Clinical manifestations of patients with ATAXIA.pptx

Approach to Patients presenting with ataxia

1. Approach to Ataxia

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 Sensory neuropathy and posterior column disease of the spinal cord (sensory ataxia) Loss of distal joint, position sense Absence of cerebellar signs such as dysarthria or nystagmus Loss of tendon reflexes Corrective effects of vision on sensory ataxia Romberg sign

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 I ntermediate  Interposed nuclei Execution of movements and gait Lateral Cortex  Dentate nucleus Motor planning, limb coordination Floculus  Vestibulo- occular reflex Neocerebellum Cerebellum

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

12. 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

13. 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

14. 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

15. TO STAND STRAIGHT : VISUAL INPUT VESTIBULR SYSTEM CEREBELLUM PROPIOCEPTION ? INTERPRET ? WHAT IS ROMBERG”S SIGN ?

16. 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

17. 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

18. 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

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

20. 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

21. 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)

22. 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

23. 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

24. 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

25. 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 B 1 and B 12 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.

26. 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)

27. 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

28. 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

29. 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

30. 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.

31. INTRODUCTION: Autosomal Dominant Cerebellar Ataxias Clinically and genetically heterogeneous neurodegenerative disorders. group of 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

32. 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

33. Spinocerebellar ataxias: Clinico genetics (CAG) n (CAG) n (CAG) n (CAG) n (CAG) n SCA1- SCA2- SCA3- SCA6- SCA7- 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 mapped Mutation (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 amyotrophy ADCA- I ADCA- II ADCA- III ADCA- IV pure cerebellar syndrome Cerebellar ataxia and Seizures

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(

41. 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.

42. 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

43. 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

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

45. 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

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

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

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

49. 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?

50. 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

51. 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

52. 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

53. 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

54. 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

55. 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

56. Creutzfeldt−Jakob Disease Rapidly progressive disorder with cerebellar ataxia. 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

57. Diagnostic approach to sporadic adult- onset ataxia

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

59. 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

60. 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

61. 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

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

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

64. 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.

65. 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

66. 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

67. 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

68. 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