approach to ataxia
TRANSCRIPT
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