

Cerebellar and Afferent

Continuum (Minneap Minn) 2013;19(5):1312–1343.

PHENOMENOLOGY tion of muscle spindles.1 Pathology in

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Presentation Autosomal Dominant

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glutamine tracts known as poly- tein,17,18 data suggest that polyQ-

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TABLE 7-3 Autosomal Dominant Spinocerebellar Ataxias Due

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1318 www.ContinuumJournal.com October 2013

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present only with noncerebellar clin- neuropathologic heterogeneity of

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TABLE 7-5 Major Non-Friedreich Autosomal Recessive Ataxias

Significant Developmental Peripheral Other Movement

Ataxia-telangiectasia Early childhood j +/j +

Ataxia with oculomotor Childhood +/j + +

Autosomal recessive Childhood j + j

Spinocerebellar ataxia Adolescence j + j

Late-onset GM2 Childhood to + j +

Abetalipoproteinemia Infancy and j + j

Refsum disease Childhood to j + j

Congenital disorder of Infancy to +/j + +

Wilson disease Childhood to j j +

, = decreased; j = increased; + = present; j = absent.

1322 www.ContinuumJournal.com October 2013

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mutations in genes encoding proteins 6. Episodic ataxia type 1 (EA1), caused

1324 www.ContinuumJournal.com October 2013

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related CACNB4 gene. In EA6, due to Hereditary Afferent Ataxias

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ataxia. The main conditions associated mellitus). Experimental evidence63

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Territory and Specific Infarction Presentation

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Continuum (Minneap Minn) 2013;19(5):1312–1343 www.ContinuumJournal.com 1331

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the pons, called the ‘‘cross sign’’ Acquired Afferent Ataxias

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caused by vitamin B12 deficiency, intellectual disability, or myoclonus.

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Continuum (Minneap Minn) 2013;19(5):1312–1343 www.ContinuumJournal.com 1335