Approach to a patient with ataxia

1. Approach to a patient with ataxia Dr Rakesh Shukla Professor Of Neurology

2. Definition Ataxia (Gk. Taxis = Order; means lack of order) Ataxia denotes a syndrome of imbalance and incoordination involving gait, limbs, and speech and usually results from the disorder of the cerebellum or its connections It is characterized by dyssynergia, dysmetria, dysdiadochokinesia (Joseph Babinski). It is a disorder of rate, range, direction and force of movements (Gordon Holmes).

5. Outline of today’s lecture • Clinical Scenario • Anatomy and Physiology • Is it Cerebellar Ataxia • History and Examination • Classification • Hereditary Ataxias • Acquired Ataxias • Treatment • Conclusion • MCQs

6. Clinical scenario • RK, 22 years young man presented with • C/O headache, double vision, difficulty in walking 20-25 days • P/H RTA 3 mths back, tractor on which he was travelling • overturned, No loss of consciousness, had a local penetrating • injury in the nape of neck from a bolt in the tractor received • local wound dressing, Eptoin (100g) 3HS • No H/o fever

7. Clinical scenario • O/E Afebrile vitals-normal, wt 43 kg GCS 15, fundus NAD • No sign of meningeal irritation, broad based gait ataxia, • tandem walking impaired, Gaze evoked nystagmus +nt, • broken smooth pursuit • Speech NAD, Romberg’s sign negative, no motor weakness, • DTR normal, planter’s bilateral flexor • Diag Acute onset cerebellar syndrome presenting as gait • ataxia • D/D chronic subdural haematoma, phenytoin intoxication

8. Investigation • HB 11 gm%, TLC 8,400 cells/cmm, DLC P58 L41E1, • Platelet count 1.8 lac/cmm • Blood sugar-R 122mg/dl, S urea 15 mg/dl • S creatinine 0.8 mg/dl • Serum electrolytes, LFT normal • HIV, HbsAg, HCV-non reactive • PT/PC/ INR normal

9. Imaging: CECT scan brain

10. Imaging: MRI scan brain

11. Outline of today’s lecture • Clinical Scenario • Anatomy and Physiology • Is it Cerebellar Ataxia • History and Examination • Classification • Hereditary Ataxias • Acquired Ataxias • Treatment • Conclusion • MCQs

12. Cerebellum has been recognised as a distinct division of the brain since Herophilus (335-280 BC) and Galen (131-200 AD) • Angevine et al., (1961) listed 24 different nomenclatures, terminology used by Larsell (1972) is used commonly at present. • It has a volume of about 144 cm3 and weighs 150g (~10% of brain weight), but its surface area is about 40% that of the cerebellar cortex.

13. Dorsal view of the cerebellum

14. Development of cerebellum • Vestibular proprioceptors provide information about the movement of head and its position. Having no limbs, primitive animals have only the flocculonodular lobe which coordinates the axial muscles that position the eyes, head and trunk • All higher animals having limbs have the anterior lobe to coordinate proprioceptive input from limbs and trunk. Emergence of vertical bipedal from the quadripedal posture places particular demands on gait coordination • The third and newest cerebral lobe (posterior lobe) expands in equal measure with the cerebrum, motor cortex, pyramidal tract, basis pontis and inferior olivary nuclei

15. Cerebro-cerebello-cerebral circuit

16. Generalisations about cerebellar disease Lesions Manifestations • Lateralized Ipsilateral signs and symptoms • Generalised Bilateral symmetrical symtomatology • Acute Severe abnormalities at onset, remarkable recovery with time • Chronic Gradual progressive decline • Vestibulo cerebellar Disequilibrium and an ataxic gait • Vermis Truncal and gait ataxia • Cerebellar hemispheres Appendicular ataxia

17. Outline of today’s lecture • Clinical Scenario • Anatomy and Physiology • Is it Cerebellar Ataxia • History and Examination • Classification • Hereditary Ataxias • Acquired Ataxias • Treatment • Conclusion • MCQs

18. Differentiation of sensory and cerebellar ataxia • Sensory ataxia is due to severe sensory neuropathy, • ganglinopathy or lesions of the posterior column of the spinal • cord. e.g. Sjogren’s syndrome, cisplatin, CCNU, Para-neoplastic • disorders, SACD, Tabes dorsalis.

19. Differentiation of vestibular and cerebellar ataxia • Vestibular ataxia is due to lesion of vestibular pathways resulting • in impairment & imbalance of vestibular inputs. e.g. vestibular, • neuronitis, streptomycin toxicity.

20. Differentiation between cerebellar and frontal lobe disorder • Frontal lobe ataxia (Brun’s ataxia) is due to involvement of • subcortical small vessels, Binswanger’s disease, multi infarct • state or NPH.

21. Outline of today’s lecture • Clinical Scenario • Anatomy and Physiology • Is it Cerebellar Ataxia • History and Examination • Classification • Hereditary Ataxias • Acquired Ataxias • Treatment • Conclusion • MCQs

22. Important points in history • Age at onset • Mode of onset • Precipitating factors • Rate of progression • Symptoms of raised ICP • Presence of systemic symptoms • Drug history and toxin exposure • Family history

23. Examination • Neck tilt and titubation • Nystagmus and other ocular movement abnormalities • Dysarthria • Intention tremor • Hypotonia • Past pointing • Rebound phenomenon • Macrographia • Stance • Ataxic Gait • Pendular knee jerk

25. Outline of today’s lecture • Clinical Scenario • Anatomy and Physiology • Is it Cerebellar Ataxia • History and Examination • Classification • Hereditary Ataxias • Acquired Ataxias • Treatment • Conclusion • MCQs

26. Individual with progressive ataxia Autosomal recessive or uncertain inheritance Negative FH Autosomal dominant inheritance <25 years old Exclude secondary causes >25 years old ARCAs, X-linked and mitochondrial inherited Consider ADCAs Test for: FRDA (GAA); AT (α-fetoprotein); AVED (vit. E level); Refsum’s (phytanic acid); Wilson’s Harding’s classification Negative ADCA I (ataxia + CNS signs) SCA 1, 2, 3, 4, 8, 12, 17, and FGF 14 ADCA II (cerebellar syndrome + pigmentary maculopathy) SCA 7 ADCA III (“pure” cerebellar syndrome) SCA 5, 6, 10, 11, 14, 15, and 22 Test for other recessive ataxias

27. Outline of today’s lecture • Clinical Scenario • Anatomy and Physiology • Is it Cerebellar Ataxia • History and Examination • Classification • Hereditary Ataxias • Acquired Ataxias • Treatment • Conclusion • MCQs

28. Diagnosis of hereditary ataxia • Insidious onset, symmetrical, and progressive • Age at onset • Early onset ataxia (age at onset below 25 years) is more likely to be consistent with autosomal recessive inheritance Exceptions Friedreich’s ataxia, Tay Sachs disease • Late onset ataxia (age at onset over 25 years) is usual for those ataxias with dominant inheritance. Exceptions, SCA7, DRPLA, EA-1, EA-2 • Family history: - Direct questioning of patient and relatives. - H/o consanguinity - Pedigree charting - Negative family history does not exclude the diagnosis

29. Causes Of negative F/H • May be seen in - Adoption - Genetic non paternity - Anticipation - De novo mutation - Small family size - In X-linked inheritance only males are affected. - In mitochondrial disorders matrilineal mode of inheritance may be apparent although penetrance is variable

30. Clinical features of Friedreich’s Ataxia • Autosomal recessive inheritance • Onset before 25 years • Progressive limb and gait ataxia • Absent DTR in legs • Electrophysiological evidence of axonal sensory neuropathy • Dysarthria* • Areflexia in all four limbs* • Distal loss of position and vibration sense* • Extensor plantar responses* • Pyramidal weakness of the legs* *Develop within 5 years of onset of disease

31. Autosomal dominant ataxias • Heterogenous group of disorders with onset after 25 years • 25 different genetic loci have been identified (SCA1 to SCA2) • Have diverse associated neurological features (retinopathy, optic atrophy, extra pyramidal or pyramidal signs, peripheral neuropathy, cognitive impairment, or epilepsy) • Most common forms-SCA1, SCA2 and SCA.

32. Bedside differentiation of SCAs • Large study n=526 patients (17 centres) with SCA 1,2, 3 or 6: • - Pyramidal signs (67%) and brainstem oculomotor • sign (74%) were most frequent in SCA 1 • - PN involvement was most frequent in SCA 2 (68%) • - 24% of patients with SCA3 had dystonia • A decrease in visual (83%) and auditory (24%) acuity was • the predominant sign in SCA7 • No clinician can accurately distinguish between different polyglutamine expansion SCAs; but this form of SCA can be distinguished from other SCA types David G, et al., Human Med Genet 1998; 7: 165-70 Maschke M, et al., Mov Disord 2005; 20: 1405-12 Schmitz-Hubsch T, et al., Neurology 2008; 71: 982-9

33. Clues to the SCAs Clinical Features Genetic Forms Age at onset Young adult: SCA 1, 2, 3, 21 Older adult: SCA 6 Childhood onset: SCA 7, 13, DRPLA Upper motor neuron SCA 1, 3, 7, 12 signs Some in SCA 6, 8 Rare in SCA 2 Slow saccades Early, prominent: SCA 2, 7, 12 Late: SCA 1, 3 Rare: SCA 6 Extra-pyramidal signs Early chorea: DRPLA Akinetic-rigid, Parkinson: SCA 2, 3, 21 Generalized areflexia SCA 2, 4, 19, 21 Late: SCA 3 Rare: SCA 1 Visual loss SCA 7 Dementia Prominent: SCA 17, DRPLA Early: SCA 2, 7 Otherwise: rare Myoclonus SCA 2, 14 Tremor SCA 12, 16, 19 Seizures SCA 10

34. Outline of today’s lecture • Clinical Scenario • Anatomy and Physiology • Is it Cerebellar Ataxia • History and Examination • Classification • Hereditary Ataxias • Acquired Ataxias • Treatment • Conclusion • MCQs

35. Classification of acquired cerebellar ataxias • Ataxias due to toxic reasons Alcoholic cerebellar degeneration (ACD) Ataxias due to other toxic reasons • Immune-mediated ataxias Paraneoplastic cerebellar degeneration (PCD) Other immune-mediated ataxias • Ataxias due to vitamin deficiency • Ataxias due to other rare causes

36. Symmetrical acquired ataxias • Acute - Drugs: phenytoin, phenobarbitone, lithium, Chemotherapeutic agents - Alcohol - Infectious: Acute viral cerebellitis, Post-infectious - Toxins: Toulene, glue, gasoline, methyl mercury • Subacute - Alcohol, or Nutritional (B1, B12) - Paraneoplastic - Antigliadin or anti GAD antibody - Prion diseases • Chronic - MSA-C - Hypothyroidism - Phenytoin toxicity

37. Asymmetrical acquired ataxias • Acute - Vascular: Cerebellar infarction or hemorrhage, Subdural Haemotoma - Infectious: Abscess • Subacute - Neoplastic : Glioma, metastates, lymphoma - Demyelination : MS - HIV related : Progressive multi-focal leuco-encephalopathy • Chronic - Congenital lesions: Arnold Chiari malformation, Dandy Walker syndrome

38. Tumors that produce ataxia • Medulloblastoma • Astrocytoma • Ependymoma • Hemangioblastoma • Metastatic tumor • Meningioma • Cerebellopontine angle schwannoma

39. Sporadic ataxia • All acquired causes have been ruled out and there is no family history • A genetic explanation for “sporadic” ataxia is obtained in 4-22% • SCA6 is the most common dominant mutation detected in between 6% and 13% of patients • The frequency of the Freiedreich’s GAA expansion among cases of adult-onset is between 4 and 8%.

40. Outline of today’s lecture • Clinical Scenario • Anatomy and Physiology • Is it Cerebellar Ataxia • History and Examination • Classification • Hereditary Ataxias • Acquired Ataxias • Treatment • Conclusion • MCQs

41. Treatment • Identify treatable causes of ataxia • No proven therapy for SCAs • Some patients with parameoplastic cerebellar syndrome improve following removal of tumour and immunotherapy • Preliminary evidence suggests that idebenone, a free radical scavenger improves myocardial hypertrophy • Genetic counselling can reduce risk in future generations

42. Treatable causes of ataxia • Hypothyroidism • AVED • Vitamin B12 deficiency • Wilson’s Disease • Ataxia with anti-gliadin antibodies and gluten senstive enteropathy • Ataxia due to malabsorption syndromes • Lyme’s disease • Mitochondrial encephalomyopathies, aminoacidopathies, Leukodystrophies and urea cycle abnormalities

43. Outline of today’s lecture • Clinical Scenario • Anatomy and Physiology • Is it Cerebellar Ataxia • History and Examination • Classification • Hereditary Ataxias • Acquired Ataxias • Treatment • Conclusion • MCQs

44. Conclusion • Thorough history and examination is required • Age at onset and family history are most important • Hereditary ataixas can be divided into early onset (<25 years) or late onset (> 25 years) • Early onset ataxias are usually recessive, while late onset ataxias are usually dominant • Friedreich’s ataxia is the most common recessive disorder while SCA2 is the most common dominant disorder. Contd…

45. Conclusion contd… • No single physical sign is specific for a single disorder • Investigations should be performed in a logical order • Treatable causes should be excluded

46. Outline of today’s lecture • Clinical Scenario • Anatomy and Physiology • Is it Cerebellar Ataxia • History and Examination • Classification • Hereditary Ataxias • Acquired Ataxias • Treatment • Conclusion • MCQs

47. 1. A horizontal gaze evoked nystagmus in which the direction of the fast phase reverses with sustained lateral gaze or beats transiently in the opposite direction when the eyes return to primary position is called A. Periodic alternating nystagmus B. Seesaw nystagmus C. Rebound nystagmus D. Dysconjugatenystagmus

48. 1. A horizontal gaze evoked nystagmus in which the direction of the fast phase reverses with sustained lateral gaze or beats transiently in the opposite direction when the eyes return to primary position is called A. Periodic alternating nystagmus B. Seesaw nystagmus C. Rebound nystagmus D. Dysconjugatenystagmus

49. 2. The typical signs of cerebellar herniation include the following EXCEPT A. Stiff neck B. Alteration of consciousness C. Ptosis and pupillary abnormality D. Cardiac and respiratory abnormalities

50. 2. The typical signs of cerebellar herniation include the following EXCEPT A. Stiff neck B. Alteration of consciousness C. Ptosis and pupillary abnormality D. Cardiac and respiratory abnormalities