Ataxia in Childhood – a collection of clinical cases

1. Ataxia in Childhood – a collection of clinical cases

2. Childhood Ataxia • 4 Clinical Case descriptions • Cerebellum: Structure & Function • Ataxia: Clinical Features • Classification of Childhood Ataxia • Discussion of selected Ataxic disorders

3. Clinical case # 1 History : • Miss M.K. a 13 year old female, previously well • Normal milestones, coping well at school • Preceding history of vesicular rash, fever and malaise • Rash erupted 10 days prior to admission • Acute onset of unsteady gait, confusion, refusing to speak • No history of immunocompromise

4. Clinical case # 1 Examination : • Thriving child, not dysmorphic • Crops of vesicles over trunk and limbs • Florid cerebellar signs: ataxia, DDK, intention tremor, truncal hypotonia, dysarthric speech, no nystagmus, mildly encephalopathic Investigations : • LP - normal pressures, chemistry, cell counts • CT Brain - NAD

5. Diagnosis Post varicella cerebellitis with encephalitis

6. Clinical case # 2 History : • Master S.K. 11year old boy, previously well, referred from Leratong hospital • c/o 5 months fatigue, loss of weight, dizziness, poor balance • Mother reported slurred speech, “drunken” gait, poor handwriting • He was previously right-handed but was now using his left hand only

7. Clinical case # 2 Examination : • Normal growth including head circumference • Not dysmorphic, no skin lesions of neurocutaneous syndromes • Systemic exam normal • CNS: alert and responsive. Nil meningism. Cranial nerves intact. • Tone : truncal hypotonia, Power : full, Reflexes : ? pendular • Sensation : intact, Proprioception : intact • Cerebellum : titubation, dysarthric speech, +DDK (marked on right), +dysmetria, +intention tremor, + heelshin test on right, horizontal nystagmus present. • Gait : broad-based ataxic gait.

8. Clinical case # 2 Investigations : • CT Brain : posterior fossa lesion, highly calcified vermal and right cerebellar hemisphere mass

9. Diagnosis Cerebellar medulloblastoma

10. Clinical case # 3 History : • Miss B.M. aged 6 yrs from Ladysmith referred to Neuro Clinic with her 8 yr old similarly affected brother • 2 year history of red eyes, poor balance, frequent falls, shaking of head, now becoming progressively worse • Milestones normal, intellectually normal • No family history of note

11. Clinical case # 3 Examination : • marked gait ataxia • DDK • Dysmetria • cerebellar speech • pendular reflexes • some dystonic posturing of trunk and arms • apraxic movement of eyes • conjunctival telangiectasia

12. Clinical case # 3 Investigations : • CT Brain: marked cerebellar atrophy • Immunoglobulins (no result) • Chromosomes………

13. Diagnosis Ataxia Telangiectasia

14. Clinical case # 4 History : • Master D.H. 9 year old male • Presented at 7 years of age with poor balance • Bumping into things & falling over regularly • Mom had noticed deformity of feet and assumed this was the cause of the problem • Taken to physiotherapist who referred him to paediatrician for investigation of ataxia • Family history: maternal grandmother had 3 cousins with weakness, who became wheelchair-bound and died in their mid 30’s

15. Clinical case # 4 Examination : • Thriving child. Normal head circumference. • No dysmorphic features. Systemic exam NAD. • CNS: Distal muscle wasting. • Significant pes cavus bilaterally with hammer toes. • Tone : globally reduced with rounded back but no kyphoscoliosis. • Power : proximally 5/5 , distally 3/5 • Reflexes : globally absent, plantars equivocal • Sensation : glove and stocking sensory loss • Proprioception : intact

16. Clinical case # 4 Examination (continued): • Cerebellum : dysarthric speech • +DDK • +dysmetria • Mild intention tremor • No nystagmus • Gait : high-stepping broad-based ataxic gait • Unable to stand on one leg Investigations : • CT Brain & MRI normal • Cardiac assessment normal • Nerve conduction – axonal sensory peripheral neuropathy • Blood investigation….

17. Diagnosis ……..homozygous expansion in frataxin gene = Friedreich’s Ataxia

18. Cerebellum: Structure & Function The cerebellum is a vast coordinator of information receiving approximately 40 times more afferent than efferent fibres. This vast afferent input gives the cerebellum a total picture of the body’s position in space, motion, head position and limb position as well as the state of contraction of different muscles. The cerebellum sythesises this information, allowing one to adjust the speed, forceanddirection of a particular movement.

19. Cerebellum: Structure & Function • Organ of learned, skilled motor movements • Stores movement patterns which are available for instant retrieval, enabling one to perform previously learned, difficult combinations of movements effortlessly • Postnatally maturing organ & so in assessing clinical signs of cerebellar disease, one has to consider the child’s stage of development.

20. Cerebellum: Structure & Function Three main anatomical subdivisions: • Central vermis • Two lateral hemispheres • Hemispheric lesions may present with ipsilateral cerebellar signs • Vermal lesions may present with central hypotonia and bilateral signs

21. Cerebellum: Structure & Function Three main functional subdivisions: Archicerebellum (Vestibular) Paleocerebellum (Spinal) Neocerebellum (Cortical) • Archicerebellum - spatial position & movement of head • Paleocerebellum - proprioceptive & regulation of muscle tone, posture and gait • Neocerebellum - coordinates skilled motor movements

22. Cerebellar disease : Clinical Features • Ataxia: - incoordination of postural control and gait - incoordination of skilled fine movements & speech • Vertigo (uncommon in children) • Vomiting (postural, projectile, positional) • Ataxia • Nystagmus • Intention tremor • Speech (slow, slurred, staccato) • Hypotonia • Dysmetria • Dysdiadochokinesia • Titubation

23. Classification of Childhood Ataxia

24. Acute Childhood Ataxias • Infections • Cerebellar abscess • Viral cerebellitis (varicella, coxsackie, mumps, EBV, polio) • Bacterial (diphtheria, pertussis, typhoid) • Toxins / Metabolic • alcohol / antiepileptic drugs • heavy metal poisoning • Hartnup / MSUD • organic & aminoacidurias • Posterior fossa tumours • Trauma - cerebellar haemorrhage • Migraine - basilar • Vascular - embolism / thrombosis / AVM (rare) • Hydrocephalus

25. Chronic Non-Progressive Childhood Ataxias • Perinatal • Birth asphyxia – Cerebral palsy (hypotonic with or without ataxia) • Hydrocephalus • Metabolic (hypoglycaemia /kernicterus) • Congenital Malformations • Primary cerebellar hypoplasia • Dandy-Walker • Arnold-Chiari • Cerebellar-Kidney associations • Meckel Gruber syndrome • Zellweger syndrome • Von Hippel Lindau • Postnatally acquired • Hypoxic insults – Cerebral Palsy • Trauma • Deficiency – thiamine, hypothyroidism

26. Chronic Progressive Childhood Ataxias 1 Brain tumours - Cerebellar astrocytoma - Von Hippel-Lindau (cerebellar haemangioblastoma & hypernephroid tumours) - Ependymoma - Medulloblastoma - Neuroblastoma (opsomyoclonus)

27. Chronic Progressive Childhood Ataxias 2 Metabolic disorders • Sphingolipidoses (Metachromatic Leukodystropy, Krabbes, Niemann-Pick, Gauchers) • Ceroid-lipofuscinosis • Abnormalities of DNA repair (Ataxia Telangiectasia, Cockayne syn.) • Energy metabolism (Leigh syndrome, pyruvate dehydrogenase deficiency) • Fatty acid metabolism (Adrenoleukodystrophy, Refsums) - Other metabolic disorders (Abetalipoproteinaemia, Hartnups, MSUD)

28. Chronic Progressive Childhood Ataxias 3 Spino-cerebellar degenerations • Hereditary Spinocerebellar degeneration - Autosomal recessive (Friedreichs ataxia, Cockayne, Behr syn.) - Autosomal dominant (SCA types 5 & 7, episodic ataxias) - X-linked • Spinocerebellar Leukodystrophies • Progressive myoclonic epilepsy

29. Friedreich’s Ataxia • Chronic progressive childhood ataxia • Hereditary spinocerebellar ataxia • Autosomal recessive : chromosome 9q13-q21 • Mutant gene (frataxin) contains expanded • GAA triplet repeats • Dying back neuropathy of the long ascending & • descending tracts of the spinal cord • Diagnostic Criteria • - onset before 20 years • - autosomal recessive inheritance • - combined involvement : peripheral nerves • cerebellar tracts • pyramidal tracts • posterior columns

30. Friedreich’s Ataxia CNS Clinical Features : (variable) Cerebellar • Progressive Ataxia (2-16years, more marked in legs, wide based gait) • Progressive cerebellar speech • Titubation • Nystagmus Corticospinal • Weakness & distal wasting calf and hand muscles • Positive Babinski reflex • Absent knee & ankle reflexes (may be present initially) Posterior column • Vibratory & proprioception loss • Positive Romberg test Peripheral nerves • Distal sensory loss

31. Friedreich’s Ataxia Associated Clinical Features : • Talipes-equino-varus • Pes cavus (early onset/birth) • Claw hand deformity • Spastic bladder • Cranial nerve involvement • Kyphoscoliosis • Cardiomyopathies – common, HOCM, progression to intractable CCF • Arrhythmias • Diabetes (abnormal glucose tolerance and insulin resistance) Prognosis: (variable) • Most wheelchair bound by mid-twenties • Disease may become static and survival into sixties is possible • Mortality from CMO and respiratory problems 2° to severe scoliosis

32. Ataxia Telangiectasia • Chronic progressive childhood ataxia • Autosomal recessive - Chromosome 11q22-q23 • Defect of DNA repair • Pathology = degeneration of cerebellar cortex, demyelination of posterior columns, spinocerebellar tracts & peripheral nerves, degeneration of posterior roots, sympathetic ganglia & AHC and loss of pigmentary cells substantia nigra, locus cereus, oculomotor complex, hypothalamus.

33. Ataxia Telangiectasia • Clinical features: • - Progressive ataxia- Abnormal eye movements • - Dystonic posturing hands & feet • - Facial grimacing / slow spreading smile • - Choreoathetosis- Cerebellar speech • - Oculocutaneous telangiectasia- Intellectual fall off- Immune abnormalities • - Increased incidence of malignancies

34. Ataxia Telangiectasia • Ataxia -Onset at 2-4 years, progresssive - Awkwardness - Initially truncal • Oculomotor apraxia - Impaired upward gaze - Concomitant eye blinking - Poor saccadic eye movements - Jerking head movements • Telangiectasia - Onset 2-6 years - Bulbar conjunctivae - Ears, neck, antecubital & popliteal fossae • Skin - Café-au-lait spots, vitiligo - Sclerodermoid changes

35. Ataxia Telangiectasia • Immune deficiency: - Cellular (thymic hypoplasia,  tonsils, adenoids, spleen, lymph nodes, lymphopaenia) - Humoral ( synthesis immunoglobulins with recurrent sinopulmonary infections with bronchiectasis)  IgG, IgA, IgE  IgM • Other clinical features - Mild polyneuropathy - Hypotonia, reduced reflexes -  Muscle bulk & weakness - Intellectual fall off - Defect in DNA repair, sensitivity to ionising radiation, increased risk of malignancy especially ALL/gliomas.

36. Ataxia Telangiectasia Associations: - Mental handicap in 1/3 cases - Hypogonadism - Hepatic dysfunction - Insulin resistance Management: - No specific treatment - Prompt Rx sinopulmonary infections to avoid bronchiectasis - Avoid exposure to radiation Investigations: - Chromosomes - Immunoglobulins ( IgG, IgA, IgE  IgM) • Other – increased AFP, CEA Prognosis: - Wheelchair bound by 10 -15 years of age - 60% mortality by 3rd decade (infections, lymphoreticular malignancy)