Approach to Ataxia

Ataxia

1. 1 PRESENTER- DR. VAIHBAV kr SOMVANSHI DM RESIDENT(NEUROLOGY) GMC,KOTA Approach to Ataxia

2. Introduction Ataxia = from Greek- a- [lack of]+ taxia [order] 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

3. Localisation Cerebellum (most common) Sensory pathways (Sensory Ataxia)-posterior columns, dorsal root ganglia, peripheral nerves Vestibular dysfunction

4. Localization of cerebellar lesions Gait ataxia Limb ataxia Dysarthria Titubation Action tremor 4 Anterior vermis Lateral hemispheres Posterior left hemisphere & vermis Ant. Vermis & associated deep nuclei Dentate nuclei, or cerebellar outflow to ventral thalamus

5. Localization of cerebellar lesions Palatal tremor Saccadic dysmetria Square wave jerks Gaze evoked nystagmus Higher cognitive changes 5 Dentate nucleus, Guillain Mollaret triangle Dorsal vermis Cerebellar outflow Flocculus & paraflocculus Lateral hemispheres

6. Neuroanatomy 6

7. 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

8. Vestibular Dysfunction Vertigo is prominent Consistent fall to one side Nystagmus Limb ataxia is absent Speech is normal Joint position sense is normal

9. Approach to ataxic patient 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 9

10. 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 ) 10

11. 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 11

12. Distribution of ataxia Symmetric - Acquired, Hereditary, degenerative ataxias Asymmetric- Vascular, Tumors , demyelinating, Infection, congenital causes Other system illness Gastrointestinal symptoms- gluten ataxia Mass lesion- paraneoplastic ataxias History 12

13. Children 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 13

14. Examination Neurological examination Ataxia (appendicular or axial) Dysmetria Dysdiadochokinesia Rebound Phenomenon Dysarthria Tremor Titubation and increased postural sway Hypotonia Nystagmus Other system evaluation Breast Lump, mass per-abdomen etc. 14

15. Neuro-ophthalmologic evaluation in ataxia Retinal pigmentosa Refsum disease, mitochondrial disorders Retinal/Macular degeneration SCA 7, aceruloplasminemia Optic atrophy/visual loss MS,FA Square wave jerks FA Occulomotor apraxia AT, AOA1, AOA2 Slow saccades Downbeat Nystagmus SCA2,SCA 7 SCA 6,EA2,anti GAD ataxia 15

16. Other Specific signs Focal and lateralized brainstem deficits( hemiparesis,facial palsy) Posterior circulation stroke, tumour , MS Paplidema , headache Posterior fossa tumours INO Posterior circulation stroke,MS Spasticity, UMN signs SCA 1,3,7,8 , Strokes,tumour compressing brainstem Basal ganglia deficits SCA 1,2,12,17, MJD,MSA,Wilson Tremor SCA 12, 15, FAXTS 16

17. 17 Deafness Mitochondrial, superficial himosiderosis Myoclonus Mitochondrial ,ceroid lipofuschinosis,SCA 7(early onset),SCA 14 Palatal myoclonus Alexander disease,SCA20 Cognitive decline Alcohol,MS,CJD,HIV,DRPLA,SCA12,13, superficial siderosis Psychiatric features SCA 12,17,27 Autonomic failure MSA,FXTAS Other Specific signs

18. Ataxia with Neuropathy Friedreich ataxia AOA2 Fragile X syndrome Vit E deficiency ataxia Anti gliadin ataxia SCA 2,3,4,12, 18,25,27 Refsum disease 18

19. Ataxia with Dementia Anti gliadin ataxia FXTAS syndrme SREAT SCA 17, 19, 21, 2, 1, 6 HIV/AIDS Mitochondrial disease Amylodosis 19

20. Ataxia with seizures Anti GAD Anti gliadin Mitochondrial ataxia Episodic ataxia 2, 4 DRPLA SCA 10, SCA 17 CJD SREAT 20

21. Investigations Neuro imaging Electro diagnostic tests Ophthalmologic examination- Pigmentary retinopathy, macular degeneration, cataracts, Kayser -Fleischer rings

22. Genetic tests Metabolic – Thyroid function, vitamins B12, E, and B1, serum cholesterol & plasma lipoprotein profile, phytanic acid, toxicology screen(mercury, bismuth, lead, ethanol) Immune function - Immunoglobulin levels, Antigliadin antibodies, GAD antibodies, paraneoplastic antibodies, Anti TPO.

23. Laboratory studies Mitochondrial( Serum lactate and pyruvate) Heavy metals,PBF for acanthocytes , VLCF, hexosaminidase A/B, alpha fetoprotein & immunoglobulins, serum ceruloplasmin & 24 hour urinary copper CSF studies - Cell count, glucose and protein, oligoclonal bands, 14-3-3 protein, GAD antibodies, paraneoplastic antibodies, lactate/pyruvate

24. Diagnostic workflow Continuum movement disorder 2019 pgno.161

25. prabhakar_sudesh_singh_gagandeep_eds_differential_diagnosis chapter 22 pg.no.251

26. Genetic Testing Protocol of ataxias Spinocerebellar Ataxia Aut.Dominant Aut.Recessive Sporadic LOCA (>25) EOCA (<25) SCA 1 SCA 2 SAC 3 SCA 7 SCA 12 FRDA NO YES YES NO SCA 6 SCA 8 SCA 17 DRPLA YES NO Rare types of SCAs (ADCA) screening Investigation for other ARCA genes Level 2 Level 1 Level 3 features suggestive of SCA LOCA-Late onset cerebellar ataxia EOCA-Early onset cerebellar ataxia SCA27 SCA28 Age at Onset (Yrs) 10-30 >30 Variable SCA11 SCA14 SCA23 SCA5 SCA13 SCA14 SCA15 SCA28 26

27. 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 SCA 2,14,19,21,23 27

28. Disease Additional features over Cerebellar Ataxia Distinguishable features Laboratory findings Sensory Axonal neuropathy MRI-spinal atrophy FA Pes cavus , Amyotrpohy , Extensor Plantar, Nystagmus Cardiomyopathy , DM GAA expansion in FXN Ataxia Vit E Def. Pes Cavus , Extensor Plantar, Head Tremor Retinitis Pigmentosa , Cardiomyopathy Low VitE MRI-Cerebellar Atrophy Infantile onset SCA Pes cavus, Amyotorphy, Ophthalmoplegia,Cognitive Impairment, Chorea Seizures,Hearing loss , Hypogonadism - MRI-Normal Abetalipoprotenemia Pes cavus, Amyotrophy Retinitis Pigmentosa , Lipid Malabsorption , Cardiomyopathy Low VitE , low lipoprotein , acanthocytes Clinical approach to ARCA MRI findings and Nerve conduction studies 28

29. Disease Additional features over Cerebellar Ataxia Distinguishable features Laboratory findings Ataxia with sensorimotor Axonal neuropathy MRI- Cerebellar Atrophy Late onset Tay sachs Amyotrophy , tremor, Myoclonus Prominent Extrapyramidal , Seizures,Psychiatric Impairment Hexoseaminidase levels- Ataxia telengiectasia Occulomotor Apraxia , Amyotrophy,Tremor Myoclonus , Extrapyramidal , Babinski Sign Telengiectasia,Lymphoid cancer , Radiosensitivity,Immunodeficiency,DM High alpha-fetoprotein and low immunoglobin AT like disorders Occulomotor Apraxia , Extrapyramidal Radiosensitivity,Immunodeficiency low immunoglobin Ataxia with OA1 Occulomotor apraxia,Pes cavus , Amyotrophy , tremor, Extrapyramidal , cognitive impairment Scoliosis Low albumin, High Cholesterol Aprataxin gene Ataxia with OA2 Occulomotor Apraxia , Pes Cavus , amyotrophyTremors , Extrapyramidal , cognition Impairment Scoliosis High alpha-fetoprotein, High cholesterol Senataxin gene 29

30. Disease Additional features over Cerebellar Ataxia Distinguishable features Laboratory findings MRI-Spinal +Cerebellar Atrophy AR ataxia Charlevoix- Saguenay Pes Cavus , Amyotrophy , Spasticity, extensor Plantar, cogitive Impairment Chromosome 13 MRI-Cerebellar Atrophy + WMH Cerebrotendinous xanthomatosis Pes Caus Amyotrophy , Spasticity, myoclonus , Parkinsonism Psychiatric Impairment,Tendon Xanthomas,Seizures,Cataract,Liver failure CYP27A1 30

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33. Sporadic ataxias Multiple system atrophy (MSA) Toxins/metabolic Paraneoplastic cerebellar degeneration Immune-mediated ataxias (gluten, anti-GAD) Infectious etiology 33

34. Antibody Condition Anti- Yo (Purkinje cell antobody type1) Breast and ovarian Ca Anti- Hu (Anti neuronal nuclear antibody type1) Small cell lung Ca (SCLC) Anti- Tr Hodgkin Lymphoma Anti-mGluR1 (metabotrpin glutamate receptor) Hodgkin Lymphoma Anti-CRMP5 ( Collapsin receptor mediated protein)/Anti-CV2 SCLC Anti-ZIC4 (zinc finger protein) SCLC Paraneoplastic ataxia associated antibodies

35. 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 35

36. 36 Cerebral Sensory frontal Base of support Wide base Looks down Wide base Velocity Variable Slow Very slow Initiation Normal Normal Hesitant Turns Unsteady Unstaedy Hesitant,multiple steps Postural instability + + +++++ Falls Late event More in night Frequent Heel shin Abnormal Abnormal,difficulty in point of initiation Normal Types of Ataxia

37. Management Corrective measures for deficiencies – Vitamin E, Thiamine Specific diet – Gluten free diet, ketogenic diet Immunologic disorder – IVIG, Plasmapharesis Miglustat for niemann pick disease Riluzole – hereditary and degenerative ataxia and dysarthria Varenicline – SCA3 4- aminopyridine , Acetazolamide – Episodic ataxia type 2 Nicotinamide, deferiprone , idebenon – friedreich ataxia, mitochondrial ataxia Rehabilitation, exercise help in SCA type 1 Zinc supplementation and DBS also help in SCA 2 Actimmune – IFN- γ analogue morbidity benefit for friedreich ataxia Antisense oigonuceotide shown to knock down toxic protein level in SCA 2 and 3 mouse model 38

38. Case Scenario 55-year-old man presented with progressive gait difficulty. He had initially noted difficulty walking downstairs, upstairs and running at the age of 47. His imbalance problems became progressively worse over the years, and he developed slurred speech, transient double vision while turning his head quickly, and loss of hand dexterity. H e had frequent falls and needed to use a walker. H e had an extensive family history of cerebellar ataxia, affecting his mother and brother. On examination, he had slurred speech and slow saccadic eye movements without nystagmus or hypermetric or hypometric saccades. He had dysmetria on finger-nose-finger tests and overshoot in finger chase tests. He also had impaired rapid alternating movements with absent reflexes in upper limb and hyporelexia in lower limb. He had a hypomimic facial expression and bradykinesia left side with retropusion test positive. His gait showed variable stride length and was wide based. 39

39. Patient Video 40

40. Genetic tests - 38 repeats CAG expansions of the ATXN2 gene (normal <32), Diagnosed as SCA 2 The patient treated with riluzole 50 mg 2 times a day which provided modest benefits for his speech. Physical therapy helped with his balance. Carbidopa/levodopa 25 mg/100 mg, 3 times a day, improved his parkinsonism by increasing the speed of her movements . 41

41. Conclusion An approach to ataxia is based on knowledge of its symptoms and causes Knowledge of differentiating clinical features takes clinicians closer to the etiological diagnosis which help in investigational decisions. Treatable causes must be identified and ruled out Genetic testing is prudent for providing better insight into the management. On going clinical trials for management of hereditary and degenerative ataxias will help in better morbidity outcome of these diseases. 42

42. Thank You

43. Bradley’s Neurology in clinical Practice, eighth 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 Continuum movement disorder 2016 Continuum movement disorder 2019 prabhakar_sudesh_singh_gagandeep_eds_differential_diagnosis chapter 22 pg.no.251 References 44

44. 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

45. 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

46. 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)

47. 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)