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Review Article

Address correspondence to
Dr Massimo Pandolfo,
Department of Neurology,
Hopital Erasme, Route de
Lennik 808, 1070
Brussels, Belgium,
massimo.pandolfo@ulb.ac.be.
Relationship Disclosure:
Dr Pandolfo receives
unrestricted support for
conferences from Santhera
Pharmaceuticals and royalty
payments from Athena
Diagnostics, Inc, for Methods
to Diagnose Friedreich Ataxia.
Dr Pandolfo serves on the
drug safety monitoring board
of and receives research
support from Repligen
Corporation. Dr Manto
receives honoraria from
Cambridge University
Press and Springer
Science+Business Media, and
receives research grants from
the Communaute Fran0aise,
the European Commission,
and the Fonds de la
Recherche Scientifique
Belgium. Dr Manto serves
as editor-in-chief of
The Cerebellum and as
associate editor of the Journal
of NeuroEngineering and
Rehabilitation.
Unlabeled Use of
Products/Investigational
Use Disclosure: Dr Pandolfo
discusses experimental
therapeutics for the treatment
of inherited ataxias and
immunomodulatory treatments
for immune-mediated ataxias.
Dr Manto reports no disclosure.
* 2013, American Academy
of Neurology.

Cerebellar and Afferent


Ataxias
Massimo Pandolfo, MD; Mario Manto, MD, PhD
ABSTRACT
Purpose of Review: Ataxia is the predominant manifestation of many acquired
and inherited neurologic disorders affecting the cerebellum, its connections, and
the afferent proprioceptive pathways. This article reviews the phenomenology and
etiologies of cerebellar and afferent ataxias and provides indications for a rational
approach to diagnosis and management.
Recent Findings: The pathophysiology of ataxia is being progressively understood
and linked to the functional organization of the cerebellum. The impact of cerebellar diseases on different neurologic functions has been better defined and
shown not to be limited to loss of motor coordination. The role of autoimmunity is
increasingly recognized as a cause of sporadic cases of ataxia. Large collaborative
studies of long duration are providing crucial information on the clinical spectrum
and natural history of both sporadic ataxias (such as the cerebellar form of multiple
system atrophy) and inherited ataxias. New dominant and recessive ataxia genes
have been identified. On the therapeutic front, progress mostly concerns the development of treatments for Friedreich ataxia.
Summary: Ataxia is the clinical manifestation of a wide range of disorders. In
addition to accurate clinical assessment, MRI plays a major role in the diagnostic
workup, allowing us to distinguish degenerative conditions from those due to other
types of structural damage to the cerebellar or proprioceptive systems. Diagnostic
algorithms based on clinical features, imaging, and neurophysiologic and biochemical parameters can be used to guide genetic testing for hereditary ataxias, the
diagnosis of which is likely to be greatly improved by the introduction of newgeneration DNA-sequencing approaches. Some rare forms of ataxia can be treated,
so their diagnosis should not be missed. Proven symptomatic treatments for ataxia
are still lacking, but intensive physical therapy appears to be helpful.
Continuum (Minneap Minn) 2013;19(5):13121343.

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PHENOMENOLOGY
The word ataxia comes from Greek
and means lack of order. Ataxia
designates the jerky or irregular character of movement or posture. Cerebellar ataxia results from a genuine
cerebellar disorder or from a combined involvement of cerebellar and
extracerebellar structures, especially
the brainstem. Afferent ataxia is attributed to a loss of proprioceptive sensory feedback during movement and
stance, probably due to loss of func-

tion of muscle spindles.1 Pathology in


afferent ataxia may be found in the
peripheral nerves, dorsal root ganglia,
and spinal cord.
Cerebellar Ataxia
Patients with cerebellar ataxia are
typically clumsy, as the cerebellum is
involved in limb coordination and
control of balance. The cerebellum is
functionally asymmetrical, for motor
as well as cognitive operations. Cerebellar signs are currently considered

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October 2013

to fall into one of the following six


categories: (1) oculomotor disturbances, (2) speech deficits, (3) disturbances in limb movements, (4)
deficits of posture and gait, (5) deficits
of cognitive operations, and (6) subtle
autonomic signs.
Oculomotor disturbances. The oculomotor disturbances encountered
in cerebellar patients are summarized
in Table 7-1.2 Cerebellar circuitry finetunes each subtype of ocular movement.3 Flocculus/paraflocculus and
nodulus/uvula play key roles in sustained pursuit eye movements and
TABLE 7-1 Most Common
Oculomotor Deficits
in Cerebellar
Ataxiasa,b
b Deficits of Fixation
Instability of gaze
Flutter
Macrosaccadic oscillations
b Impaired Pursuit
Saccadic pursuit
b Nystagmus
Gaze-evoked
Rebound
Upbeat
Downbeat
Periodic alternating
b Deficits of Saccades
Hypermetric
Hypometric
b Misalignment
Skew deviation
b Deficits of Reflexes
Impaired vestibuloocular responses
Impaired optokinetic reflex
a

Adapted from Manto MU, Cambridge


University Press.2 B with permission of
Cambridge University Press.
Apraxia of gaze and ophthalmoparesis
not listed.

Continuum (Minneap Minn) 2013;19(5):13121343

gaze holding, as well as vestibuloocular responses. The dorsal oculomotor vermis and the fastigial nuclei
are critically involved in saccades and
pursuit initiation.
Speech deficits. Speech deficits
include dysarthria and mutism.
Speech is typically slow, with slurring,
and may evolve into an explosive and
scanning speech, often having a nasal
character. Cerebellar mutism designates an absence of speech occurring
after posterior fossa surgery in children. Paroxysmal attacks of dysarthria
and limb ataxia have been reported
after midbrain infarction involving the
cerebellothalamocortical pathway.4
Disturbances in limb movements.
Contrary to apraxia, ataxic movements
have a correct motor plan and involve
the correct body parts but show
irregularity of speed and acceleration
and delayed timing of some components, as already recognized by
Holmes.5 These basic abnormalities
translate into a number of disturbances,
including dysmetria (hypermetria,
hypometria), kinetic tremor, action
tremor, impaired muscle tone, dysdiadochokinesia, decomposition of
movement/asynergia, dysrhythmokinesis, and impaired check and rebound. Holmes5 also described the
occurrence of hypotonia, particularly
after acute cerebellar lesions, and
thought that it contributed to the movement abnormality. Hypotonia, however, is not invariably present in ataxic
patients, many of whom have normal
muscle tone. It is most common in
children. In some specific conditions,
such as the inherited spastic ataxias and
multiple system atrophy, ataxic patients
may instead have spasticity or extrapyramidal rigidity.
Although weakness is not a direct
consequence of cerebellar disease,
many patients report easy fatigability,
which resolves after acute lesions but

KEY POINTS

h Flocculus/paraflocculus
and nodulus/uvula play
key roles in sustained
pursuit eye movements
and gaze holding, as
well as vestibulo-ocular
responses. The dorsal
oculomotor vermis and
the fastigial nuclei are
critically involved in
saccades and pursuit
initiation.

h Cerebellar mutism
designates an absence
of speech occurring
after posterior fossa
surgery in children.

h Contrary to apraxia,
ataxic movements have
a correct motor plan
and involve the correct
body parts, but they
show irregularity of
speed and acceleration
and delayed timing of
some components.

h Hypotonia is not
invariably present in
ataxic patients, many of
whom have normal
muscle tone. Muscle
tone may be increased
in multiple system
atrophy (rigidity) and in
spastic ataxia.

h Ataxic patients complain


of easy fatigability,
which resolves after
acute lesions but
remains a problem in
individuals with chronic
cerebellar pathology.

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1313

Cerebellar and Afferent Ataxias


KEY POINT

h The main features of the


cerebellar cognitive
affective syndrome are
impaired executive
functions, impaired
visuospatial skills,
agrammatism, and
inappropriate behavior.

FIGURE 7-1

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remains a problem in individuals with


chronic cerebellar pathology.
Cerebellar fits are episodes of
alteration of consciousness and extensor posturing, which may progress to
respiratory compromise and death,
associated with different posterior
fossa pathologies. Their physiopathology remains unclear. Ganglioglioma of
the cerebellum and hamartoma of the
floor of the fourth ventricle may cause
paroxysmal facial contractions.6
Deficits of posture and gait. Ataxia
of posture/gait is very common in cerebellar disorders and is the most disabling deficit during activities of daily
living. Ataxia of posture/gait needs to be
distinguished from psychogenic ataxia,
a common presentation of psychogenic
movement disorders, and primary orthostatic tremor (Figure 7-1), where
the perception of upright unsteadiness
is reduced by walking.
Cognitive deficits. Impaired executive and visuospatial functions,

agrammatism, and inappropriate behavior have been reported in patients


with cerebellar impairment.7,8 The
most common neuropsychiatric symptoms reported in cerebellar patients
are distractibility, perseveration, difficulty in shifting attention, impulsiveness, anhedonia, and passivity. The
dysregulation of affect occurs mainly
in lesions affecting the so-called limbic cerebellum which includes the
vermis and the fastigial nuclei.
Autonomic disturbances. The cerebellum tunes the activity of autonomic
centers in the brain.9 A minority of
cerebellar patients shows abnormal
vasomotor responses to voluntary
movements, such as pupil dilatation
and flushing of the face, hyperventilation, or bradycardia. These usually
overlooked signs of distorted autonomic control are subtle as compared
to the dysautonomia associated with
multiple system atrophy (MSA) or
spinocerebellar ataxia type 3 (SCA3).

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.

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Afferent Ataxia
Clinically, afferent ataxia is often distinguished from a genuine cerebellar
ataxia by (1) the heavy dependence on
visual guidance, (2) the minor degree
of oculomotor deficits, and (3) the
absence of dysarthria. In most cases,
afferent ataxia is associated with impaired tendon reflexes and sensory
deficits.10
Psychogenic Ataxia
Like other psychogenic movement disorders, psychogenic ataxia should be
suspected in the presence of unusual,
bizarre clinical features, which may
correct when attention is manipulated.
Onset is often abrupt and spontaneous
remissions may occur. In some cases,
particularly in onset after minor trauma,
ongoing litigation with search for compensation may be a factor.
Presentation
Presentation may be acute, subacute,
or slowly progressive in both children
and adults. In addition, there are
congenital and episodic ataxias. Etiologies include hereditary and acquired
conditions (summarized below).
HEREDITARY ATAXIAS
The hereditary ataxias are a large and
complex group of diseases affecting
the cerebellum or its connections. Although they are all characterized by
ataxia as an early and prominent
feature, the genetic, clinical, pathophysiologic, pathogenic, and neuropathologic characteristics of these
diseases are quite diverse.
Most hereditary ataxias are transmitted as autosomal dominant or
autosomal recessive traits. X-linked
ataxias are rare, with fragile X tremorataxia syndrome (FXTAS) being the
most prominent. Mitochondrial DNA
(mtDNA) mutations may cause ataxia,
usually accompanied by other neuroContinuum (Minneap Minn) 2013;19(5):13121343

logic signs and symptoms (such as


myoclonus, seizures, intellectual disability, paresis, visual loss, deafness,
and myopathy) and by systemic involvement. Point mutations of mtDNA
are maternally transmitted; single deletions of mtDNA are usually sporadic,
while multiple mtDNA deletions and
mtDNA depletion may be due to
dominant or recessive nuclear DNA
mutations.
Congenital ataxias are developmental disorders of the cerebellum, which
may be associated with other neurologic or systemic involvement. Inheritance is autosomal or X-linked
recessive. Some ataxias are paroxysmal
disorders (episodic ataxias), which may
in some cases be associated with a
slowly progressive degenerative component. Episodic ataxias are dominant
disorders.

KEY POINTS

h Pure afferent ataxia


differs from cerebellar
ataxia by (1) the heavy
dependence on visual
guidance, (2) the minor
degree of oculomotor
deficits, and (3) the
absence of dysarthria.

h Clues for psychogenic


ataxia are abrupt onset,
history of spontaneous
remissions, search for
compensation, context
of litigation,
somatizations, and
response to placebo.

h Ethnic differences in the


prevalence of hereditary
ataxias should be taken
into account in the
diagnostic workup.

Autosomal Dominant
Progressive Degenerative
Ataxias
The current nomenclature for the
dominantly inherited degenerative
ataxias uses the acronym SCA (for
spinocerebellar ataxia) followed by
a progressive number. Even after
excluding some inappropriate designations (SCA9, a reserved but never
assigned SCA designation; SCA24, an
autosomal recessive ataxia; SCA29, a
congenital nonprogressive ataxia; and
SCA15/16 and 19/22, allelic disorders
[ie, due to mutations in the same
gene]), more than 30 SCA genetic subtypes exist, with ethnic differences in
their prevalence (Table 7-2) (Supplemental Digital Content 7-1, links.lww.
com/CONT/A84) that should be taken
into account in the diagnostic workup.
Several SCAs, including the most
common ones, are due to CAG repeat
expansions in the coding regions of
the respective genes (SCA1, 2, 3, 6,
7, and 17), resulting in expanded
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1315

Cerebellar and Afferent Ataxias


KEY POINT

h Anticipation occurs
in polyglutamine
spinocerebellar ataxias
(SCAs) and may be
extreme in the case of
SCA7 and SCA2, with
infantile cases
occasionally occurring
in the offspring of a
still-asymptomatic
mutation-carrying
parent.

TABLE 7-2 Geographical Distribution of the Most Common


Autosomal Dominant Spinocerebellar Ataxias
Spinocerebellar Ataxia
(SCA) Type

Most Common Countries

SCA1

Australia, Japan, India, Italy, South Africa

SCA2

India, Italy, Mexico, Spain, United States

SCA3

Brazil, France, Germany, Japan, Portugal, Spain,


United States (very rare in Italy)

SCA6

Australia, Germany, Taiwan, United States

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
atrophy (DRPLA)

Caribbean, Japan, United States (in African


Americans)

glutamine tracts known as polyglutamine (polyQ) in the encoded


proteins. Pathogenic mechanisms vary
depending on the normal function
and interactions of the mutated protein, which are affected by the presence of the polyQ tract.11 However,
changes in gene expression appear to
be a common mechanism, because all
mutated proteins in polyQ SCAs regulate gene expression, either directly at
the level of transcription (SCA1, 3, 7,
and 17, and possibly SCA6), or by
modulating RNA processing (SCA1
and 2) and micro-RNA pathways
(SCA2). In addition, polyQ proteins
(or fragments) have an intrinsic tendency to aggregate and are found in
inclusion bodies, mostly intranuclear,
that are a pathologic hallmark of
polyQ diseases.12Y15 While the formation of such inclusion bodies may be
dissociated from pathogenicity in animal models,16 and even be protective
by sequestration of the toxic pro-

1316

tein,17,18 data suggest that polyQcontaining microaggregates may interfere with various cellular components
and sequester transcription factors,
contributing to altered gene expression.19,20 Expanded CAG repeat mutations have some common properties,
including intergenerational instability.
The resulting variation in repeat
length correlates with variable age of
onset, with longer repeats causing
earlier onset. Accordingly, the phenomenon of anticipation (ie, earlier
onset of the disease in successive
generations), is largely due to progressive repeat expansion at every
parent-child transmission. Anticipation may be extreme, particularly in
SCA7 and SCA2, with infantile cases
occasionally occurring in the offspring
of a still-asymptomatic mutationcarrying parent.21 Additional genetic
(and perhaps nongenetic) modifiers
also affect age of onset and clinical
presentation.

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SCA10, 12, 31, and 36 are due to


noncoding repeat expansions. The most
recently discovered SCA of this group
is SCA36, a type of spinocerebellar
ataxia accompanied by motor neuron
involvement that is more common in
Japan and caused by an intronic
GGCCTG hexanucleotide repeat expansion in the NOP56 gene. In the
presence of an expanded GGCCTG
repeat, the RNA transcribed from this
gene forms nuclear aggregates, called
nuclear foci, in which specific RNAbinding proteins remain sequestered,
resulting in altered expression of many
genes.22 A similar pathogenic mechanism of RNA toxicity is shared by other
diseases due to noncoding repeat
expansions, such as myotonic dystrophy and FXTAS (see below). RNA
metabolism appears to be primarily
affected in SCA31 as well.22,23 These
noncoding repeats have a much lower
tendency to cause anticipation than
the coding CAG repeats.

SCA8 is linked to an expanded CTG


repeat, whose pathogenicity has been
questioned because of its occasional
presence in control subjects and in
patients with other subtypes of ataxia.24
A possible explanation of these contradictory findings is that the expression
of an antisense CAG-containing, polyQencoding transcript may be critical for
the SCA8 repeat to be pathogenic.25
The remaining SCAs are due to
point mutations or deletions in the
respective genes. Clinical variability in
these conditions may be related to the
specific mutation and also to modifiers. Mutated genes encode proteins
whose functions are relevant for the
cerebellar system (Table 7-3), including calcium homeostasis, intracellular
signaling, cytoskeleton, mitochondria,
neuropeptides, and membrane ion
channels. Some recently discovered
genes include the voltage-gated potassium channel Kv4.3-encoding gene
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

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1317

Cerebellar and Afferent Ataxias


KEY POINT

h SCAs may present


with a pure cerebellar
syndrome or with
associated weakness,
pyramidal signs, sensory
loss, cranial nerve
involvement, other
movement disorders,
dementia, epilepsy,
peripheral neuropathy,
optic atrophy, and, in
the case of SCA7,
retinal macular
degeneration.

and the vesicle-associated membrane


protein 1 (VAMP1) gene, mutated in a
dominantly inherited spastic ataxia29
not included in the SCA classification,
but also causing prominent cerebellar
symptoms.
SCAs may present with a pure
cerebellar syndrome with few, if any,
additional neurologic signs and symptoms, or with associated weakness,
pyramidal signs, sensory loss, cranial
nerve involvement, other movement
disorders, dementia, epilepsy, peripheral neuropathy, optic atrophy, and, in
the case of SCA7, retinal macular degeneration (Case 7-1) (Supplemental
Digital Content 7-2, links.lww.com/
CONT/A85). Gait imbalance is usually
the first manifestation of disease,
followed by progressive limb ataxia,
dysarthria, dysphagia, and oculomotor
disturbances.30 However, patients may

have had diplopia, episodic vertigo,


dysarthria, and impaired handwriting
for years before the frank appearance
of the gait disorder.31 In most cases,
symptoms appear in the third to fifth
decade, but age of onset is variable,
particularly for the SCAs that are due
to CAG repeat expansion mutations,
which may have infantile (SCA2 and
SCA7 in particular) to late adult onset
(the rule for SCA6).
Table 7-4 summarizes the noncerebellar signs and symptoms that
suggest specific genetic subtypes of
SCA. It should be kept in mind,
however, that none of these is sensitive or specific enough to allow a
clinical diagnosis of SCA subtype,
except for macular degeneration,
which is systematically and exclusively
found in SCA7. Furthermore, some
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 patients 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 patients
father developed gait instability at age 60, but his vision remained normal.
The patients 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 patients family
history clearly illustrates the great variability in severity and the marked
anticipation that may occur in this disease.

1318

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October 2013

KEY POINT

h Some patients carrying

TABLE 7-4 Non-Ataxia Signs and Symptoms Suggesting Specific


Genetic Subtypes of Autosomal Dominant
Spinocerebellar Ataxia
Sign or Symptom

Spinocerebellar Ataxia (SCA) Type

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 clinical features. Examples include SCA2


patients carrying CAG repeats in the
low pathologic range who present with
levodopa-responsive parkinsonism32 or
motor neuron disease,33 SCA3 patients
with peripheral neuropathy and restless legs syndrome,34 and SCA14 patients who may develop prominent
action myoclonus well before the appearance of ataxia.35
Some autosomal dominant diseases
not included in the SCA classification can also present with ataxia as
a prominent clinical feature. These
include dentatorubral-pallidoluysian
atrophy (DRPLA), neuroferritinopathy,
prion diseases (in particular, GerstmannStr.ussler-Schenker syndrome), Alexander
disease, and adult-onset leukodystrophy.
Neuroimaging studies show cerebellar atrophy with variable brainstem,
supratentorial, and spinal cord involvement, reflecting the clinical and
Continuum (Minneap Minn) 2013;19(5):13121343

SCA mutations may


present only with
noncerebellar clinical
features.

neuropathologic heterogeneity of
SCAs. Cerebellar atrophy tends to be
more progressive in SCAs due to
repeat expansions than in SCAs due
to point mutations.36 Atrophy follows
genotype-specific patterns, which have
been investigated in detail for SCA1, 2,
3 and 6.37 Recent work indicates that
atrophy of specific extracerebellar
structures (pontine volume in SCA1,
striatal volume in SCA3, caudate volume in SCA6), as assessed by MRI
volumetric analysis, is more sensitive
to progression than measures of clinical decline, suggesting that it may be
used as a biomarker in clinical trials.38
Autosomal Recessive
Degenerative Ataxias
Degenerative recessive ataxias are progressive, severe, disabling diseases of
complex etiology characterized by
progressive alterations of either the
cerebellum, the spinocerebellar tracts,
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1319

Cerebellar and Afferent Ataxias


KEY POINTS

h Among white patients,


Friedreich ataxia
accounts for at least
one-third of the cases of
recessive ataxia.

h A proportion of
recessive ataxias appear
to be mild variants of
metabolic diseases.

1320

or the posterior columns of the spinal


cord. 39 Different combinations of
these pathologic sites, and therefore
of cerebellar and afferent ataxia, are
often observed. Ataxia may occur in
combination with other neurologic
and extraneurologic alterations (eg,
peripheral nerves; pyramidal and extrapyramidal systems; cortical, ocular,
auditory, or visceral dysfunction). In
most cases, onset of the disease is in
childhood or before the third decade
of life, but late-onset cases are known
for several of these conditions. Disease progression is variable but often
leads to severe disability.
Friedreich ataxia (FRDA) accounts
for at least one-third of the cases
of recessive ataxia in white populations (Supplemental Content 7-3,
links.lww.com/CONT/A86), while in
Japan the most common recessive
ataxia is ataxia with oculomotor apraxia
type 1 (AOA1). A growing list of molecular defects accounts for another
20% of cases. Nearly 50% of the cases
remain without a diagnosis.40 Table 7-5
summarizes the clinical and genetic
characteristics of the major nonFriedreich autosomal recessive ataxias
(Case 7-2).
The number of recessive ataxia
genes has grown to more than 30.
Some recent discoveries include mutations in "-glucosidase 2 (GBA2) in a
form of recessive spastic ataxia,41,42 in
the metabotropic glutamate receptor
1 in a recessive congenital ataxia in
Roma people,43 and in synaptotagmin
14 (SYT14) (a protein involved in
vesicle exocytosis highly expressed in
the cerebellum) in an adult-onset
recessive spinocerebellar ataxia with
psychomotor retardation.44
FRDA is due to a GAA repeat
expansion, which is present in homozygosis in affected individuals, since
the disease is recessive.45 The FRDA
GAA expansion mutation occurs in an

intron of the gene encoding frataxin, a


small mitochondrial protein participating in the biogenesis of iron-sulfur
(Fe-S) clusters,46 important cofactors
for many proteins with different function (energy production, iron, aminoacid and purine metabolism, DNA
repair) and cellular localization. The
expanded GAA repeat induces a condensed chromatin conformation that
is not permissive for gene transcription,47 so frataxin is not produced in
sufficient amounts. Rare FRDA patients
are compound heterozygotes for the
GAA repeat expansion, including a lossof-function point mutation or deletion
in frataxin.48
The most common pathogenic
mechanism in recessive ataxias involve
altered mitochondrial function (FRDA,
vitamin E deficiency, possibly autosomal recessive spastic ataxia of
Charlevoix-Saguenay [ARSACS]), DNA
repair defects (ataxia telangiectasia,
AOA1 and 2), and altered protein
quality control (Marinesco-Sjo
gren syndrome, ARSACS), but as new causative
genes are discovered, it is clear that
other cellular functions may be altered,
such as lipid metabolism, cannabinoid metabolism, and ion channels.
Oxidative stress may have a causative
role in many of these disorders, particularly when mitochondria are primarily altered or DNA lesions (which
in neurons are mostly due to oxidative damage) cannot be properly
repaired.49
A proportion of recessive ataxias
appear to be mild variants of metabolic
diseases, including leukodystrophies
(metachromatic leukodystrophy,
Krabbe disease, adrenoleukodystrophy), variants of Tay-Sachs disease,
Sandhoff disease, cerebrotendinous
xanthomatosis, carbohydrate glycoprotein deficiency type 1a, and NiemannPick disease type C. The atypical
presentation of these patients, often

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October 2013

associated with mild metabolic alterations, often makes early diagnosis


difficult.
Most degenerative recessive ataxias
have symptom onset in childhood or
adolescence, but variability is considerable. In the case of FRDA, the
instability of the causative repeat expansion mutation explains part of the
variability in onset and severity, with
larger expansions associated with earlier onset and more severe disease.50,51
However, diseases due to classical
mutations may also show substantial
clinical variability, including in age of
symptom onset, often without any
clear genotype-phenotype correlation.
As in the case of SCAs, the first symptom is usually gait imbalance, followed
by limb ataxia and dysarthria. The type
of ataxiaVafferent, cerebellar, or mixedV
and the additional (including extra-ataxic
and systemic) clinical features, if present, may guide the diagnosis, although
confirmation by genetic or biochemical
testing is necessary. A useful distinction
is between cases with marked cerebellar atrophy and those with mild or
absent cerebellar atrophy. In the latter
case, a genetic test for FRDA is indicated even if onset has been unusually
late and the clinical picture is atypical.
In addition to late onset, up to the
seventh decade (Case 7-3), atypical
FRDA cases may present with retained
reflexes, spasticity, mild or absent
limb ataxia, lack of dysarthria, and no
cardiomyopathy. Conversely, FRDA is
virtually excluded in the presence of
prominent cerebellar atrophy.
X-Linked Degenerative Ataxias
The major X-linked ataxia is FXTAS, a
condition occurring in carriers of
intermediate length (premutation) alleles (50 to 200 triplets) of the CGG
repeat whose full expansion (9200
triplets) causes the fragile X syndrome
of mental retardation. FXTAS mostly
Continuum (Minneap Minn) 2013;19(5):13121343

affects men older than 50 years and is


characterized by ataxia and action
tremor (Supplemental Digital Content
7-4, links.lww.com/CONT/A87). Typical MRI findings are fluid-attenuated
inversion recovery (FLAIR) middle
cerebellar peduncle and cerebral
periventricular white matter hyperintensities. A recent study pointed out
that the clinical picture may be more
complex than previously thought.52
Main findings were as follows: (1)
tremor may be essential-like, cerebellar, or parkinsonian; (2) peripheral neuropathy is very common and may be
length-dependent or not; and (3) 60%
of patients have parkinsonism. The
same study found no family history of
fragile X syndrome in almost half
(46%) of the cases. FXTAS also occurs
in women, although the characteristic
clinical manifestation of fragile X premutation in females is premature ovarian failure.

KEY POINTS

h In recessive or sporadic
cases of degenerative
ataxia with mild or
absent cerebellar
atrophy, a genetic test
for Friedreich ataxia is
indicated even if onset
has been unusually late
and the clinical picture
is atypical.

h Fragile X tremor-ataxia
syndrome mostly affects
men over 50 years of
age and is characterized
by ataxia and action
tremor. Typical MRI
findings are fluidattenuated inversion
recovery (FLAIR) middle
cerebellar peduncle and
cerebral periventricular
white matter
hyperintensities.

Congenital Ataxias
This group of disorders includes cerebellar malformations that cause impaired motor development with usually
nonprogressive ataxia. Other malformations affecting the CNS or other
organs may coexist. MRI is a very useful
tool to guide diagnosis. Joubert syndrome and related disorders are the
most common genetic congenital
ataxias. These recessive conditions are
characterized by vermis hypoplasia and
large, horizontal superior cerebellar peduncles, which, in axial MRI images,
generate the pathognomonic molar
tooth sign. Clinically, nonprogressive
ataxia is accompanied by hypotonia,
oculomotor apraxia, episodes of apnea/
hyperpnea in infancy, and variable
intellectual disability. Eyes, liver, and
kidneys may be variably affected in a
group of diseases related to Joubert
syndrome, collectively called ciliopathies.53 These diseases are all due to
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1321

Cerebellar and Afferent Ataxias

TABLE 7-5 Major Non-Friedreich Autosomal Recessive Ataxias


Significant Developmental Peripheral
Other Movement
Delay/ Intellectual Disability Neuropathy Disorders

Condition

Onset Age

Ataxia with Vitamin E


deficiency (AVED)

Late childhood,
adolescence

+/j

Ataxia-telangiectasia

Early childhood

+/j

Ataxia with oculomotor


apraxia type 1

Childhood

+/j

Ataxia with oculomotor


apraxia type 2

Late childhood to
early adulthood

Autosomal recessive
spastic ataxia of
Charlevoix-Saguenay

Childhood

Cholestanolosis

Childhood to
adulthood

+/j

Marinesco-Sjogren
syndrome

Childhood

Spinocerebellar ataxia
with neuropathy 1

Adolescence

Giant axonal
neuropathy

Early to
mid-childhood

Coenzyme Q10 deficiency Childhood to


(various diseases)
adulthood

Late-onset GM2
gangliosidosis

Childhood to
adulthood

Abetalipoproteinemia

Infancy and
childhood

Refsum disease

Childhood to
young adulthood

Congenital disorder of
glycosylation 1a

Infancy to
adulthood

+/j

Wilson disease

Childhood to
adulthood

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


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

1322

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Ophthalmic
Abnormalities

Other Clinical
Features

Early Cerebellar Other MRI


Atrophy
Features

Diagnostic Tests
and Results

, acuity, retinitis
pigmentosa

Prominent posterior
column loss, pyramidal
signs, cardiomyopathy

,vitamin E, TTPA genetic


testing

Oculomotor apraxia

Telangiectasia,
immunodeficiency

j !-fetoprotein, low
immunoglobulins, ATM
genetic testing

Oculomotor apraxia

Hypoalbuminemia,
hypercholesterolemia

APTX genetic testing

Oculomotor apraxia

Moderately elevated
!-fetoprotein, raised
creatine kinase in some

SETX genetic testing

Marked spasticity,
hypermyelinated
retinal fibers

Linear pontine
hypointensities

SACS genetic testing

Cataracts

Tendon xanthomas, chronic +


diarrhea, seizures

Cerebral atrophy, white j cholestanol, CYP27A1


matter abnormalities
genetic testing

Cataracts

Myopathy,
+
hypogonadism, short
stature, skeletal anomalies

Cerebellar cortical
T2 abnormalities

Electron dense structures


on muscle biopsy, SIL1
genetic testing

Hypoalbuminemia,
hypercholesterolemia

TDP1 genetic testing

Kinky hair, pyramidal


signs

White matter signal


abnormalities

Giant axons on nerve biopsy,


GAN genetic testing

+/j

Seizures, myopathy,
pyramidal signs

Coenzyme Q10 deficiency


in muscle/fibroblasts,
genetic testing (various genes)

Optic atrophy, retinitis


pigmentosa

Seizures, cognitive
regression, psychiatric
disturbance

"-Hexosaminidase A
enzymatic testinga, HEXA
genetic testing

Retinitis pigmentosa

Diarrhea, fat malabsorption j


(including vitamin E
deficiency), red blood
cell acanthocytosis

Extremely low cholesterol


levels, abnormal lipoprotein
profile, MTP genetic testing

Retinitis pigmentosa

Deafness, anosmia,
ichthyosis

j Phytanic acid, deficiency


of phytanoyl-CoA hydroxylase enzyme activity, genetic
testing of PHYH, PEX7

White matter
abnormalities

Abnormal transferrin isoform


pattern, deficient
phosphomannomutase
activity, PMM2 genetic testing

Basal ganglia, thalamic,


and brainstem
abnormalities

, Serum copper and


ceruloplasmin, j urinary
copper excretion, ATP7B
genetic testing

Retinitis pigmentosa, Seizures, hypogonadism, +


strabismus
skeletal abnormalities

Kayser-Fleischer rings

Liver disease, psychiatric


disturbance

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1323

Cerebellar and Afferent Ataxias


KEY POINT

h Episodic ataxias are a


group of disorders,
caused by mutations
of ion channel genes,
that are characterized
by attacks of ataxia of
variable duration,
which may be
accompanied by other
neurologic symptoms.

Case 7-2
A 35-year-old woman had a history of ataxia since the age of 13. First
symptoms were loss of balance and falls. Gait instability progressed
relentlessly until, at age 20, she was entirely wheelchair dependent. Limb
ataxia developed later but became severe enough to make her dependent
on others for most activities of daily living. At examination, the patient
was unable to stand without strong support and unable to walk. Her
speech was slurred and irregular; occasionally, she needed to repeat
words. Cognitive function appeared to be preserved. Eye movements were
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 patients 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


of the primary cilium, a microtubulecontaining extension of the cell membrane essential for the development of
many tissues.
Episodic Ataxias
Episodic ataxias are a group of disorders, caused by mutations of ion
channel genes, that are characterized
by attacks of ataxia of variable duration, which may be accompanied by
other neurologic symptoms. Eight
genetic subtypes have been identified.
The causative gene is known in four of
them: episodic ataxia types 1, 2, 5, and

1324

6. Episodic ataxia type 1 (EA1), caused


by mutations in the potassium channel gene KCNA1, gives short (seconds
to minutes) attacks of ataxia, with
interictal myokymia and, in some
cases, seizures and neuromyotonia.
EA2 is due to (mostly nonsense) mutations in the calcium channel gene
CACNA1A, so it is allelic to SCA6 and
to a form of familial hemiplegic migraine. Attacks in EA2 are of longer
duration (hours to days) and are accompanied by interictal nystagmus and
slowly progressive ataxia with cerebellar atrophy. EA5 is clinically similar to
EA2 and caused by mutations in the

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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
patients 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


mutations in a glial glutamate transporter gene (SLC1A3), alternating
hemiplegia and seizures may occur in
addition to episodic ataxia.
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Hereditary Afferent Ataxias


Several hereditary ataxias have an afferent
component. FRDA is the main example,
as it is characterized by proprioceptive
loss and prominent pathology in the
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1325

Cerebellar and Afferent Ataxias


KEY POINTS

h The main causes of


acute ataxia in adults
are vascular lesions,
cranial trauma,
infections, intoxications,
immune ataxias,
vestibular disorders, and
psychogenic causes.

h Alcohol is the most


common cerebellotoxic
agent. Chronic
consumption causes
cerebellar atrophy
predominating in the
anterior vermis and gait
more than limb ataxia.

dorsal root ganglia and dorsal columns.


Other conditions with an afferent contribution to ataxia include ataxia with
vitamin E deficiency (AVED), ataxia
telangiectasia, AOA1 and 2, abetalipoproteinemia, and some SCAs (SCA18 is
a pure afferent ataxia).
Hereditary neuropathies may cause
afferent ataxia, in particular CharcotMarie-Tooth disease (CMT) type 2B, an
axonal form with mutations in the RAB7
gene; Dejerine-Sottas disease (due to
mutations in PMP22 [CMT1E] or
periaxin genes [CMT4F]; Refsum disease; the hereditary sensory and autonomic neuropathies (HSAN IYV).10,54
Rare recessive afferent ataxia disorders include posterior column ataxia
and retinitis pigmentosa, due to FLVCR
mutations; and sensory ataxia, neuropathy, dysarthria, and ophthalmoparesis
(SANDO), due to POLG1 mutations.
Whereas posterior column ataxia and
retinitis pigmentosa presents with afferent ataxia, night blindness, and
areflexia in infancy, with further progression in the second decade,55
SANDO is of late onset.56 Mitochondrial recessive ataxia syndrome is a recessive ataxia due to a specific POLG1
mutation that differs from SANDO because of juvenile onset, cerebellar involvement, mild cognitive impairment,
involuntary movements, psychiatric
symptoms, and epilepsy.57
DIAGNOSIS OF ATAXIAS IN
DAILY PRACTICE
Table 7-6 provides the main differential diagnoses of ataxia in children.
Blood studies, genetic tests, and brain
imaging play a determinant role in the
diagnosis. To fully delineate the phenotype, nerve conduction studies/
EMG (presence versus absence of peripheral neuropathy, axonal versus
demyelinating) and referral to an ophthalmologist (retinitis pigmentosa, cataract, and cherry red spot, etc) should

1326

be considered. Table 7-72 lists some


complementary investigations that may
guide the diagnosis in adults.
Sporadic Cerebellar Ataxias
The main causes of acute cerebellar ataxia
in adults are vascular lesions, cranial
trauma, infections, intoxications, immune
ataxias, vestibular disorders, and psychogenic causes. The clinical presentations of
ischemic cerebellar strokes are summarized in Table 7-8.2 A representative MRI
of vascular lesions in the cerebellum is
shown in Figure 7-2.
Paraneoplastic cerebellar degeneration often presents as a subacute cerebellar syndrome and may occur before
the identification of an underlying cancer, usually a small cell lung cancer, a
breast or ovarian cancer, or a lymphoma. A profound cerebellar atrophy
of rapid progression characterizes most
of these syndromes (Figure 7-3).
Posterior fossa trauma should not
be overlooked for obvious anatomic
reasons, and the possibility of a dissection of neck vessels should be kept
in mind. Figure 7-4 shows recordings
of a severe action tremor following
cerebellar trauma. Cerebellar contusion,
cerebellar hematoma and subarachnoid hemorrhage, diffuse axonal injury, and subdural/epidural hematoma
represent the various forms of cerebellar lesions associated with head
trauma.
Alcohol is the most common cerebellotoxic agent (Table 7-9). Chronic consumption causes cerebellar atrophy
predominating in the anterior vermis
(Figure 7-5)58 and gait more than limb
ataxia. In these patients, ataxia of gait is
also more severe than limb ataxia.
Wernicke encephalopathy, which occurs due to thiamine (vitamin B1) deficiency, combines a mental confusional
state, oculomotor deficits (most often
nystagmus and various degrees of paralysis of external rectus muscles), and gait

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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-Sjogren 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

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1327

Cerebellar and Afferent Ataxias


KEY POINT

h Some cases of cerebellar


and afferent ataxia are
due to autoimmune
causes. Although
some entities remain
controversial, an
autoimmune cause
must be considered
in the differential
diagnosis.

TABLE 7-6 Differential Diagnosis of Ataxias in Children (continued )


Immune
Multiple sclerosis
Acute disseminated encephalomyelitis (ADEM)
Miller Fisher syndrome
Bickerstaff encephalitis
Vestibular
Benign paroxysmal positional vertigo (BPPV)
Menie`re 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


with Wernicke encephalopathy are alcoholism, hyperemesis gravidarum,
gastroplasty/intestinal surgery, prolonged
parenteral nutrition, long stay in critical
care units, dialysis, chemotherapy or
immunosuppressive drugs, thyrotoxicosis, and food refusal (psychogenic).59
In addition to multiple sclerosis, in
which lesions commonly affect the
cerebellum and its afferent and efferent
connections, several immune ataxias
have been recognized.60,61 Antibodies
to glutamic acid decarboxylase are
found in the serum of most patients
with type 1 diabetes mellitus as well as
those with immune-mediated syndromes affecting the CNS, including
stiff-person syndrome, and in a few patients with cerebellar ataxia62 (mostly
women also affected with diabetes

1328

mellitus). Experimental evidence63


supports the concept that antibodies
directly cause stiff-person syndrome
and cerebellar ataxia, but it remains to
be determined whether the antiY
glutamic acid decarboxylase autoantibodies or other autoantibodies made
by these patients are responsible. Gluten ataxia is a type of autoimmune
ataxia described to occur in genetically
susceptible patients (the human leukocyte antigen class II type DQ2 is
overrepresented) who produce circulating antigliadin antibodies following
exposure to gliadin in food.64 Ataxia
may develop in the absence of enteropathy and may have an insidious course.
Neurophysiologic investigations show
evidence of a sensorimotor axonal neuropathy in half of the patients. However,
this entity remains controversial, as

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TABLE 7-7 Laboratory


Investigations
in Adult-Onset
Cerebellar Ataxiasa
b Blood Studies
Sedimentation rate
C-reactive protein
Serum electrolytes
Glucose, glycosylated hemoglobin
Renal and liver function tests
Cholesterol, triglycerides,
low-density lipoprotein,
very-low-density lipoprotein
Vitamin E
Vitamin B12, homocysteine,
folic acid
Copper and ceruloplasmin
Protein electropheresis
Acanthocytes
Lactate/pyruvate
Heavy metals
Antinuclear antibodies
Thyroid stimulating hormone,
antithyroid peroxidase and
antithyroglobulin antibodies
Antigliadin/endomysium
antibodies
Antiglutamic acid decarboxylase
antibodies
Anticerebellar antibodies
b CSF Studies
Cell count and cytology
Protein, glucose, lactate
Immunoglobulin G index,
oligoclonal bands
14-3-3 protein
Anticerebellar antibodies
Cultures
b Urine Studies
Metabolic screening
Protein electrophoresis
Heavy metals
Bile alcohols
a

Adapted from Manto MU, Cambridge


University Press.2 B with permission of
Cambridge University Press.

Continuum (Minneap Minn) 2013;19(5):13121343

antigliadin antibodies are found in


asymptomatic individuals and have
been reported in subjects with other
forms of degenerative ataxia, including
hereditary diseases.65 Ataxia can occur
in the context of Hashimoto encephalopathy, but, rarely, subacute or chronic
progressive ataxia has been reported
to be the main neurologic symptom in
individuals with antithyroid antibodies,
in most of whom cerebellar atrophy
was shown on MRI.66,67 Case reports of
improvement with IV immunoglobulin
suggest a role of autoimmunity in these
patients, but again, it remains uncertain
whether the antithyroid antibodies
are directly involved or whether other
immune mechanisms are responsible.
Ataxia may also occur in the context of
a systemic autoimmune disease, such as
systemic lupus erythematosus and
Sjo
gren syndrome. In these conditions,
a role for autoantibodies directed against
cellular components of the nervous
system has been postulated, but pathogenic mechanisms have not yet been
fully elucidated. In the case of Sjo
gren
syndrome, an autoimmune sensory neuronopathy may cause afferent ataxia.10
Multiple system atrophy (MSA)
combines symptoms of dysautonomia,
parkinsonism, and cerebellar ataxia
and corticospinal signs at various degrees (Case 7-4).68 Pathologically, glial
cytoplasmic !-synuclein inclusions are
the hallmark of the disease. Predominant parkinsonian features that respond poorly to levodopa treatment
characterize the parkinsonian variant
of MSA (MSA-P), whereas the group of
MSA-C refers to patients who exhibit
predominant cerebellar deficits (Supplemental Digital Content 7-6,
links.lww.com/CONT/A89 ). Symptoms of autonomic impairment may
appear before motor symptoms. They
consist of urinary tract dysfunction (incontinence, urinary urgency or retention), orthostatic hypotension,
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1329

Cerebellar and Afferent Ataxias

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


syndrome

Dizziness, diplopia, drowsiness,


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 (constipation or diarrhea), erectile dysfunction,


and dyshydrosis. Sleep disorders such
as REM sleep behavior disorder, central

1330

sleep apnea, and stridor may also


predate the onset of motor symptoms.68 MSA represents the most
common nonhereditary degenerative

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October 2013

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


around 55 years of age. MSA is a
progressive, eventually fatal disease
with a median survival of around 10
years after symptom onset.68 Several
signs not suggestive of MSA should
prompt reconsideration of the diagnosis, such as the presence of clas-

FIGURE 7-3

sical pill rolling tremor, marked


dementia, good/long-standing response to levodopa, gaze palsy, or
slowing of saccades.69 In MSA, MRI
shows progressive cerebellar and pontine atrophy. Atrophy of pontocerebellar
fibers gives a characteristic appearance on axial T2-weighted images of

Magnetic resonance sagittal T1-weighted images showing severe cerebellar


atrophy associated with a paraneoplastic cerebellar syndrome induced by a
thymic carcinoma.

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1331

Cerebellar and Afferent Ataxias

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


(Figure 7-670).
Idiopathic late-onset cerebellar
ataxia (ILOCA) often starts between
40 and 55 years of age and presents
with a slowly progressive cerebellar
syndrome for which known causes
have been excluded. In some cases, a
follow-up of several years may be necessary to differentiate ILOCA from an
early case of MSA-C that has not yet
developed overt autonomic failure.
Figure 7-7 shows computed posturographies illustrating the gait and balance abnormalities in ILOCA and
other acquired and inherited ataxias.

1332

Acquired Afferent Ataxias


Acquired afferent ataxias may be
immune-mediated (including paraneoplastic), toxic (including iatrogenic),
vitamin-related, or of unknown
cause.10 Acquired peripheral sensory
neuropathies that may cause afferent
ataxia are listed in Table 7-10.
Paraneoplastic afferent ataxia has a
subacute to chronic course and may
be associated with bronchogenic carcinoma, small cell lung cancer, breast
cancer, ovarian cancer, sarcoma, and
Hodgkins lymphoma. It is due to T-cellY
mediated sensory ganglionopathy.
Onconeural antibodies such as anti-Hu

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TABLE 7-9 Toxins Causing


Cerebellar Ataxia
b Ethanol
b Heavy metals
b Drugs
Lithium salts
Phenytoin
Metronidazole and other azoles
Calcineurin inhibitors
Amiodarone
b Chemotherapy
b Drug abuse (cocaine, heroin,
methadone, phencyclidine,
herbs)
b Solvents

FIGURE 7-5

and antiYcollapsin response mediator


protein-5 can be found in most cases,
but not invariably.
Other immune-mediated sensory
ganglionopathies causing afferent
ataxia also have a subacute to chronic
course and may be associated with
Sjo
gren syndrome, unclassified autoimmune disorders, chronic autoimmune hepatitis, or monoclonal
gammopathy of unknown significance. The specific serology findings
for each of these conditions assist in
the diagnosis.
Toxic and vitamin-related afferent
ataxias tend to have a slower, subacute to
chronic course. In addition to the wellknown myelopathy and neuropathy

Magnetic resonance sagittal T1-weighted images showing marked atrophy of the


vermis in a patient with history of chronic alcohol intake.

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1333

Cerebellar and Afferent Ataxias


KEY POINT

h When an inherited
condition is suspected,
family history should be
the first criterion used to
direct testing.

Case 7-4
A 70-year-old man started to lose his balance 6 years ago. Family history
was negative for ataxia. At age 66, neurologic examination had demonstrated
a clearly abnormal gait with polydirectional sway and enlarged base,
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 patients 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,


afferent ataxia may also be a symptom of copper-deficient myelopathy71
and nitrous oxide toxicity (through
vitamin B12 deficiency).72 Sensory
neuronopathies causing ataxia may be
associated with deficiencies of riboflavin, nicotinic acid, or vitamin E (also
found in genetic forms), and with
pyridoxine intoxication.
Hereditary Ataxias
When an inherited condition is suspected, family history should be the
first criterion used to direct testing.
Also, it is important to document family
history of neurologic conditions other
than ataxia because some SCAs may
present with parkinsonism, neuropathy, motor neuron disease, spasticity,

1334

intellectual disability, or myoclonus.


Evidence of dominant inheritance
should initially prompt testing for the
most common SCAs due to CAG expansion mutations (ie, SCA1, 2, 3, 6, 7, and
17), which is often offered as a panel.
Patients of Asian and African origin
should also be screened for DRPLA. If
these genetic investigations are negative,
the patient should be referred to a
specialized center for testing of less
common SCAs, which should be prioritized based on clinical and epidemiologic
considerations. Clinical features should
also guide genetic testing for the autosomal dominant episodic ataxias.
When family history supports recessive inheritance (ie, when multiple
siblings are affected and parents are
unaffected), patients should be first

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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 cerebellar atrophy is prominent. Further


testing should be guided by clinical
and biochemical findings whose alteration indicates or suggests a specific
diagnosis, such as high cholestanol
(cholestanolosis), low vitamin E
(AVED), high cholesterol and low
albumin (AOA1), or high !-fetoprotein
(AOA2 and AT). As a further step,
mutation analysis of the SACS, POLG,
APTX, and SPG7 genes (taking into
account specific phenotypes) and biochemical testing for white blood cell
enzymes for metachromatic leukodystrophy and Krabbe disease, phytanic
acid for Refsum disease, and long-chain
fatty acids for adrenoleukodystrophy
may be requested. If still no diagnosis
can be established, referral to a specialized center is recommended in
order to perform skin or muscle biopsy
targeted at diagnoses such as NiemannPick disease type C, recessive ataxia
with coenzyme Q deficiency (ADCK3/
SCAR9), and mitochondrial disorders.
Continuum (Minneap Minn) 2013;19(5):13121343

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.
In addition to atypical cases of diseases
usually presenting earlier in life, in
some recently discovered recessive
ataxias (such as the form due to mutations in ANO10), symptoms usually
begin after the age of 40.73 Dominant
diseases may also appear as sporadic
when family history is unknown or a
potentially affected parent died before
developing symptoms, or, rarely, because of reduced penetrance or de
novo mutations. In SCA2 and SCA7,
large repeat expansions may cause
extreme anticipation, so a child may
become affected before the parent who
transmitted the mutation. Testing for
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1335

Cerebellar and Afferent Ataxias

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


considered in the presence of a suggestive family history, for example, when

relatives include children with fullblown fragile X syndrome or women


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)

1336

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October 2013

in sporadic cases when clinical and


imaging features are suggestive of this
diagnosis.
All of the above recommendations
for genetic testing may soon become
surpassed by the progressive introduction of next-generation sequencing in
the diagnostic arena. While exome and
whole-genome sequencing still remain
research tools, several laboratories are
already developing targeted nextgeneration sequencing approaches to
sequence all known ataxia genes. The
benefits of such increased diagnostic
power may be great if it is considered a
complement rather than a replacement
of careful clinical assessment.
TREATMENT
Acquired ataxias should be treated
according to their specific etiology.
This may include treatment of strokes,
tumors, multiple sclerosis, avoidance
of toxic agents, and vitamin supplementation. Some evidence has shown
that immunomodulatory treatments,
like IV immunoglobulin, may be effective for some immune-mediated
ataxias, but there have been no controlled randomized trials.74 Results
depend on the cause of ataxia and
the extent of neuronal damage.
Specific treatment exists for only a few
hereditary ataxias. AVED responds to
high-dose vitamin E supplementation
(800 mg/d to 1500 mg/d).49 Vitamin E
supplementation should also be prescribed for abetalipoproteinemia, in addition to a low-fat diet. Recessive ataxias
with coenzyme Q deficiency should be
treated with coenzyme Q10 supplementation, 150 mg/d to 300 mg/d. 75
Cerebrotendinous xanthomatosis
should be treated with chenodeoxycholic acid, which suppresses
cholestanol synthesis, at the dose of
750 mg/d.76 For Refsum disease, the
basic treatment is avoidance of phytanic
acid and a high-calorie diet; plasmapheContinuum (Minneap Minn) 2013;19(5):13121343

resis has also been proposed to remove


phytanic acid. In Niemann-Pick type C
disease, treatment with miglustat, a
molecule that inhibits glycolipid synthesis, at the dose of 200 mg 3 times a day,
has resulted in partial improvement and
slowed disease progression.77 The observation that ataxia telangiectasia patients treated with steroids (originally
for lymphoma) showed improvement of
ataxic symptoms prompted further consideration of glucocorticoids for this
condition.78 Glucocorticoids may be
beneficial because they penetrate the
CNS, where they act as anti-inflammatory
and antioxidant drugs. However, their
side effects, particularly an increased risk
of infection in the already immunocompromised ataxia telangiectasia patients,
impose caution before this treatment
can be recommended.
At least 12 drugs are in the development pipeline for the treatment of
FRDA.79 These include lipid-soluble
antioxidants such as the short-chain
coenzyme Q analog idebenone and
compound A0001 (!-tocopheryl quinone), related to both coenzyme Q
and vitamin E. Despite some promising results in a phase 2 study,80 no
efficacy of idebenone in improving
ataxia or cardiomyopathy could be
demonstrated in two phase 3 studies.81 A phase 2A trial with A0001
showed signs of efficacy on ataxia,82
but the short duration of the study (4
weeks) imposes caution. Deferiprone
is an orally administered, membranepermeable iron chelator, thought to
be useful in FRDA by removing excess
redox-active iron from mitochondria.83 Despite an encouraging openlabel pilot study,84 a 6-month phase 2
randomized controlled trial in FRDA,
however, was inconclusive (unpublished data). Human recombinant
erythropoietin has been shown to
increase frataxin levels in cultured
cells,85 providing the rationale for

KEY POINTS

h Acquired ataxias should


be treated according to
their specific etiology.
This may include
treatment of strokes,
tumors, multiple
sclerosis, avoidance
of toxic agents,
and vitamin
supplementation.

h Some evidence
has shown that
immunomodulatory
treatments, like IV
immunoglobulin, may
be effective for some
immune-mediated
ataxias, but no
controlled randomized
trials have been
conducted.

h Specific treatment exists


for only a few hereditary
ataxias: ataxia with
vitamin E deficiency,
coenzyme Q10
deficiency,
cerebrotendinous
xanthomatosis
(cholestanolosis), and
Niemann-Pick disease
type C.

h Corticosteroids may
improve symptoms of
ataxia-telangiectasia,
but their use is not
recommended until
supported by evidence
from controlled trials.

h At least 12 drugs are


in the development
pipeline for the
treatment of Friedreich
ataxia, but none has yet
been proven effective in
phase 3 randomized
controlled trials.

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1337

Cerebellar and Afferent Ataxias


KEY POINTS

h Attempts to develop a
symptomatic treatment
for ataxia have so far
met with limited success
and only in specific
conditions.

h Some evidence
suggests that intensive
coordinative training
(at least 3 times a week
for 4 weeks) may
help improve motor
performance and
reduce ataxia symptoms
in patients affected
with cerebellar ataxia,
with less effect on
afferent ataxia.

1338

clinical testing in FRDA. However, the


only randomized controlled trial that
used human recombinant erythropoietin was negative.86 Results from a
controlled trial with a similar molecule, carbamylated erythropoietin,
which does not induce erythropoiesis
but preserves the ability to upregulate
frataxin in vitro, are not yet available.
Robust induction of frataxin expression has been obtained in cultured
cells and animal models using a family
of histone deacetylase inhibitors acting
on the chromatin changes triggered by
GAA repeat expansions.48,87Y89 Early
clinical development of these molecules has been initiated.
Attempts to develop a symptomatic
treatment for ataxia have so far met
with limited success, with a few exceptions. The potassium channel blocker
4-aminopyridine has been shown to
shorten attacks, decrease nystagmus,
and improve quality of life in patients
with episodic ataxia.90 Some episodic
ataxias, in particular EA2, may respond
to acetazolamide, and a limited response to the same drug has also been
reported for SCA6.91 Varenicline, a
nicotinic acetylcholine receptor agonist
used to help smoking cessation, at the
dose of 1 mg twice a day has improved gait and stance in SCA3 patients in a randomized controlled
trial.92 A single randomized controlled
trial of riluzole at the dose of 100 mg/d,
involving a very heterogeneous group
of patients with ataxia of varied etiologies showed an improvement of the
International Cooperative Ataxia Rating
Scale score after 8 weeks.93 Several
drugs that act on serotonin receptors
(5-hydroxytryptophan, buspirone,
tandospirone), as well as amantadine,
thyrotropin-releasing hormone, and
zinc supplementation, have been tested for a symptomatic effect in ataxia,
mostly in open-label trials, but results
remain inconclusive.

Finally, some evidence indicates


that intensive coordinative training
(at least 3 times a week for 4 weeks)
may help improve motor performance
and reduce ataxia symptoms in patients affected with cerebellar ataxia,
with less effect on afferent ataxia.94
CONCLUSION
Ataxias are characterized by quite diverse genetic, clinical, pathophysiologic, pathogenetic, and neuropathologic
features. Although in some cases a
complete diagnostic workup may eventually require referral to a specialized
center, the general neurologist can
identify and manage the most common
conditions causing ataxia. The diagnostic process must consider the age of the
patient; the mode of presentation and
the rate of progression of the disease;
the associated signs and symptoms; the
presence of a history of alcohol abuse
or exposure to toxic substances (including drugs), of previous or concurrent
infection, of neoplasia, or of a family
history of a similar disorder.
Progress in research and the progressive availability of advanced diagnostic technologies is rapidly
increasing our power to specifically
diagnose even the rarest forms of
ataxia, but similar progress in therapy
still has to come. However, many patients presenting with ataxia have a
condition that can be treated, if not
cured, such as vascular disease, tumor,
multiple sclerosis or another inflammatory disease, infection, autoimmune
disease, or drug toxicity. Even for some
of the rare genetic diseases, progress is
being made toward the development
of treatments, making the quest for a
diagnosis even more important.
VIDEO LEGENDS
Supplemental Digital Content 7-1

Spinocerebellar ataxia type 12. Video shows a


68-year-old woman with onset of postural and

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October 2013

action hand tremor at age 48, progressing slowly


to include gait ataxia at age 58, then dementia at
age 65. She had a family history of severe tremor
in three of her four siblings, her mother (also
rigidity and falls), two maternal uncles, and her
maternal grandfather. Her examination also
revealed appendicular and gait ataxia, titubation,
apraxia, paratonia, and dementia. SCA12, a type
of dominant ataxia common in India but rare
elsewhere, was confirmed by genetic testing.
links.lww.com/CONT/A84
Video courtesy of Andrew P. Duker, MD.
B 2013 American Academy of Neurology.
Supplemental Digital Content 7-2

Spinocerebellar ataxia type 2. Video shows a


32-year-old woman with 49 CAG repeat expansions in ataxin-2 who had onset of gait impairment in her late teens, with slowly progressive
ataxia. The slowness of saccades is the diagnostic feature on examination.
links.lww.com/CONT/A85
Video courtesy of Alberto J. Espay, MD, MSc, FAAN.
B 2013 American Academy of Neurology.
Supplemental Digital Content 7-3

Friedreich ataxia. Video shows a 25-year-old


man with Friedreich ataxia since childhood, who
has been in wheelchair for 3 years. Note the
evident proximal weakness of the upper limbs,
slowness of movement, and lack of an obvious
kinetic tremor. The video also shows the characteristic eye movement abnormality of Friedreich
ataxia, and fixation instability with square-wave
jerks. Note the absence of nystagmus.
links.lww.com/CONT/A86

Supplemental Digital Content 7-5

Autosomal recessive spastic ataxia of


Charlevoix-Saguenay. Video shows a 28-yearold woman with early-onset (at 2 years of age)
spasticity of lower limbs, followed by progressive trunk and limb ataxia, dysarthria, and
neuropathy. She had been using a wheelchair
for 7 years. A baclofen pump placed 3 years
before the video markedly improved the discomfort caused by her severe lower limb
spasticity. Note the relatively mild upper limb
ataxia compared to the severe involvement of
her lower limbs. Eye movement abnormalities
include gaze-evoked nystagmus, saccadic pursuit, and dysmetria of saccades.
links.lww.com/CONT/A88
B 2013 American Academy of Neurology.
Supplemental Digital Content 7-6

Cerebellar variant of multiple system atrophy. Video shows a 59-year-old woman with
an 8-year history of progressive difficulty with
walking, balance, and speech. The earliest
reported difficulty was stiffness in her legs
and staggering while walking, followed by
slurring of speech and trouble with fine motor
skills (eating and getting dressed) within 1 year
of symptom onset. She then developed a left
hand resting tremor and dystonia. Response to
levodopa was poor. She died from her illness
shortly after this video was taken. Neuropathologic examination demonstrated classical oligodendroglial inclusions typical of multiple
system atrophy, cerebellar type.
links.lww.com/CONT/A89

B 2013 American Academy of Neurology.

Video courtesy of Alberto J. Espay, MD, MSc, FAAN.


B 2013 American Academy of Neurology.

Supplemental Digital Content 7-4

REFERENCES

Fragile X tremor-ataxia syndrome. Video


shows a patient who developed bilateral hand
tremor at age 67, initially occurring with action
and posture (later also at rest). Tremor slowly
progressed to involve his head. At age 70, he
developed short-term memory impairment; at
71, he started falling because of poor balance.
Examination revealed mild parkinsonian features and peripheral neuropathy. A grandson
had mental retardation due to fragile X syndrome. The patient was found to have 92 CGG
repeats in the FMR1 gene, diagnostic of fragile
X tremor-ataxia syndrome. Brain MRI showed
hyperintensity in the middle cerebellar peduncle (the MCP sign) and the corpus callosum.
links.lww.com/CONT/A87
B 2013 Fredy J. Revilla, MD. Used with permission.
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