Approach to Ataxia

Presenter: Dr Divya
Preceptor: Prof Achal K Srivastava
 Search strategy
• Bradley’s Neurology in clinical Practice, sixth edition
• Handbook of Clinical Neurology, Vol. 103 (3rd series),
Ataxic Disorders
• http://www.ataxia.org -National Ataxia Foundation web
site
• http://www.ncbi.nlm.nih.gov/books/NBK1138/ Detailed
information about ataxias
• http://www.clinicaltrials.gov – clinical trials information
• Pubmed-with the search terms “spinocerebellar
ataxia”,“Friedreich’s ataxia”, “sporadic ataxia”, “sensory
ataxia”, “approach to ataxia”, “ataxia diagnosis”
• The Cochrane Library
 Ataxia
 Ataxia = from Greek- a- [lack of]+ taxia [order]
"lack of order

 Of rate, rhythm and force of contraction of voluntary

movements
 Disorganized, poorly coordinated, or clumsy movements
 Traditionally used specifically for lesions involving

– Cerebellum or it’s pathways

– Proprioceptive sensory pathways
 Neural-Localization

Cerebellum (most common)

Sensory pathways (Sensory Ataxia)

 posterior columns, dorsal root ganglia, peripheral N.

Frontal lobe lesions-fronto-cerebellar fibers

 Sensory Ataxia

• Sensory neuropathy and posterior column disease of the

spinal cord (sensory ataxia)

 Loss of distal joint, position sense

 Absence of cerebellar signs such as dysarthria or nystagmus

 Loss of tendon reflexes
 Corrective effects of vision on sensory
ataxia
 Romberg sign
 Causes of sensory ataxia
Polyneuropathy Paraneoplastic sensory neuronopathy
Sjogren’s syndome
Miller Fisher Syndrome
Dysproteinemia
Cisplatin
Pyridoxine excess
Acute sensory neuronopathy
Chronic ataxic neuropathy
Myelopathy Multiple sclerosis
Tumour or cord compression
Vascular malformation
Vacuolar myelopathy
Myeloneuropathy Freidriech’s Ataxia
Vitamin B12 deficiency
Vitamin E deficiency
Tabes dorsalis
Nitrous oxide
 Cortical Ataxias

 FRONTAL LOBE ATAXIA refers to disturbed coordination due to

dysfunction of the contralateral frontal lobe

 Results from disease involving the frontopontocerebellar fibers

en route to synapse in the pontine nuclei.

 Hyper reflexia, increased tone and Release reflexes

 A lesion of the “SUPERIOR PARIETAL LOBULE” (areas 5 and 7 of

Brodmann) may rarely result in ataxia of the contralateral
limbs
 Vestibular dysfunction

 Vertigo is prominent
 Consistent fall to one side
 Nystagmus
 Limb ataxia is absent
 Speech is normal
 Joint position sense is normal

Patient complains of vertigo rather than imbalance

 Thalamic Ataxias

 transient ataxia affecting contralateral limbs after lesion of

anterior thalamus

 may see associated motor (pyramidal tract) signs from

involvement of internal capsule

 also can result in asterixis in contralateral limbs (hemiasterixis)

 Cerebellum

Paleocerebellum Vermis  Fastigial nucleus

Balance and
ocular movement

Intermediate Interposed nuclei

Execution of movements
and gait

Lateral Cortex Dentate nucleus

Motor planning, limb coordination

FloculusVestibulo-occular reflex
Neocerebellum

Archicerebellum
 Clinical features of cerebellar disease

 Ataxia (appendicular or axial)  Tremor

 Dysmetria  Titubation and increased
 Dyssynergia postural sway
 Dysdiadochokinesia  Hypotonia
 Rebound Phenomenon  Asthenia
 Dysarthria  Nystagmus
 Cerebellar Sensory Ataxia Frontal Ataxia
Base of support Wide-based Narrow base, looks down Wide-based

Velocity Variable Slow Very slow

Stride Irregular, Regular with path Short, shuffling

lurching deviation
Romberg +/– Unsteady, falls +/–

Heel-shin Abnormal +/– Normal

Initiation Normal Normal Hesitant

Turns Unsteady +/– Hesitant, multistep

Postural + +++ ++++

instability
Falls Late event Frequent Frequent
 Differentiation of imbalance due to frontal gait
disorder and extra pyramidal disorders from
cerebellar ataxia
Features Frontal gait disorder Extrapyramidal Cerebellar ataxia
Posture Upright Stooped, flexed trunk Stooped, leans forward
Stance Wide based Narrow Wide based
Initiation of gait Start hesitation Start hesitation Normal
Stepping Shuffles Shuffles Staggers, lurches
Stride length Short Short Variable
Speed Very slow Slow Normal, slow
Festination Rare Common Absent
Arm swing Exaggerated Reduced, absent Normal, exaggerated
Heel – toe Unable Normal Unable
Turning corners Freezes, shuffles Freezes Veers away
Heel –shin test Normal Normal Abnormal
Postural reflexes Impaired Preserved till late +/-
Falls Common Late uncommon
 Cerebellar Ataxia: Classifications

 Congenital or acquired
 Acute or subacute or chronic
 Familial or non familial
 AD or AR or SPORADIC
 Ipsilateral signs or bilateral signs
 Symmetrical or asymmetrical
 Progressive or slowly progressive, static or improving,
recurrent/episodic
 A/W HF,CN, Pyramidal, Extrapyramidal, Peripheral Neuropathy
Features

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 Classification

Hereditary Group
Autosomal dominant cerebellar Ataxias
Spinocerebellar ataxia type 1-31, SCA36, Episodic ataxias

Autosomal Recessive cerebellar Ataxias

Friedreich’s ataxia, Ataxia Telengiectasia, spastic ataxia

X-linked cerebellar ataxias

Fragile X tremor ataxia syndrome

Mitochondrial
Myoclonus Epilepsy with Ragged Red Fibers(MERRF),
Kearns Syre Syndrome (KSS)

Contd…
Cerebellar Ataxias classification (Contd..)

Non hereditary Group (Sporadic)

Degenerative progressive
MSA-C, Idiopathic late onset cerebellar ataxia (IOCA)
Non-progressive developmental disorders
Cayman ataxia, Joubert syndrome
Toxins induced cerebellar degeneration
Alcohol, Anticonvulsants, Anticancer drugs etc
Autoimmunity associated
Multiple sclerosis, Gluten ataxia, Ataxia with anti-GAD Ab
Paraneoplastic cerebellar degeneration
Infection mediated
Post viral infection cerebellitis, Enteric fever, Adeno/retroviral,
malaria, Prions
Cerebellar Ataxias classification (Contd..)

Developmental malformation/congenital
Dandy-Walker Malformation
Chiari Malformation
Vermial Agenesis etc.
 Diagnostic Approach
Meticulous evaluation of History
 Age at Onset
 Course of disease
 Drug intake
 Family History
 Personal Social & Occupational information
 Distribution of ataxia
 History of other system illness

Neurological evaluation

Ancillary tests
 History
• Age at onset
 Childhood (congenital, metabolic, infectious, posterior fossa
tumors, hereditary ataxias - more common)

 Adult (sporadic ataxias, hereditary ataxias)

• Course of illness/progression
 Acute (metabolic/toxic, infectious, inflammatory, traumatic)

 Subacute (metabolic/toxic, infectious, inflammatory,

paraneoplastic, tumor)

 Chronic (more likely genetic, degenerative, tumor,

paraneoplastic)
 History
• Drug intake
– Phenytoin, barbiturates, lithium, immunosuppressants
(methotrexate, cyclosporine), chemotherapy (fluorouracil,
cytarabine)

• Family history
– Study at least 3 generations
– Consanguinity
– Ethnicity

• Social/Occupational History
– Alcohol and drug use, toxins (heavy metals, solvents,
thallium), smoking (Vascular)
 History
• Distribution of ataxia
– Symmetric - Acquired, Hereditary, degenerative ataxias

– Asymmetric- Vascular, Tumors, congenital causes

• Other system illness

– Gastrointestinal symptoms- gluten ataxia

– Mass lesion- paraneoplastic ataxias

 In Children
History:
 refusal to walk or with a wide-based, "drunken" gait.
 Vertigo, dizziness and vomiting
 Personality and behavioral changes.
 Abnormal mental status
 A history of head trauma ,neck trauma
 Patients with a recent infection or vaccination
 Previous similar episodes of acute ataxia.
 Children with family members with ataxia
 symmetrical signs Focal and Ipsilateral Cerebellar Signs

Acute (Hours to Subacute (Days to Chronic (Months Acute (Hours to Subacute (Days Chronic (Months
Days) Weeks) to Years) Days) to Weeks) to Years)

Intoxication: Intoxication: Paraneoplastic Vascular: Neoplastic: Stable gliosis

alcohol, lithium, mercury, solvents, syndrome cerebellar cerebellar glioma or secondary to
diphenylhydantoin, gasoline, glue; Anti-gliadin infarction, metastatic tumor vascular lesion or
barbiturates cytotoxic antibody syndrome hemorrhage, or (positive for demyelinating
(positive history chemotherapeutic Hypothyroidism subdural neoplasm on plaque (stable
and toxicology drugs Inherited diseases hematoma MRI/CT) lesion on MRI/CT
screen) Alcoholic- Tabes dorsalis Infectious: Demyelinating: older than several
Acute viral nutritional (tertiary syphilis) cerebellar multiple sclerosis months)
cerebellitis (CSF (vitamin B1 and Phenytoin toxicity abscess (positive (history, CSF, and Congenital lesion:
supportive of acute B12 deficiency) Hereditary ataxia mass lesion on MRI are consistent) Chiari or Dandy-
viral infection) Lyme disease AD/AR MRI/CT, positive AIDS-related Walker
Postinfection history in support multifocal malformations
syndrome of lesion) leukoencephalopat (malformation
hy (positive HIV test noted on MRI/CT)
and CD4+ cell count
for AIDS)

Abbreviations: CSF, cerebrospinal fluid; CT, computed tomography; MRI, magnetic resonance imaging.
 Examination

• Neurological examination
• Other system evaluation
 Breast Lump, mass per-abdomen etc.
• Rating scales
 International Cooperative Ataxia Rating Scale (ICARS)
 Scale for the assessment and rating of ataxia(SARA)
 Tremor scales
 Unified MSA Rating Score (UMSARS)
 Ancillary tests
Neuro imaging
 MRI of brain and spine

Electro diagnostic tests

 EMG/NCV, EEG, evoked potentials, ERG

Tests of autonomic dysfunction

 Tilt-table tests, sympathetic skin responses and other
tests

Ophthalmologic examination
 Pigmentary retinopathy, macular degeneration,
 cataracts, Kayser-Fleischer rings
 Ancillary tests
• Genetic tests (available in India)
 AD: SCA 1, 2, 3, 6, 7, 8, 10, 11,12, 14, 17,23 and 28; DRPLA
 AR: FRDA, AOA1 and 2, AT, ARSACS
 X-linked: FXTAS
 Mitochondrial –entire genome sequencing
• Laboratory studies
 Metabolic
Thyroid function, vitamins B12, E, and B1, serum
cholesterol & plasma lipoprotein profile, serum
cholestanol & urine bile alcohol, phytanic acid, toxicology
screen
 Immune function
Immunoglobulin levels, Antigliadin antibodies, GAD
antibodies, paraneoplastic antibodies
 Ancillary tests
• Laboratory studies
 Mitochondrial
• Serum lactate and pyruvate
 Other
• Heavy metals, peripheral blood smear for acanthocytes,
very long chain fatty acids, hexosaminidase A/B,
alpha fetoprotein & immunoglobulins,
serum ceruloplasmin & 24 hour urinary copper

• Tissue studies
 Muscle, skin and nerve biopsies

• CSF studies
 Cell count, glucose and protein, oligoclonal bands,
14-3-3 protein, GAD antibodies, paraneoplastic antibodies,
Hereditary Group
Autosomal dominant cerebellar Ataxias
Spinocerebellar ataxia type 1-31, SCA36, Episodic ataxias

Autosomal Recessive cerebellar Ataxias

Friedreich’s ataxia, Ataxia Telengiectasia, spastic ataxia

X-linked cerebellar ataxias

Fragile X tremor ataxia syndrome

Mitochondrial
Myoclonus Epilepsy with Ragged Red Fibers(MERRF),
Kearns Syre Syndrome (KSS) etc.
INTRODUCTION:

Autosomal Dominant Cerebellar Ataxias

 Clinically and genetically heterogeneous group of
neurodegenerative disorders.

 Characterised by progressive cerebellar and spinal cord dysfunction.

 Clinical Features:
Gait Ataxia, Limb Incoordination, Dysarthria
Pyramidal and Extrapyramidal involvement
Occulomotor incordination
Peripheral Neuropathy
Retinal degeneration
 Harding classification- Clinico genetic

Signs of cerebellar ataxia

Pyramidal features
ADCA -I SCA -1, 2, 3, 4, 8, 12, 13, 17, 18*, 19/22*, 20*,
Extrapyramidal signs
amyotrophy
21*, 23*, 24*, 25*, 27, 28*, 29*, DRPLA

Signs of cerebellar ataxia

ADCA-II Pigmentory retinal SCA 7
degeneration
Ophthalmoplegia

ADCA-III SCA -4, 5, 6, 11, 14, 15, 22*, 26*

pure cerebellar syndrome

* Mapped loci (disease gene unknown)

Harding AE. Classification of the hereditary ataxias and paraplegias.Lancet. 1983;1:1151–115

 Spinocerebellar ataxias: Clinico genetics
Repeat expansion Mutation (point/Ins/del) Linkage mapped

SCA1- (CAG)n SCA 4- PLEKHG4 SCA 9 undescribed

SCA2- (CAG)n SCA 5- β III spectrin SCA 18 7q22-q32
SCA3- (CAG)n SCA11- TTBK-2 SCA 20 11p13-q11
SCA6- (CAG)n SCA13- KCNC3 SCA 21 7p21.3-p15.1
SCA7- (CAG)n SCA 14- PRKCG SCA19/ 22 1p21-q21
SCA8- (CTG)n SCA 16/15-ITPR1 SCA 24 1p36
SCA10- (ATTCT)n SCA23- PDYN2 SCA 25 2p21-p13
SCA12- (CAG)n SCA 27- FGF14 SCA 26 19p13.3
SCA17- (CAG)n SCA28- AFG3L2 SCA 29 3p26
SCA31- (TGGAA)n SCA30 4q34.3-q35.1
SCA36- (GGCCTG)n
DRPLA-(CAG)n
FRDA- (GAA)n Cerebellar ataxia
Pyramidal Extrapyramidal SCA -1, 2, 3, 8, 12, 13, 17, 18*, 19/22*, 20*,
ADCA-I amyotrophy 21*, 23*, 24*, 25*, 27, 28*, 29*, DRPLA

Cerebellar ataxia
ADCA-II SCA -7
Pigmentory retinal degeneration

ADCA-III SCA -4, 5, 6, 11, 14, 15, 22*, 26*

pure cerebellar syndrome

Cerebellar ataxia and SCA -10, 17

ADCA-IV
Seizures
Clinical behavior of Common SCA subtypes
Late onset 3rd to 4th decade

Diffuse Neuro degeneration

predominantly OPCA

Variable rates of progression

Rapid progression: ADCA-I, ADCA-II and ADCA-IV

Repeat expansion SCA progresses rapidly (except SCA6)

Higher repeats leads to increase severity of the disease

Slow progression: ADCA-III (Pure cerebellar forms)

Variable age at onset

Anticipation
SCA Subtypes and distinguishing features
Signs that Distinguishes SCA subtypes

Benign course SCA 6

UMN signs SCA 1,7,8 and 3
Akinetic rigid syndrome SCA 3,2,17 & 12,21
Chorea SCA 2,1,3
Action tremor SCA 12,16
Slow saccades SCA 2 & 7 may be in 1,3
Downbeat nystagmus SCA 6
Hyporeflexia/Areflexia SCA 2,4,3 & 19,21
Vision loss SCA 7
Seizure SCA 10
Myoclonus SCA14 or SCA19
Cognitive impairment SCA2,14,19,21,23
Guide to efficient genetic testing

THE LANCET Neurology Vol 3 May 2004

Hereditary Group
Autosomal dominant cerebellar Ataxias
Spinocerebellar ataxia type 1-31, SCA36, Episodic ataxias

Autosomal Recessive cerebellar Ataxias

Friedreich’s ataxia, Ataxia Telengiectasia, spastic ataxia

X-linked cerebellar ataxias

Fragile X tremor ataxia syndrome

Mitochondrial
Myoclonus Epilepsy with Ragged Red Fibers(MERRF),
Kearns Syre Syndrome (KSS) etc.
 Autosomal recessive cerebellar ataxias
Introduction:

Autosomal recessive cerebellar ataxia (ARCAs) are group of

neurodegenerative disorders

More than 20 genes are known to cause ARCAs

Infantile-adult onset (generally <25 yrs)

Cerebellar ataxias with predominant peripheral neuropathy

Other features: Cardiac involvement, Muscular involvement,

immunodeficiency, metabolic derangements etc.

FRDA accounts for the major prevalent ARCA

 Friedreich ataxia
 One of the most common hereditary ataxias
 Prevalence: 2 – 4/100,000
 1 in 40,000 in Caucasians populations
 Carrier frequency: 1/60 – 1/100

• Slowly progressive ataxia

• Initial presentation b/n 5-15yrs
• Most are wheelchair bound by late teens -early 20s
• Scoliosis and pes cavus in 10%
• Heart abnormalities cause premature death in 60% to 80%
 Intronic GAA repeat expansions in the FXN gene
 About 25% of FXN mutation carriers have an atypical phenotype,
such as late onset, for example up to 64 years
 FA with retained tendon reflex

The Cochrane Library 2012, Issue 4

Diagnostic criteria

Journal of Child Neurology 27(9

 Autosomal recessive cerebellar ataxia: The
Implicated genes and pathology
Mitochondrial Gene Chromosome Pathogenic mechanism
Friedreich's Ataxia FXN 9q13 Mitochondrial Fe overload
Infantile onset cerebellar Ataxia (IOCA) C10orf2 10q24 Mitochondrial DNA replication
CoQ10 deficiency (Adult) UK UK Reduced ATP synthesis in Mitochondria

Metabolic
(Met.)Impaired a-tocopherol mediated Vit E and VLDL
Ataxia with Vitamin E deficiency (AVED) TTPA 8q13.1-13.3 interaction
Abetalipoproteinemia (ABL) MTP 4q22-24 (Met.)Impaired Lipoprotein metabolism
Cerebello tendinous Xanthomatosis (CTX) CYP27 2q33-ter Imapired Bile acid Biosynthesis
Late Onset Tay sac's disease (LOTS) HEXA 15q23-24 Glicosphingolipid accumulation

DNA repair defect

Ataxia Telengiectasia (AT) ATM 11q22-23 DNA damage
Ataxia Telengiectasia like disorder (ATLD) MRE11 11q21 DNA damage
Ataxia with Occulomotor Apraxia 1 (AOA1) APTX 9p13 Imapired DNA repair
Ataxia with Occulomotor Apraxia 2 (AOA2) SETX 9q34 Imapired DNA repair
Spinocerebellar ataxia with axonal neuropathy (SCAN1) TDP1 14q31-32 DNA repair
Mitochondrial recessive ataxia syndrome(MIRAS) POLG 15q22-26 Impaired Mitochondrial DNA replication and damage repair

Protein folding defect

Autosomal recessive ataxia of Charlevoix-Saguenay
(ARSACS) SACS 13q11 Deficient Chaperon mediated protein folding
Marinesco-Sjögren’s syndrome (MSS) SIL1 5q31 Impaired HSP70- mediated protein folding
PHYH,
Refsum Disease PEX7 10pter-11.2, 6q21-22.2
Clinical approach to ARCAs-
using MRI findings and Nerve conduction studies
Disease Additional features over Distinguishable features Laboratory
Cerebellar Ataxia findings
Cerebellar ataxia with sensory Axonal neuropathy
MRI-spinal atrophy
FRDA Pes cavus, Amyotrpohy, Extensor Cardiomyopathy, DM GAA expansion in
Plantar, Nystagmus FXN
MRI-Spinal +Cerebellar Atrophy
IOSCA Pes cavus, Amyotorphy, Seizures,Hearing loss, -
Ophthalmoplegia,Cognitive Hypogonadism
Impairment, Chorea
MRI-Normal
AVED Pes Cavus, Extensor Plantar, Retinitis Pigmentosa, Low VitE
Head Tremor Cardiomyopathy
ABL Pes cavus, Amyotrophy Retinitis Pigmentosa, Low VitE, low
Lipid Malabsorption, lipoprotein,
Cardiomyopathy acanthocytes
Disease Additional features over Cerebellar Ataxia Distinguishable features Laboratory findings
Cerebellar ataxia with sensorymotor Axonal neuropathy
MRI-Cerebellar Atrophy
LOTS Amyotrophy, tremor, Myoclonus Saccadic Intrusion, Prominent -
Extrapyramidal,
Seizures,Psychiatric Impairment
SCAN1 Pes Cavus, Amyotrophy Low albumin
AT Occulomotor Apraxia, Amyotrophy,Tremor Telengiectasia,Lymphoid cancer, High alpha-fetoprotein
Myoclonus, Extrapyramidal, Babinski Sign Radiosensitivity,Immunodeficiency, and low immunoglobin
DM
ATL Occulomotor Apraxia, Extrapyramidal Radiosensitivity,Immunodeficiency low immunoglobin
AOA1 Occulomotor apraxia,Pes cavus, Scoliosis Low albumin, High
Amyotrophy, tremor, Extrapyramidal, Cholesterol
cognitive impairment
AOA2 Occulomotor Apraxia, Pes Cavus, Saccadic Intrusion,Scoliosis High alpha-fetoprotein,
amyotrophyTremors, Extrapyramidal, High cholesterol
cognition Impairment
MRI-Spinal +Cerebellar Atrophy
ARSACS Pes Cavus, Amyotrophy, Spasticity, Saccadic Intrusion, Hypermyelinated -
extensor Plantar, cogitive Impairment Retinal fibers
MRI-Cerebellar Atrophy + WMH
CTX Pes Caus Amyotrophy, Spasticity, Psychiatric Impairment,Tendon High cholesterol, High
myoclonus, Parkinsonism Xanthomas,Seizures,Cataract,Liver bile alcohols
failure
MIRAS Pes cavus, Amyotrophy, tremors, Saccadic Intrusion, Psychiatric Liver failure
Myoclonus, Choreoathetosis Impairment,Seizures,Migraine,Heari
 Disease Additional features over Cerebellar Ataxia Distinguishable features Laboratory findings
Cerebellar ataxia with sensorymotor Demyelinating neuropathy
MRI-Cerebellar Atrophy
MSS Amyotrophy, tremor, Hypotonia Psychomotor and cognitive, -
Impairment, Scoliosis,Cataract,
Hypertropic Hypogonadism,
Rhabdomyolysis
MRI-Normal
Refsum Pes cavus, Amyotrophy Retinitis Renal failure, high
Disease Pigmentosa,Cardiomyopathy,Hearin phytanic acid,High CSF
g,Renal Failure proteins
Others
Cerebellar ataxia and Hypogonadotropic Hypogonadism
BNS Cerebellar ataxia, hypotrophic hypotrophic Hypogonadism -
Hypogonadism
CoQ10 CoQ10 deficiency (Adult onset) -
deficiency
(Adult
onset)
Congenital cerebellar Ataxia
CA (Cayman Hypotonia, Tremor, Cognitive Impairment MRI-Cerebellar hypoplasia -
ataxia)
JS (Vermial Infantile Onset, Vertical gaze Molar Tooth Sign,Episodic -
Agenesis) paresis,Nystagmus, ptosis, Hypernea or apnea of new Born
(JST1-JST10) Retinopathy,Mental retardation
 Genetic Testing Protocol of ataxias(AIIMS)
Spinocerebellar Ataxia

Aut.Dominant Sporadic Aut.Recessive

SCA 1
LOCA (>25) EOCA (<25)
FRDA
SCA 2
SAC 3 features suggestive of SCA
SCA 7 Level 10
SCA 12
NO YES

YES NO

SCA 6 Trying to establish

SCA 8 investigation
Level 20
SCA 17 guidelines for ARCA
DRPLA genes

YES NO

Rare types of SCAs

(ADCA) screening

Age at 10-30 >30 Variable

Onset (Yrs)
SCA27 SCA11 SCA5
Level 30
SCA28 SCA14 SCA13
SCA23 SCA14 LOCA-Late onset cerebellar ataxi
SCA15 EOCA-Early onset cerebellar atax
SCA28
Hereditary Group
Autosomal dominant cerebellar Ataxias
Spinocerebellar ataxia type 1-31, SCA36, Episodic ataxias

Autosomal Recessive cerebellar Ataxias

Friedreich’s ataxia, Ataxia Telengiectasia, spastic ataxia

X-linked cerebellar ataxias

Fragile X tremor ataxia syndrome

Mitochondrial
Myoclonus Epilepsy with Ragged Red Fibers(MERRF),
Kearns Syre Syndrome (KSS) etc.
 X-linked ataxia
Fragile X associated Tremor-Ataxia syndrome
(FXTAS)

Major Diagnostic criteria:

 Onset >50 years, M>F
 Neurologic: Gait ataxia, tremor,
parkinsonism, cognitive decline,
polyneuropathy, autonomic dysfunction
 Systemic: Premature ovarian failure
 Brain MRI: cerebral/cerebellar atrophy,
T2 signal in middle cerebellar peduncles
 Neuropathology: intranuclear inclusions
in brain and spinal cord

Brunberg et al, 2002

 FXTAS Genetic features
 Expanded CGG repeat
 FMR gene
 Chromosome Xq27.3

 Premutation repeat length

 55-200

 Elevated levels FMR1 mRNA

 Toxic gain of function?
 Decreased FMR1 mRNA translational efficiency

Hagerman and Hagerman, 2004

 Sporadic ataxias
• Multiple system atrophy (MSA)

• Toxins/metabolic

• Paraneoplastic cerebellar degeneration

• Immune-mediated ataxias (gluten, anti-GAD)

• Infectious etiology
 Beware of MSA C
 Clinical features:
– Parkinsonism
• Asymmetric, postural/action
tremor, early gait problems, +
dopa responsive
– Cerebellar
• Gait and limb ataxia, nystagmus,
dysarthria
– Autonomic
• Orthostatic hypotension, bladder
dysfunction, impotence
– Other
• Hyperreflexia, antecollis,
inspiratory stridor, RBD, dystonia

• Pathology:
– Neuronal cell loss and gliosis
– Glial cytoplasmic inclusions
– No Lewy bodies
MSA diagnosis Gilman S Neurology2008
 Toxins-
Alcoholic cerebellar degeneration(ACD)
Central ataxia, Lower limb tremor, Psychosis,
Dementia
Pathophysiology

Damage to GABA-A receptor, Impaired Glucose

metabolism,VitB1 deficiency
MRI

MRI-Superior cerebellar and cerebral atrophy

Treatment

Alcohol abstinence,VitB1 replacement

 Toxins-

Drug induced ataxias

Agent Clinical features Pathology Inv Rx

•Anticonvulsant-
Metals Bismuth,
Mild-ModerateMercury
dose dependent(parasthesiass,
Loss of PC and restricted
Serum visual
level of drug, Stop the drug,
defects), Lead
Phenytoin, ataxia,nystagmus,peripheral granule cells MRI-variable atrophy Hemodialysis
carbamazepine neuropathy and brisk DTR of cerebellum and Intensive
• Solvents  Paint thinners , toluene (Cognitive defects PLUS management
Anticancer Drugs- Generalized cerebellar - MRI-pancerebellar Stop the drug,
pyramidal
5-fluorouracil,Cytosin
tract signs)
synndrome, encephalopathy atrophy Hemodialysis
arabinoside and Intensive
management
Lithium cerebellar syndrome, Tremors, - Serum Li level, Hemodialysis
Hyper-reflexias history of and Intensive
concomittent care
treatment-CPZ management
Amiadarone Cerebellar ataxia, Peripheral - MRI-cerebellar Drug withdrawl
neuropathy,Myoclonus, atrophy and treatment
encephalopathy and rest tremor of drug related
hypothyroidism
 Immune mediated – Gluten ataxia
Etiology- IgA/IgG Anti-Gliadin Ab,
Anti-endomysial Ab and
Ab against Tissue Trans-glutaminase
Clinical features-50-60 Yrs onset,
Gait Ataxia, Peripheral neuropathy and gluten
sensitivity
Patho-Ab targets PC due to share antigenicity of gluten

Invg-Serum-IgA,IgG-antigliadin, anti endomyseium, TTG, MRI-

Cerebllar atrophy and WMH, Intestinal Biopsy

Rx-Gluten free diet, I.V.-IG

 224 patients with various causes of ataxia from North Trent
and 44 patients with sporadic idiopathic ataxia from The
Institute of Neurology, London, were screened for the
presence of antigliadin antibodies
 A total of 1200 volunteers were screened as normal controls
The prevalence of antigliadin antibodies in the familial group
was
8 out of 59 (14%)
54 out of 132 (41%) in the sporadic idiopathic group
5 out of 33 (15%) in the MSA-C group
 149 out of 1200 (12%) in the normal controls

The prevalence in the sporadic idiopathic group from London

was 14 out of 44 (32%)

The difference in prevalence between the idiopathic sporadic

groups and the other groups was highly significant (P < 0.0001
and P < 0.003, respectively)

Hadjivassiliou et al. Brain(2003),126,685-691

Hadjivassiliou et al. Brain(2003),126,685-691
 Immune mediated – GAD ataxia
• Clinical phenotype
 Onset 20-75 years
 F>M
 Neurologic: Ataxia, nystagmus, dysarthria
 Systemic: Autoimmune disease
 Studies: Anti-GAD Antibodies in serum, CSF
 Brain MRI: cerebellar atrophy in some

• Treatment
 Steroids, IVIG?
Arch Neurol. 2001;58:225-230
Arch Neurol. 2001;58:225-
 SREAT
 Sub acute onset, formerly known as Hashimoto’s encephalopathy
 Ataxia progressing over weeks, with cognitive disturbance,
myoclonus, seizures
 Patients have high serum thyro peroxidase antibody levels,
although thyroid function is normal in half of the cases
 The mean age at onset is 45–55 years,
 Five times more common in women than
 Patients often have other autoimmune disorders
 Readily treatable and improves dramatically with corticosteroids
 The sooner treatment is started, the better the outcome
Hashimoto’ Encephalopathy: Systematic Review
(The Journal of Neuropsychiatry and Clinical
of the Literature Neurosciences 2011; 23:384 –390)
 Paraneoplastic cerebellar degeneration
 Clinical features:

 Onset precedes neoplasm

 Pancerebellar syndrome: Gait and limb ataxia, dysarthria, nystagmus,
oculomotor dysfunction
 Evolution: Rapid over weeks to months, then stabilize

 Loss of Purkinje cells in the cerebellar cortex, deep cerebellar

nuclei & inferior olivary nuclei
 ? T cell mediated
 PCD can be associated with any cancer, but most common:
– Lung cancer (small-cell)
– Ovarian/Breast carcinoma
– Hodgkins lymphoma
Brain (2003), 126, 1409-1418
Paraneoplastic ataxia associated antibodies
Antibody Condition Freq.
Anti-Yo (Purkinje cell antobody type1) Breast and ovarian Ca 0.38
Anti-Hu (Anti neuronal nuclear antibody
type1) Small cell lung Ca (SCLC) 0.32
Anti-Tr Hodgkin Lymphoma 0.14
Anti-mGluR1 (metabotrpin glutamate
receptor) Hodgkin Lymphoma 0.04
AntiRi (Anti neuronal nuclear antibody
type1) SCLC, Breast, Ovarian ca 0.12
Anti-VGCC (Voltage gated calcium
channel) SCLC
Anti-CRMP5 (Collapsin receptor mediated
protein)/Anti-CV2 SCLC
Anti-ZIC4 (zinc finger protein) SCLC
 When to suspect?
Brain (2003):126; 1409-1418
• Age :Late (60 -70 yrs)
• Onset: Sub acute
• Progression: weeks to months then stabilize

• Compatible clinical history

• CSF : Pleocytosis, oligoclonal bands

• MRI: Normal in initial stage, cerebellar atrophy develops in

subsequent months

• FDG-PET Scan: Hypermetabolism

• If initial screening is negative , repeat screening is advisable

• In a 12-year period, >5000 samples for the presence of
antineuronal antibodies
• A total of 137 patients were identified with a paraneoplastic
neurological syndrome and high titer (>400) antineuronal
antibodies
• Fifty (36%) of these patients had antibody associated PCD,
including 19 anti-Yo, 16 anti-Hu, seven anti-Tr, six anti-Ri and
two anti-mGluR1
• While 100% of patients with anti-Yo, anti-Tr and anti-mGluR1
antibodies suffered PCD, 86% of anti-Ri and only 18% of anti-
Hu patients had PCD
• All patients presented with subacute cerebellar ataxia
progressive over weeks to months and stabilized within 6
months
• The majority had both truncal and appendicular ataxia
Brain (2003), 126, 1409±1418
 Management

• Symptomatic treatment

• Early detection & treatment of cancer

• Immunosuppersion: Corticosteroids / IVIg

 Vitamin deficiency induced Ataxias
Agent Clinical features Pathology Investigati Rx
ons
VitB1 Acute or subacute Hemorrhagic Serum VitB1 VitB1
onset, Psychosis, lesion around 3rd level and MRI replaceme
dementia, confusion, ventricle, nt
seizures, peripheral mamillary body
neuropathy and thalamic
nuclei
VitB12 sensory ataxia, Peripheral nerve serum Vit B12 VitB12
megalblastic anemia damage level and replaceme
peripheral nt
smear
VitE cerebellar Cerebellar atrophy VitE level VitE
syndrome,sensory replaceme
neuropathy and nt
arreflexia
 INFECTIONS

 VZV in children
 EBV in children
 Bickerstaff’s encephalitis (brainstem ophthalmoplegia,
ataxia, lower cranial nerve palsies)
 HIV ( Lymphomas, PML, Infections, Toxoplasmosis)
 CJD (17% classic CJD, Ataxic variant of CJD)
 Syphilis (Tabes Dorsalis)
 Whipple’s disease
 Creutzfeldt–Jakob Disease
• Rapidly progressive disorder with cerebellar ataxia.
• Sooner or later, patients develop a plethora of other neurological signs:
dementia, myoclonus and Parkinsonism
• Gerstmann Sträussler-Scheinker disease is characterized by onset at age
20–40 years with progressive cerebellar ataxia and, In many patients,
spastic paraparesis
• The pathological changes are unique with amyloid plaques throughout
the brain
• MRI features: Pulvinar sign and cortical ribboning on DWI
• CSF: 14-3-3 protein and increased tau levels
• EEG: periodic synchronous biphasic or triphasic sharp wave complexes
• Patients usually die within a year
• Familial CJD has earlier age of onset and longer clinical course than
sporadic CJD

http://neurology.thelancet.com Vol 4 October

2005
Diagnostic approach to sporadic adult-onset
ataxia

www.thelancet.com/neurology Vol 9 January

2010
Diagnostic approach to sporadic adult-onset
ataxia

www.thelancet.com/neurology Vol 9 January

 Idiopathic late-onset cerebellar ataxia

 Diagnosis of exclusion
 One can debate where early-onset cerebellar ataxia ends and
idiopathic late onset cerebellar ataxia begins
 Some prefer the term ‘sporadic adult-onset ataxia’
 This is clearly an aetiologically heterogeneous group
 Long term follow-up is needed to identify ‘conversion’ to MSA
that may occur later

Postgrad Med J 2012;88:407e417. doi:10.1136/postgradmedj-2011-000108rep

Ataxia with seizures Ataxia with Dementia
• Anti GAD ataxia • Anti gliadin ataxia
• Anti gliadin ataxia
• FXTAS syndrme
• Mitochondrial ataxia
• Episodic ataxia • SREAT
• DRPLA • SCA 17, 19, 21, 2, 1, 6
• SCA 10, SCA 7 • HIV/AIDS
• CJD • Mitochondrial disease
• SREAT
• Amyloid ataxia
• SeSAME syndrome
• Co Q deficiency
• SCN2A mutations
• OPCA
 Ataxia with Neuropathy

• Friedreich ataxia
• AOA2
• Fragile X syndrome
• Vit E deficiency ataxia
• Anti gliadin ataxia
• SCA 12, 18,25,27,8,3,4
• ARSACS
• Refsum disease
• Ataxic sensory neuronopathy of
Sjogren syndrome
Neuro-ophthalmologic evaluation in ataxia

Handbook of Clinical Neurology, Vol. 103 (3rd series)

Non-cerebellar neurological signs in ataxias

Handbook of Clinical Neurology, Vol. 103 (3rd series)

 Conclusions:
An approach to ataxia is based on knowledge of its symptoms and
causes

Knowledge of differentiating clinical and investigative features takes

clinicians closer to the etiological diagnosis

Treatable causes must be identified and ruled out

Autosomal Dominant cerebellar ataxias in India are more prevalent

than recessive ataxias

Genetic testing is prudent for providing better insight into the

management.
Genotype-Phenotype correlations in SCA1
Higher repeats are associated with earlier onset and severe disease

Homozygous expansion- no increase in severity

Small disease alleles (39-44) interrupted: Mild Phenotype, Ataxic/non ataxic features

Medium Size alleles (39-50) Pure CAG: Ataxia and Pyramidal syndrome

Large Size Alleles (>50) Pure CAG: Ataxia and Pyramidal syndrome
&
Amytrophic Lateral sclerosis

Higher Size Alleles (>91): Juvenile disease

Genotype-Phenotype correlations in SCA2
Higher repeats are associated with earlier onset

Homozygous expansion- no increase in severity

Allelic variations of RAI 1 and CACNA1A influences age at onset

Disease duration X CAG length affects occurrence of slow saccades,

Fasciculation, Amyotrophy, Areflexia and Vibration senses

Small disease alleles (32-37): Postural Tremors and Parkinsonism, late onset disease

Medium Size alleles (38-44) : Ataxia, areflexia and slowing of saccades

Large Size Alleles (>45) : Onset <20 years, Chorea and dementia

Higher Size Alleles (>91) : Ataxia, Dystonia, Myoclonus, Cardiac failure, optic atrophy
Genotype-Phenotype correlations in SCA3

Earlier onset with Higher repeats and inverse correlation

Homozygous expansion- confers increasing severity

Small disease alleles (52-73): Axonal Neuropathy and Parkinsonism (Type-III MJD)

Medium Size alleles (73-80) : Ataxia and Diplopia (Type-II MJD)

Large Size Alleles (80-86) : Ataxia, Dystonia and spasticity (Type-I MJD)

Higher Size Alleles (>86) : Rare cases predominant Dystonia (Type-IV)

Genotype-Phenotype correlations in SCA7
Earlier onset with higher repeats and anticipation

Greater expandability during transmission of alleles

Recurrent denovo expansions

Small disease alleles (36-41): Cerebellar ataxia without Retinal involvement

Medium Size alleles (42-49) : Ataxia preceedes Vision diminution

Large Size Alleles (49-60) : Vision loss preceedes Ataxia

Higher Size Alleles (>80) : Juvenile Onset

Extreme High Length Alleles : Infantile Onset, Developmental failure, Multisystem

involvement
(>200)
Genotype-Phenotype correlations in SCA 17
Weaker anticipation in SCA17

Transmission of alleles are relatively stable due to interruptions

Homozygous individual shows increasing severity

Small disease alleles (43-50): Involuntary movements and Impaired cognition

Huntington disease like phenotype

Medium Size alleles (50-60) : Ataxia,Brisk reflexes and Dystonia

Large Size Alleles (>60) : Ataxia, spasticity, Psychiatric impairment and dementia
Where to next??
Phenotypic dilemma and challenges for novel gene identifications in
Uncharacterized SCAs
Characterized Uncharacterized

SCA1 SCA2 SCA3 AD AR EOCA LOCA

Gait ataxia 100 100 100 71.4 79.3 91.6 87.8
Cerebellar UL-ataxia 100 96 89.4 71.4 96.5 84.7 80.4
Dysarthria 92.8 90 94.7 66.6 68.9 83.3 78
Nystagmus 35.7 6 57.8 23.8 31 37.5 21.9
Occulomotor Slowing of Saccades 35.7 78 57.8 33.3 31 41.6 39
Broken pursuit 26 3 57.8 42.8 31 54 48.7
Muscle cramps 9.5 11 0 0 0 4.1 2.4
Motor system Fasciculations 11.9 37 15.7 9.5 6.8 13.8 9.7
Amyotrophy 0 2 84.9 0 0 0 0
Extrapyramidal Extrapyramidal 9.5 18 13.9 14.2 6.8 9.7 21.9
Hyperreflexia 33.3 16 68.4 23.8 24.1 36.1 21.9 AD: Autosomal dominant
Pyramidal Arreflexia 7.1 23 0 9.8 6.8 12.5 4.8
Extensor plantar 23.8 18 26.3 23.8 27.8 26.3 7.3 AR:Autosomal recessive
NCV 60 73 38.4 35.2 37.5 47.9 44.8
EPS AFT 75 65 53.8 61.1 75 55 64 EOCA: early onset sporadic
Dementia 4.7 4 15.7 0 17.2 11.1 0 cerebellar ataxia
Myoclonus 0 2 0 0 6.8 0 0
Seizures 0 1 0 0 6.8 5.5 0 LOCA: Late onset sporadic
VERTIGO 0 0 15.7 0 0 0 0 cerebellar ataxia
PES
other CAVUS/SCOLIOSIS
0 0 0 0 6.8 0 0
Polyphagia 0 1 0 0 0 0 0
Parkinson Phenotype 0 3 0 0 0 0 0
Visual 0 0 5.2 4.7 6.8 5.5 4.8
Dysphagia 9.5 6 0 14.3 0 6.9 2.4
1 100
Frequency %
Absent
 DIAGNOSIS OF ATAXIA PATIENTS IN ATAXIA CLINIC,
AIIMS (Unpublished)
Total Families= 1500
Characterized= 585 7%
Uncharacterized= 915
12%

SCA1
3%
1%
SCA2

SCA3
12%
61% SCA7

SCA12
4%

FRDA

Uncharacterized-SCA
 Clinical Scenario
• 62/M, no prior co morbidities
• 3-year history of gradually worsening unsteadiness and shaking of
his hands on action
• His speech and swallowing were normal, but with some urinary
urgency
• He drank 3–4 glasses of wine a day
• No family history
• O/E : titubation, a bilateral terminal tremor on finger–nose testing,
dysmetria during finger-chasing, abnormal heel-to-shin testing,
mild gait ataxia and clearly disturbed tandem gait, and brisk tendon
re- fl exes with bilateral extensor plantar responses
• Normal serum vitamin levels and thyroid function
• MR scan of the brain showed cerebellar atrophy, mainly of the
vermis
 Case follow-up

 Besides ataxia, our patient reported urinary urgency and had

pyramidal features due to spinal cord involvement
 The cerebellar atrophy and slow progression suggested a
degenerative process
 Routine blood tests were normal, including the gluten
sensitivity screen
 Alcohol excess seemed an unlikely cause
 Could this be genetic?

• A negative family history, even done properly

does not exclude a genetic cause.
• Patients with sporadic ataxia may particularly
have recessive disorders, but also occasionally
dominant, X linked and mitochondrial diseases
 Case follow-up

 In our patient, mutation analysis of the CACNA1A

gene was positive, with 22 CAG repeats on the
expanded allele
 The final diagnosis was therefore SCA-6
 Localization of cerebellar lesions
Signs and symptoms Regions most probably involved

Gait ataxia Anterior vermis

Limb ataxia Lateral hemispheres
Dysarthria Posterior left hemisphere & vermis
Titubation Any zone, esp. ant. Vermis & associated deep nuclei

Action tremor Dentate & interposed nuclei, or cerebellar outflow to

ventral thalamus

Palatal tremor Dentate nucleus, Guillain Mollaret triangle

Saccadic dysmetria Dorsal vermis
Square wave jerks Cerebellar outflow
Gaze evoked nystagmus Flocculus & paraflocculus
Higher cognitive changes Lateral hemispheres
Gilman S Neurology2008