Approach to ataxia

Approach to Ataxia

Presenter: Dr DivyaPreceptor: 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

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)

Causes of sensory ataxiaPolyneuropathy Paraneoplastic sensory neuronopathy

Sjogren’s syndomeMiller Fisher SyndromeDysproteinemiaCisplatinPyridoxine excessAcute sensory neuronopathyChronic ataxic neuropathy

Myelopathy Multiple sclerosisTumour or cord compressionVascular malformationVacuolar myelopathy

Myeloneuropathy Freidriech’s AtaxiaVitamin B12 deficiencyVitamin E deficiencyTabes dorsalisNitrous 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)

Paleocerebellum

Archicerebellum

Vermis Fastigial nucleus Balance and ocular movement

Intermediate Interposed nucleiExecution of movements and gait

Lateral Cortex Dentate nucleusMotor planning, limb coordination

FloculusVestibulo-occular reflexNeocerebellum

Cerebellum

Clinical features of cerebellar disease

Ataxia (appendicular or axial) Dysmetria Dyssynergia Dysdiadochokinesia Rebound Phenomenon Dysarthria

Tremor Titubation and increased

postural sway Hypotonia Asthenia Nystagmus

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

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

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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

Hereditary GroupAutosomal dominant cerebellar Ataxias

Spinocerebellar ataxia type 1-31, SCA36, Episodic ataxias

Autosomal Recessive cerebellar AtaxiasFriedreich’s ataxia, Ataxia Telengiectasia, spastic ataxia

X-linked cerebellar ataxiasFragile X tremor ataxia syndrome

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

Contd…

Classification

Cerebellar Ataxias classification (Contd..)

Non hereditary Group (Sporadic)

Degenerative progressiveMSA-C, Idiopathic late onset cerebellar ataxia (IOCA)

Non-progressive developmental disordersCayman ataxia, Joubert syndrome

Toxins induced cerebellar degenerationAlcohol, Anticonvulsants, Anticancer drugs etc

Autoimmunity associatedMultiple sclerosis, Gluten ataxia, Ataxia with anti-GAD Ab

Paraneoplastic cerebellar degenerationInfection mediated

Post viral infection cerebellitis, Enteric fever, Adeno/retroviral, malaria, Prions

Developmental malformation/congenitalDandy-Walker MalformationChiari MalformationVermial Agenesis etc.

Cerebellar Ataxias classification (Contd..)

Diagnostic ApproachMeticulous 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)

• 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

History

In ChildrenHistory: 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 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 drugsAlcoholic-nutritional (vitamin B1 and B12 deficiency)Lyme disease

Paraneoplastic syndromeAnti-gliadin antibody syndromeHypothyroidismInherited diseasesTabes dorsalis (tertiary syphilis)Phenytoin toxicityHereditary ataxiaAD/AR

Vascular: cerebellar infarction, hemorrhage, or subdural hematomaInfectious: 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 leukoencephalopathy (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.

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 testsNeuro 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

•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, lactate/pyruvate

Ancillary tests

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

Autosomal Recessive cerebellar AtaxiasFriedreich’s ataxia, Ataxia Telengiectasia, spastic ataxia

X-linked cerebellar ataxiasFragile 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, DysarthriaPyramidal and Extrapyramidal involvementOcculomotor incordinationPeripheral NeuropathyRetinal degeneration

Signs of cerebellar ataxiaPigmentory retinal degenerationOphthalmoplegia

pure cerebellar syndrome

Signs of cerebellar ataxiaPyramidal featuresExtrapyramidal signsamyotrophy

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;1:1151–1155

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- PLEKHG4SCA 5- β III spectrinSCA11- TTBK-2SCA13- KCNC3SCA 14- PRKCGSCA 16/15-ITPR1SCA23- PDYN2SCA 27- FGF14SCA28- AFG3L2

SCA 9 undescribedSCA 18 7q22-q32SCA 20 11p13-q11SCA 21 7p21.3-p15.1SCA19/ 22 1p21-q21SCA 24 1p36SCA 25 2p21-p13SCA 26 19p13.3SCA 29 3p26SCA30 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 ataxiaPigmentory retinal degeneration

Cerebellar ataxiaPyramidal Extrapyramidal

amyotrophyADCA-I

ADCA-II

ADCA-III

ADCA-IV

pure cerebellar syndrome

Cerebellar ataxia and Seizures

Clinical behavior of Common SCA subtypes

Late onset 3rd to 4th decade

Diffuse Neuro degenerationpredominantly OPCA

Variable rates of progressionRapid 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 onsetAnticipation

SCA Subtypes and distinguishing features

Signs that Distinguishes SCA subtypes

Benign course SCA 6UMN signs SCA 1,7,8 and 3Akinetic rigid syndrome

SCA 3,2,17 & 12,21

Chorea SCA 2,1,3Action tremor SCA 12,16Slow saccades SCA 2 & 7 may be in 1,3Downbeat nystagmus SCA 6Hyporeflexia/Areflexia SCA 2,4,3 & 19,21Vision loss SCA 7Seizure SCA 10Myoclonus SCA14 or SCA19 Cognitive impairment SCA2,14,19,21,23

Guide to efficient genetic testing

THE LANCET Neurology Vol 3 May 2004

Hereditary GroupAutosomal dominant cerebellar Ataxias

Spinocerebellar ataxia type 1-31, SCA36, Episodic ataxias

Autosomal Recessive cerebellar AtaxiasFriedreich’s ataxia, Ataxia Telengiectasia, spastic ataxia

X-linked cerebellar ataxiasFragile 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)

Mitochondrial Gene Chromosome Pathogenic mechanismFriedreich'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 damageAtaxia Telengiectasia like disorder (ATLD) MRE11 11q21 DNA damageAtaxia with Occulomotor Apraxia 1 (AOA1) APTX 9p13 Imapired DNA repairAtaxia with Occulomotor Apraxia 2 (AOA2) SETX 9q34 Imapired DNA repairSpinocerebellar ataxia with axonal neuropathy (SCAN1) TDP1 14q31-32 DNA repairMitochondrial 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 foldingMarinesco-Sjögren’s syndrome (MSS) SIL1 5q31 Impaired HSP70- mediated protein folding

Refsum DiseasePHYH, PEX7 10pter-11.2, 6q21-22.2  

Autosomal recessive cerebellar ataxia: The Implicated genes and pathology

Disease Additional features over Cerebellar Ataxia

Distinguishable features Laboratory findings

Cerebellar ataxia with sensory Axonal neuropathyMRI-spinal atrophy

FRDA Pes cavus, Amyotrpohy, Extensor Plantar, Nystagmus

Cardiomyopathy, DM GAA expansion in FXN

MRI-Spinal +Cerebellar AtrophyIOSCA Pes cavus, Amyotorphy,

Ophthalmoplegia,Cognitive Impairment, Chorea

Seizures,Hearing loss,Hypogonadism

-

MRI-NormalAVED Pes Cavus, Extensor Plantar,

Head TremorRetinitis Pigmentosa,

CardiomyopathyLow 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

Disease Additional features over Cerebellar Ataxia Distinguishable features Laboratory findingsCerebellar ataxia with sensorymotor Axonal neuropathy

MRI-Cerebellar AtrophyLOTS Amyotrophy, tremor, Myoclonus Saccadic Intrusion, Prominent

Extrapyramidal,Seizures,Psychiatric Impairment

-

SCAN1 Pes Cavus, Amyotrophy Low albuminAT Occulomotor Apraxia, Amyotrophy,Tremor

Myoclonus, Extrapyramidal, Babinski SignTelengiectasia,Lymphoid cancer,

Radiosensitivity,Immunodeficiency,DM

High alpha-fetoprotein and low immunoglobin

ATL Occulomotor Apraxia, Extrapyramidal Radiosensitivity,Immunodeficiency low immunoglobinAOA1 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 AtrophyARSACS Pes Cavus, Amyotrophy, Spasticity,

extensor Plantar, cogitive ImpairmentSaccadic Intrusion, Hypermyelinated

Retinal fibers-

MRI-Cerebellar Atrophy + WMHCTX Pes Caus Amyotrophy, Spasticity,

myoclonus, ParkinsonismPsychiatric 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

ng

Liver failure

Disease Additional features over Cerebellar Ataxia Distinguishable features Laboratory findingsCerebellar ataxia with sensorymotor Demyelinating neuropathy

MRI-Cerebellar AtrophyMSS Amyotrophy, tremor, Hypotonia Psychomotor and cognitive,

Impairment, Scoliosis,Cataract,Hypertropic Hypogonadism,

Rhabdomyolysis

-

MRI-NormalRefsum Disease

Pes cavus, Amyotrophy Retinitis Pigmentosa,Cardiomyopathy,Hearin

g,Renal Failure

Renal failure, high phytanic acid,High CSF

proteinsOthers

Cerebellar ataxia and Hypogonadotropic HypogonadismBNS Cerebellar ataxia, hypotrophic

Hypogonadismhypotrophic Hypogonadism -

CoQ10 deficiency (Adult onset)

CoQ10 deficiency (Adult onset) -

Congenital cerebellar AtaxiaCA (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

-

Genetic Testing Protocol of ataxias(AIIMS)Spinocerebellar Ataxia

Aut.Dominant Aut.RecessiveSporadic

LOCA (>25) EOCA (<25)SCA 1SCA 2SAC 3SCA 7

SCA 12

FRDA

NO YES

YES NO

SCA 6SCA 8

SCA 17DRPLA

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 ataxiaEOCA-Early onset cerebellar ataxia

SCA27SCA28

Age at Onset (Yrs)

10-30 >30 Variable

SCA11SCA14SCA23

SCA5SCA13SCA14SCA15SCA28

Hereditary GroupAutosomal dominant cerebellar Ataxias

Spinocerebellar ataxia type 1-31, SCA36, Episodic ataxias

Autosomal Recessive cerebellar AtaxiasFriedreich’s ataxia, Ataxia Telengiectasia, spastic ataxia

X-linked cerebellar ataxiasFragile X tremor ataxia syndrome

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

X-linked ataxiaFragile 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

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

MSA diagnosis Gilman S Neurology2008

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)

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)

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

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;58:225-230

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 of the Literature

(The Journal of Neuropsychiatry and ClinicalNeurosciences 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

Antibody Condition Freq.Anti-Yo (Purkinje cell antobody type1) Breast and ovarian Ca 0.38Anti-Hu (Anti neuronal nuclear antibody type1) Small cell lung Ca (SCLC) 0.32Anti-Tr Hodgkin Lymphoma 0.14Anti-mGluR1 (metabotrpin glutamate receptor) Hodgkin Lymphoma 0.04AntiRi (Anti neuronal nuclear antibody type1) SCLC, Breast, Ovarian ca 0.12Anti-VGCC (Voltage gated calcium channel) SCLCAnti-CRMP5 (Collapsin receptor mediated protein)/Anti-CV2 SCLCAnti-ZIC4 (zinc finger protein) SCLC

Paraneoplastic ataxia associated antibodies

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 every 6 months

for 4 years

Brain (2003):126; 1409-1418

• 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 ataxiaBrain (2003), 126, 1409±1418

Management

• Symptomatic treatment

• Early detection & treatment of cancer

• Immunosuppersion: Corticosteroids / IVIg

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 Investigations

Rx

Vitamin deficiency induced Ataxias

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

www.thelancet.com/neurology Vol 9 January 2010

Diagnostic approach to sporadic adult-onset ataxia

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

• 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

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)Ataxic Disorders

Non-cerebellar neurological signs in ataxias

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

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.

Thank You

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

UncharacterizedCharacterized

Where to next??Phenotypic dilemma and challenges for novel gene identifications in Uncharacterized SCAs

  SCA1 SCA2 SCA3 AD AR EOCA LOCA

CerebellarGait ataxia 100 100 100 71.4 79.3 91.6 87.8UL-ataxia 100 96 89.4 71.4 96.5 84.7 80.4Dysarthria 92.8 90 94.7 66.6 68.9 83.3 78

OcculomotorNystagmus 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 39Broken pursuit 26 3 57.8 42.8 31 54 48.7

Motor systemMuscle cramps 9.5 11 0 0 0 4.1 2.4Fasciculations 11.9 37 15.7 9.5 6.8 13.8 9.7Amyotrophy 0 2 84.9 0 0 0 0

Extrapyramidal Extrapyramidal 9.5 18 13.9 14.2 6.8 9.7 21.9

PyramidalHyperreflexia 33.3 16 68.4 23.8 24.1 36.1 21.9

Arreflexia 7.1 23 0 9.8 6.8 12.5 4.8Extensor 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 44.8AFT 75 65 53.8 61.1 75 55 64

other

Dementia 4.7 4 15.7 0 17.2 11.1 0Myoclonus 0 2 0 0 6.8 0 0Seizures 0 1 0 0 6.8 5.5 0

VERTIGO 0 0 15.7 0 0 0 0PES

CAVUS/SCOLIOSIS 0 0 0 0 6.8 0 0

Polyphagia 0 1 0 0 0 0 0Parkinson Phenotype 0 3 0 0 0 0 0

Visual 0 0 5.2 4.7 6.8 5.5 4.8Dysphagia 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

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= 1500Characterized= 585Uncharacterized= 915

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 lesionsSigns 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