DM Seminar Dr Divya SR Neuro, AIIMS

1. Approach to Ataxia
Presenter: Dr Divya
Preceptor: Prof Achal K Srivastava

2. 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

3. 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

4. Neural-Localization
Cerebellum (most common)
Sensory pathways (Sensory Ataxia)
 posterior columns, dorsal root ganglia, peripheral N.
Frontal lobe lesions-fronto-cerebellar fibers

5. 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
• Sensory neuropathy and posterior column disease of the
spinal cord (sensory ataxia)

6. 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

7. 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

8. 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

9. 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)

10. Paleocerebellum
Archicerebellum
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
Cerebellum

12. Clinical features of cerebellar disease
 Ataxia (appendicular or axial)
 Dysmetria
 Dyssynergia
 Dysdiadochokinesia
 Rebound Phenomenon
 Dysarthria
 Tremor
 Titubation and increased
postural sway
 Hypotonia
 Asthenia
 Nystagmus

13. Cerebellar Sensory Ataxia Frontal Ataxia
Base of support Wide-based Narrow base, looks down Wide-based
Velocity Variable Slow Very slow
Stride Irregular,
lurching
Regular with path
deviation
Short, shuffling
Romberg +/– Unsteady, falls +/–
Heel-shin Abnormal +/– Normal
Initiation Normal Normal Hesitant
Turns Unsteady +/– Hesitant, multistep
Postural
instability
+ +++ ++++
Falls Late event Frequent Frequent

14. 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

15. 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
9/13/2016 15

16. 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…
Classification

17. 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

18. Developmental malformation/congenital
Dandy-Walker Malformation
Chiari Malformation
Vermial Agenesis etc.
Cerebellar Ataxias classification (Contd..)

19. 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

20. 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)

21. • 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

22. • Distribution of ataxia
– Symmetric - Acquired, Hereditary, degenerative ataxias
– Asymmetric- Vascular, Tumors, congenital causes
• Other system illness
– Gastrointestinal symptoms- gluten ataxia
– Mass lesion- paraneoplastic ataxias
History

23. 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

24. symmetrical signs Focal and Ipsilateral Cerebellar Signs
Acute (Hours to
Days)
Subacute (Days to
Weeks)
Chronic (Months
to Years)
Acute (Hours to
Days)
Subacute (Days
to Weeks)
Chronic (Months
to Years)
Intoxication:
alcohol, lithium,
diphenylhydantoin,
barbiturates
(positive history
and toxicology
screen)
Acute viral
cerebellitis (CSF
supportive of acute
viral infection)
Postinfection
syndrome
Intoxication:
mercury, solvents,
gasoline, glue;
cytotoxic
chemotherapeutic
drugs
Alcoholic-
nutritional
(vitamin B1 and
B12 deficiency)
Lyme disease
Paraneoplastic
syndrome
Anti-gliadin
antibody syndrome
Hypothyroidism
Inherited diseases
Tabes dorsalis
(tertiary syphilis)
Phenytoin toxicity
Hereditary ataxia
AD/AR
Vascular:
cerebellar
infarction,
hemorrhage, or
subdural
hematoma
Infectious:
cerebellar
abscess (positive
mass lesion on
MRI/CT, positive
history in support
of lesion)
Neoplastic:
cerebellar glioma or
metastatic tumor
(positive for
neoplasm on
MRI/CT)
Demyelinating:
multiple sclerosis
(history, CSF, and
MRI are consistent)
AIDS-related
multifocal
leukoencephalopat
hy (positive HIV test
and CD4+ cell count
for AIDS)
Stable gliosis
secondary to
vascular lesion or
demyelinating
plaque (stable
lesion on MRI/CT
older than several
months)
Congenital lesion:
Chiari or Dandy-
Walker
malformations
(malformation
noted on MRI/CT)
Abbreviations: CSF, cerebrospinal fluid; CT, computed tomography; MRI, magnetic resonance imaging.

25. 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)

26. 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

27. • 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

28. • 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,
Ancillary tests

29. 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.

30. 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

31. Signs of cerebellar ataxia
Pigmentory retinal
degeneration
Ophthalmoplegia
pure cerebellar syndrome
Signs of cerebellar ataxia
Pyramidal features
Extrapyramidal signs
amyotrophy
ADCA -I
ADCA-II
ADCA-III
SCA -1, 2, 3, 4, 8, 12, 13, 17, 18*, 19/22*, 20*,
21*, 23*, 24*, 25*, 27, 28*, 29*, DRPLA
SCA 7
SCA -4, 5, 6, 11, 14, 15, 22*, 26*
* Mapped loci (disease gene unknown)
Harding classification- Clinico genetic
Harding AE. Classification of the hereditary ataxias and paraplegias.Lancet. 1983;1:1151–115

32. Spinocerebellar ataxias: Clinico genetics
SCA1- (CAG)n
SCA2- (CAG)n
SCA3- (CAG)n
SCA6- (CAG)n
SCA7- (CAG)n
SCA8- (CTG)n
SCA10- (ATTCT)n
SCA12- (CAG)n
SCA17- (CAG)n
SCA31- (TGGAA)n
SCA36- (GGCCTG)n
DRPLA-(CAG)n
FRDA- (GAA)n
SCA 4- PLEKHG4
SCA 5- β III spectrin
SCA11- TTBK-2
SCA13- KCNC3
SCA 14- PRKCG
SCA 16/15-ITPR1
SCA23- PDYN2
SCA 27- FGF14
SCA28- AFG3L2
SCA 9 undescribed
SCA 18 7q22-q32
SCA 20 11p13-q11
SCA 21 7p21.3-p15.1
SCA19/ 22 1p21-q21
SCA 24 1p36
SCA 25 2p21-p13
SCA 26 19p13.3
SCA 29 3p26
SCA30 4q34.3-q35.1
Repeat expansion Linkage mappedMutation (point/Ins/del)
SCA -1, 2, 3, 8, 12, 13, 17, 18*, 19/22*, 20*,
21*, 23*, 24*, 25*, 27, 28*, 29*, DRPLA
SCA -7
SCA -4, 5, 6, 11, 14, 15, 22*, 26*
SCA -10, 17
Cerebellar ataxia
Pigmentory retinal degeneration
Cerebellar ataxia
Pyramidal Extrapyramidal
amyotrophyADCA-I
ADCA-II
ADCA-III
ADCA-IV
pure cerebellar syndrome
Cerebellar ataxia and
Seizures

33. 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

34. SCA Subtypes and distinguishing features

35. 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

36. Guide to efficient genetic testing
THE LANCET Neurology Vol 3 May 2004

37. 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.

38. 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

39. 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

40. Diagnostic criteria
Journal of Child Neurology 27(9

41. 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
Ataxia with Vitamin E deficiency (AVED) TTPA 8q13.1-13.3
(Met.)Impaired a-tocopherol mediated Vit E and VLDL
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
Refsum Disease
PHYH,
PEX7 10pter-11.2, 6q21-22.2
Autosomal recessive cerebellar ataxia: The
Implicated genes and pathology

42. Disease Additional features over
Cerebellar Ataxia
Distinguishable features Laboratory
findings
Cerebellar ataxia with sensory Axonal neuropathy
MRI-spinal atrophy
FRDA Pes cavus, Amyotrpohy, Extensor
Plantar, Nystagmus
Cardiomyopathy, DM GAA expansion in
FXN
MRI-Spinal +Cerebellar Atrophy
IOSCA Pes cavus, Amyotorphy,
Ophthalmoplegia,Cognitive
Impairment, Chorea
Seizures,Hearing loss,
Hypogonadism
-
MRI-Normal
AVED Pes Cavus, Extensor Plantar,
Head Tremor
Retinitis Pigmentosa,
Cardiomyopathy
Low VitE
ABL Pes cavus, Amyotrophy Retinitis Pigmentosa,
Lipid Malabsorption,
Cardiomyopathy
Low VitE, low
lipoprotein,
acanthocytes
Clinical approach to ARCAs-
using MRI findings and Nerve conduction studies

43. 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
Myoclonus, Extrapyramidal, Babinski Sign
Telengiectasia,Lymphoid cancer,
Radiosensitivity,Immunodeficiency,
DM
High alpha-fetoprotein
and low immunoglobin
ATL Occulomotor Apraxia, Extrapyramidal Radiosensitivity,Immunodeficiency low immunoglobin
AOA1 Occulomotor apraxia,Pes cavus,
Amyotrophy, tremor, Extrapyramidal,
cognitive impairment
Scoliosis Low albumin, High
Cholesterol
AOA2 Occulomotor Apraxia, Pes Cavus,
amyotrophyTremors, Extrapyramidal,
cognition Impairment
Saccadic Intrusion,Scoliosis High alpha-fetoprotein,
High cholesterol
MRI-Spinal +Cerebellar Atrophy
ARSACS Pes Cavus, Amyotrophy, Spasticity,
extensor Plantar, cogitive Impairment
Saccadic Intrusion, Hypermyelinated
Retinal fibers
-
MRI-Cerebellar Atrophy + WMH
CTX Pes Caus Amyotrophy, Spasticity,
myoclonus, Parkinsonism
Psychiatric Impairment,Tendon
Xanthomas,Seizures,Cataract,Liver
failure
High cholesterol, High
bile alcohols
MIRAS Pes cavus, Amyotrophy, tremors,
Myoclonus, Choreoathetosis
Saccadic Intrusion, Psychiatric
Impairment,Seizures,Migraine,Heari
Liver failure

44. 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
Disease
Pes cavus, Amyotrophy Retinitis
Pigmentosa,Cardiomyopathy,Hearin
g,Renal Failure
Renal failure, high
phytanic acid,High CSF
proteins
Others
Cerebellar ataxia and Hypogonadotropic Hypogonadism
BNS Cerebellar ataxia, hypotrophic
Hypogonadism
hypotrophic Hypogonadism -
CoQ10
deficiency
(Adult
onset)
CoQ10 deficiency (Adult onset) -
Congenital cerebellar Ataxia
CA (Cayman
ataxia)
Hypotonia, Tremor, Cognitive Impairment MRI-Cerebellar hypoplasia -
JS (Vermial
Agenesis)
(JST1-JST10)
Infantile Onset, Vertical gaze
paresis,Nystagmus, ptosis,
Retinopathy,Mental retardation
Molar Tooth Sign,Episodic
Hypernea or apnea of new Born
-

45. Genetic Testing Protocol of ataxias(AIIMS)
Spinocerebellar Ataxia
Aut.Dominant Aut.RecessiveSporadic
LOCA (>25) EOCA (<25)SCA 1
SCA 2
SAC 3
SCA 7
SCA 12
FRDA
NO YES
YES NO
SCA 6
SCA 8
SCA 17
DRPLA
YES NO
Rare types of SCAs
(ADCA) screening
Trying to establish
investigation
guidelines for ARCA
genes
Level 20
Level 10
Level 30
features suggestive of SCA
LOCA-Late onset cerebellar ataxi
EOCA-Early onset cerebellar atax
SCA27
SCA28
Age at
Onset (Yrs)
10-30 >30 Variable
SCA11
SCA14
SCA23
SCA5
SCA13
SCA14
SCA15
SCA28

46. 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.

47. 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

48. 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

49. Sporadic ataxias
• Multiple system atrophy (MSA)
• Toxins/metabolic
• Paraneoplastic cerebellar degeneration
• Immune-mediated ataxias (gluten, anti-GAD)
• Infectious etiology

50.  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
Beware of MSA C

51. MSA diagnosis Gilman S Neurology2008

52. Central ataxia, Lower limb tremor, Psychosis,
Dementia
Damage to GABA-A receptor, Impaired Glucose
metabolism,VitB1 deficiency
MRI-Superior cerebellar and cerebral atrophy
Alcohol abstinence,VitB1 replacement
Pathophysiology
MRI
Treatment
Toxins-
Alcoholic cerebellar degeneration(ACD)

53. Anticonvulsant-
Phenytoin,
carbamazepine
Mild-Moderate dose dependent
ataxia,nystagmus,peripheral
neuropathy and brisk DTR
Loss of PC and
granule cells
Serum level of drug,
MRI-variable atrophy
of cerebellum
Stop the drug,
Hemodialysis
and Intensive
management
Anticancer Drugs-
5-fluorouracil,Cytosin
arabinoside
Generalized cerebellar
synndrome, encephalopathy
- MRI-pancerebellar
atrophy
Stop the drug,
Hemodialysis
and Intensive
management
Lithium cerebellar syndrome, Tremors,
Hyper-reflexias
- Serum Li level,
history of
concomittent
treatment-CPZ
Hemodialysis
and Intensive
care
management
Amiadarone Cerebellar ataxia, Peripheral
neuropathy,Myoclonus,
encephalopathy and rest tremor
- MRI-cerebellar
atrophy
Drug withdrawl
and treatment
of drug related
hypothyroidism
Agent Clinical features Pathology Inv Rx
Drug induced ataxias
Toxins-
• Metals Bismuth, Mercury (parasthesiass, restricted visual
defects), Lead
• Solvents  Paint thinners , toluene (Cognitive defects PLUS
pyramidal tract signs)

54. Etiology- IgA/IgG Anti-Gliadin Ab,
Anti-endomysial Ab and
Ab against Tissue Trans-glutaminase
Rx-Gluten free diet, I.V.-IG
Invg-Serum-IgA,IgG-antigliadin, anti endomyseium, TTG, MRI-
Cerebllar atrophy and WMH, Intestinal Biopsy
Patho-Ab targets PC due to share antigenicity of gluten
Clinical features-50-60 Yrs onset,
Gait Ataxia, Peripheral neuropathy and gluten
sensitivity
Immune mediated – Gluten ataxia

55.  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

56. 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

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

58. 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?

60. Arch Neurol. 2001;58:225-230

61. Arch Neurol. 2001;58:225-

62. 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

65. Hashimoto’ Encephalopathy: Systematic Review
of the Literature
(The Journal of Neuropsychiatry and Clinical
Neurosciences 2011; 23:384 –390)

66. 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

67. 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
Paraneoplastic ataxia associated antibodies

68. When to suspect?
• 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
Brain (2003):126; 1409-1418

70. • 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

73. Management
• Symptomatic treatment
• Early detection & treatment of cancer
• Immunosuppersion: Corticosteroids / IVIg

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

75. 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

76. 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

77. Diagnostic approach to sporadic adult-onset
ataxia
www.thelancet.com/neurology Vol 9 January
2010

78. www.thelancet.com/neurology Vol 9 January
Diagnostic approach to sporadic adult-onset
ataxia

79. 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

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

81. 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

82. Neuro-ophthalmologic evaluation in ataxia
Handbook of Clinical Neurology, Vol. 103 (3rd series)

83. Non-cerebellar neurological signs in ataxias
Handbook of Clinical Neurology, Vol. 103 (3rd series)

84. 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.

86. 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

87. 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

88. 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)

89. 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)

90. 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

91. UncharacterizedCharacterized
Where to next??
Phenotypic dilemma and challenges for novel gene identifications in
Uncharacterized SCAs
SCA1 SCA2 SCA3 AD AR EOCA LOCA
Cerebellar
Gait ataxia 100 100 100 71.4 79.3 91.6 87.8
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
Occulomotor
Nystagmus 35.7 6 57.8 23.8 31 37.5 21.9
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
Motor system
Muscle cramps 9.5 11 0 0 0 4.1 2.4
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
Pyramidal
Hyperreflexia 33.3 16 68.4 23.8 24.1 36.1 21.9
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
EPS
NCV 60 73 38.4 35.2 37.5 47.9 44.8
AFT 75 65 53.8 61.1 75 55 64
other
Dementia 4.7 4 15.7 0 17.2 11.1 0
Myoclonus 0 2 0 0 6.8 0 0
Seizures 0 1 0 0 6.8 5.5 0
VERTIGO 0 0 15.7 0 0 0 0
PES
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
1001
Absent
Frequency %
AD: Autosomal dominant
AR:Autosomal recessive
EOCA: early onset sporadic
cerebellar ataxia
LOCA: Late onset sporadic
cerebellar ataxia

92. DIAGNOSIS OF ATAXIA PATIENTS IN ATAXIA CLINIC,
AIIMS (Unpublished)
7%
12%
3%
1%
12%
4%
61%
SCA1
SCA2
SCA3
SCA7
SCA12
FRDA
Uncharacterized-SCA
Total Families= 1500
Characterized= 585
Uncharacterized= 915

93. 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

94. 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

95. 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

96. 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

97. 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

98. Gilman S Neurology2008