Professional Documents
Culture Documents
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.
1312
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-
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October 2013
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.
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FIGURE 7-1
1314
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
KEY POINTS
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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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.
SCA1
SCA2
SCA3
SCA6
SCA7
SCA10
SCA12
India
SCA13
France, Philippines
SCA14
SCA28
SCA31
SCA36
Japan
Dentatorubral-pallidoluysian
atrophy (DRPLA)
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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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October 2013
Mutated Gene
Protein, Function
SCA5
SPTBN2
SCA11
TTBK2
SCA13
KCNC3
SCA14
PRKCG
SCA15/16
ITPR1
SCA19/22
KCND3
SCA20
250 Kb dupl.
Unknown
SCA23
PDYN
SCA27
FGF14
SCA28
AFG3L2
SCA35
TGM6
Transglutaminase 6
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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.
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KEY POINT
Pyramidal features
Peripheral neuropathy
Slow saccades
SCA2, SCA7
Ophthalmoparesis
SCA1, SCA28
SCA7
Eyelid retraction
SCA3
Tremor
Parkinsonian features
Dystonia
Myoclonus
Chorea
SCA17
Dementia
Intellectual disability
SCA13
Seizures
SCA10
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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h A proportion of
recessive ataxias appear
to be mild variants of
metabolic diseases.
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October 2013
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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Condition
Onset Age
Late childhood,
adolescence
+/j
Ataxia-telangiectasia
Early childhood
+/j
Childhood
+/j
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
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
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October 2013
Ophthalmic
Abnormalities
Other Clinical
Features
Diagnostic Tests
and Results
, acuity, retinitis
pigmentosa
Prominent posterior
column loss, pyramidal
signs, cardiomyopathy
Oculomotor apraxia
Telangiectasia,
immunodeficiency
j !-fetoprotein, low
immunoglobulins, ATM
genetic testing
Oculomotor apraxia
Hypoalbuminemia,
hypercholesterolemia
Oculomotor apraxia
Moderately elevated
!-fetoprotein, raised
creatine kinase in some
Marked spasticity,
hypermyelinated
retinal fibers
Linear pontine
hypointensities
Cataracts
Cataracts
Myopathy,
+
hypogonadism, short
stature, skeletal anomalies
Cerebellar cortical
T2 abnormalities
Hypoalbuminemia,
hypercholesterolemia
+/j
Seizures, myopathy,
pyramidal signs
Seizures, cognitive
regression, psychiatric
disturbance
"-Hexosaminidase A
enzymatic testinga, HEXA
genetic testing
Retinitis pigmentosa
Retinitis pigmentosa
Deafness, anosmia,
ichthyosis
White matter
abnormalities
Kayser-Fleischer rings
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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.
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October 2013
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.
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a
TABLE 7-8 Main Presentations of Territorial Cerebellar Infarctions
Presentation
No additional features
Massive infarction
Medial syndrome
Classic infarct
Vestibular form
Adapted from Manto MU, Cambridge University Press.2 B with permission of Cambridge
University Press.
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KEY POINT
FIGURE 7-2
Axial T2-weighted MRI showing multiple vascular lesions in the posterior fossa
(arrows).
FIGURE 7-3
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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.
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FIGURE 7-5
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1333
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.
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KEY POINT
FIGURE 7-6
1335
FIGURE 7-7
1336
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October 2013
KEY POINTS
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 Corticosteroids may
improve symptoms of
ataxia-telangiectasia,
but their use is not
recommended until
supported by evidence
from controlled trials.
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1337
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.
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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
REFERENCES
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