NEUROLOGY SUBSPECIALTY SEMINAR -SEP 29/2006

1. NEUROLOGY SUBSPECIALTY SEMINAR -SEP 29/2006

2. CEREBELLAR DISEASES

3. ANATOMY • Derived from the somatic afferent portion of the alar plate • acts as a monitor or modulator of motor activity "originating" in other brain centers. • One of the major cerebellar functions is automatic excitation of antagonist muscles at the end of a movement with simultaneous inhibition of the agonist muscles that initiated the movement. • cerebellum is located in the posterior fossa of the skull, dorsal to pons and medulla oblongata and separated from the occipital lobes by the tentorium cerebelli. • On coronal planes has two portions the midline, vermis and cerebellar hemispheres. • vermis - older- receives mainly spinocerebellar afferents • Hemispheres have more complex fiber connections

4. Histologically. the cerebellar cortex has 3 layers: • the outer - molecular layer , the middle - Purkinje cell layer , the inner most - granule cell layer • - five cell types are distributed in these layers outer basket cell and inner stellate cells in the molecular layer: purkinjie cells arranged in a single row , granule and Golgi cells in granule cell layer • - The white matter of the cerebellum is made up of intrinsic, afferent, and efferent fibers. • - 4 pairs of nuclei on each side of the midline with in the white matter core of the cerebellum receive input from the cerebellar cortex and incoming afferents and cerebellar efferent. • Fastgial nucleus,nucleus globose, nucleus emboli form and dentate (lateral cerebellar) nucleus.

5. considering connections of these nuclie and sagital organization, the cerebellum can be divided longitudinally • a) midline (vermal ) zone - contain cerebellar neurons projecting to the fastigial nucleus. Abnormal stance,gait,truncal titubation,disturbance of extraoccular movement • b) an intermediate (paravermal) zone contain neuron projecting to the nucleus interposed • c) the lateral (hemisphere) zone contain neuron projecting to the dentate nucleus. Similar Sx plus decomposition of movement,dysdiaokinesia,dysarthria,tremer,hypotonia,excessive rebound - Each nucleus controls a different type of mode of movements.

6. connections • inferior and superior cerebellar peduncles are afferents and efferents. • Inferior cerebellar peduncle connects cerebellum to medulla oblongata. afferents • dorsal spinocerbellar tract (T1-L2) , cuneocerebellar tract , vestibulocerbillar tract , reticulo cerebellar tract , trigeminocerebellar tract Efferent :fastigiobulbar,cerebelloreticular, Middle cerebellar pudncle:cotcopontocerebellar tracts Superior cerebellar pud-cerebellum to midbrain mainly efferents

7. CLINICAL MANIFSTATIONS OF CEREBELLAR DYSFUNCTION Hypotonia • - accompanies acute, less often in chronic • - ipsilateral • - more noticeable in the upper limbs- proximal muscles • - decreased resistance to passive stretch of muscles • - Occurs in neocerebellar lesions.

8. Ataxia or Dystaxia • - result from defective timing of sequential contractions of agonist and antagonist muscles. • - due to disturbance in the smooth performance of voluntary motor acts. • - movements errantic in speed, range, force, and timing • - due to absence of cerbellar inhibitory and modulating influences. • - ataxia may affect limbs, trunk, gait, may be acute onset ,episodic or progressive - ataxia includes asynergia (dysdiadokinesia, past pointing, excessive rebound phenomenon. • - Wide based stance and gait characterized by staggering and impaired tandem walking. • - Truncal instability -falls in any directions. • - Titubation or truncal ataxia suggest midline cerebella lesion

9. cerebellar dysarthria • abnormality in articulation and prosody • described as scanning, slurring, staccato, explosive, hesistant, garbled. Tremor • specially lesion of dentate nucleus gives kinetic (intention) tremor. because intrupt rubro-olivo-cerebellar circuit • static (postral) tremor also may ccur. Nystagmus • frequently • gaze evoked, upbeat, rebound nystagmus

10. Nonmotor manifestations. • cerebellar cognitive affective syndrome- characterized by impaired executive functioning, personality changes associated with blunted affect or disinherited and inappropriate behavior , visuospatial disorganization, impaired visual-spatial memory, mild anomia, agrammatism and dysprosodia • macrographia

11. Rostral vermis syndrome • - Wide based stance and gait • - ataxia of gait- little ataxia on heel to shin manuever • - Normal or only slightly impaired arm coordination • - Infrequent presence of hypotonia, nustagmus, and dysarthria. in chronic alcoholic patients. • - remarkable purikinje cell loss caudal vermis syndrome • - axial disequilibrium and staggering gait, • - little or no limb ataxia, • - spontaneous nystagmus and rotated postures or head. • - seen in damage of flocculondular lobe especially medulloblastoma in children as it grows superimposed neocerebellum cerbellar hemispheric syndrome • - typically incoordination of ipsilateral appendicular movements. • - affects muscles involved in speech and finger movements etiologies- in farcts, neoplasm and abscess pancerbellar syndrome • - combination of all other cerebellar syndromes • - characterized by bilateral signs of cerebellar dysfunction affecting the trunck, limbs, and cranial musculature. • etilogy - ifections, parainfections, hypogycemia, hyperthermia, paraneoplastic disorders, toxic metabolic disorder.

12. APPROACH TO PATIENTS WITH ATAXIC DISORDERS • Careful Hx/P/E accurate Dx and appropriate Mx • Age of onset • Tempo of progression,associated neurologic and systemic signs • Family Hx,ethinic origin, country • True cerebellar ataxia Vs ataxia associated with vestibular or labyrinthine disease- associated with dizziness or vertigo , sensory disturbance (Roberg sign) • Rate and pattern of development of cerebellar symptoms help to narrow ddx • Gradual, progressive, bilateral, symmetric - Biochemical, metabolic, immune, or toxic etiology. • Focal, unilateral Sx with headache and impaired level of consciousness with ipisilateral cranial nerve palsy and cotralateral weakness imply a space-occupying cerebellar lesion.

13. symmetric ataxia • progressive, symmetiric reclassified with respect to onset as acute (over hours or days) subacute (weeks or months) or chronic (months of yrs.) • acute /Reversible ataxia intoxication with alcohol, phenytoin, lithium, barbiturates. • subacute degeneration of cerebellar vermis due to combined effect of alcoholism and malnutrition. deficiency of B1 and B12 vitamins, hyponatremia ,paraneoplastic, CJD, • Chronic symmetric inherited ataxia metabolic disorder hypothyroidism, chronic infections meningovascular syphilis

14. Focal ataxia • acute focal- ischemic infarction, cerebellar hemorrhage • - ipsilateral to the injury • - may be associated with impaired level of consciousness due to BS compression or ↑ ICP • ipsilateral pontine sugns (CN, VI and VII palsy) • - posterior fossa subdural hematoma, bacterial abcess, primary or metastatic cerebellar tumor. • - CT or MRI • - most true neurologic emergencies / sudden herniation • - acute surgical decompression may be required • - acute or subacute focal cerebellar syndrome in AIDS are lymphoma or PML. • - chronic focal - MS, Chiari malfo, congenital cyst of posterior fossa (Dandy -Walker syndrome)

15. Symmetric and Progressive Signs Focal and Ipsilateral Cerebellar Signs

16. INVESTIGATION • CBC • ESR,U/A,CXR, • CSF- protein,VDRL,oligoclonal,PCR,culture,cytology, • Serology-HIV,toxo,AntiYo,Ri,Hu,GAD,gladian Chemistry:OFT,TFT,Parathyroid,RBS,electrolyte,Vitamins,special test • Toxicology-matals,drugs(blood,urine) • ECG,ECHO,NCS • IMAGING-CT,MRI,U/S, • Genetics

17. CEREBELLAR ATAXIAS • result of insult to the cerebellum and its connecting pathways. • - Acquired, Inherited, Sporadic ataxia Acquired ataxias • - In many progressive ataxia result from environmental insults Hypothyroidism - occasionally -mild gait ataxia in conjunction with • - its systemic symptoms • - TFT needed in patient with progressive ataxia • Dx - clinical + TFT • Rx replacement Hypoparathyroidism Hypoglycemia Hypoxia damages Purkinje cells-ataxi ,myoclonus may result Hyperthermia damage purknije cells Hyperammonia in child Wilsons dx-tremor,dystonia; Rx is copper restriction ,chelation

18. Toxic Alcohol- -The major exogenous agent causing ataxia significant proportion f alcoholics have midline cerebellar degeneration at autopsy. - characterized by progressive gait disturbance of a cerebellar type with little in the way of upper limb ataxia, speech difficulties, or eye movements abnormalities (relative sparing of cerebellar hemispheres - Imaging- typical vermial atrophy. -Chronic alcoholism - significant cerebellar atrophy (1% severe alcoholics)

19. Chemotherapy - Adverse effect of 5- FU (used in breast and GI cancer) - Conventional dose of 5-FV may cause cerebellar ataxia if there is an abnormality of pyrimidine dehydrogenase deficiency. - Higher dose 5-FU - pancerebellar syndrome (acute or sub acute coarse) - cytosine arabinoside in high dose ( 3 gm/m2 for 8-12 doses- conventional dose 1000-2000 mg/m2 for 5-7 days) significant pts develop cerebellar syndrome. Pathologically characterized by loss of Purkinje cells, gliosis , loss of dentate neurons, and spongiform changes.

20. Metals Organic mercury contamination from mercury -containg fungicides. - Mercury toxic cerebellar granule cells and visual cortex. - causes parasthesia, ataxia, restricted visual field. Manganese- Parkinson + ataxia Bismuth- gait ataxia, confusion. mycoclonus Solvents - chronic solvents abuse (esp. toluene) - spray paint - paint thinners

21. Anticonvulsants - Issue of cerebellar atrophy and anticonvulsant (phenytoin) is controversial. - Transient cerebellar signs in supratherapetic dose many anticonvulsants seen. - Persistent ataxia and purkinje cell loss seen prolonged phenytoin use - Pathogenesis is unclear - Hypothesis direct toxic effect of phenytoin, a result of repeated hypoxia related seizures, the effect of seizure related electrical discharge on cerebellar Purkinje cells. - avoid phenytoin in an epileptic patient if ataxia /cerebellar atrophy present.

22. Infections • may be feature of post infectious encephalomyelitis but usually accompanies more diffuse cerebral process. • In children restricted cerebellar syndromes seen when acute ataxic disorder that is not associated with a more diffuse process reflected by seizures, meningismus or obtundation. • In most children preceded by a non specific viral syndrome or varicella-peak incidence 5-6yr. • similar picture from EBV in teenage years. • Dx CSF protein elevation and modest mononuclear pleocytosis and MRI -signal density changes in the cerebellum. • Px - excellent. • Brain stem encephalitis - ataxia ophtalmoplegia and other lower cranial nerve palsies- resemble MFS of GBS

23. HIV - Many neurologic syndrome - ataxia - Most pts have focal lesions, like lymphoma, chronic meningeal infection, PML or toxoplasmosis. - 30% ADC - have ataxia prior dementia - MRI - cerebellar atrophy - Pathology - marked granule cell loss.

24. CJD - progressive ataxia. • Rapidly progressive dementing illness. - Due to accumulation of mutant prion protein (result from post translational modification of normal prion protein) • Among CJD - 17% early ataxia 60% cerebellar pathology at autopsy. • Upper motor neuron signs are common, - myclonus -25% and dementia evolves late. - Survival 7wk - 8 years - Pathological- cerebellum shows striking granule cell loss - Dx - protein 14-3-3 in CSF and coden 29 homozygosisty tall-by ELISA

25. Autoimmune causes of ataxia Paraneoplastic cerebellar degeneration syndrome • that reaches its nadir with in a few months of onset. • Produces severe ataxia wit dysarthria and oscillopsia, diplopia, vertigo other neurologic sn-dementia, extra pyramidal signs, hearing loss, dysphagia. • MRI- typically-cerebellar atrophy and high density signal in deep white matter. • CSF- mononuclear pleocytosis and oligoclonal bands. • The syndrome results from autoimmune process triggered by the cancer. • Anti Yo in ovarian ca • Anti-Hu. Ab. in SCLC. • Purkinjec cell degeneration in 25 % with Anti.Hu.Ab. • Anti Ri Ab - truncal ataxia and opsoclonus in breast cancer.

26. Ataxia with Gluten Sensitivity • Seen as neurological complication in celiac disease 68% had antigliadin Ab. • Slowly progressing ataxia associated with brisk tendon reflexes, peripheral neuropathy, cognitive changes, mycolonus. • Pathology - cerebellar Purkinje cell loss, infiltration by Tcell lymphocyte, posterior column degeneration • Variable proportion show celiac sprue on duodenal Bx. • Whether gluten -free diet or other immunomodulation will improve gliadin Ab- associated ataxia is unclear.

27. Ataxia and antiglutamate decarboxylase antibodies. • - Recently reported Anti GAD in progressive ataxia. • - Usually middle aged women - associated with peripheral neuropathy, slow saccades, stiff- person syndrome. • - Many pts had multiple organ specific Ab including Ab to thyroid cell, pancreatic islet cell, • Abs are seen in higher titers in adult onset diabetes and cerebellar purkinje cells. Nutritional vit E deficiency • Rare • In some lipid malabsorption eg. In cystic fibrosis,cholestatic dx Demyelinating (ms) • - clinical feature other CNS involvement CSF findings

28. Vascular • Lesions –cerebellum or pathways • Infarction - thrombotic or embolic occlusion of cerbellar vessels • clinical manifestation depends on specific vessels involved and extent of collateral circulation • main symptoms vertigo dizziness, nausea, vomitting gait unsteadiness, limb clumsiness, headache dysarthria, diplopia and decreased alertness, nystagmus. • 2 clinical syndromes - cerebellar infarcts with fourth ventricular and brainstem compression and those without. • Large cerebellar infarcts - cause brainstem compression with onset of occipital headache, vertigo, nausea, vomiting gait, and dysarthria impaired consciousness. Obstructive hydrocephalus, upward or down ward hernia tion. • small (border zone) infarcts specific boundaries causes cardiac arrest4% atheroma or hypercoagulable 20% focal cerebellar hypo perfusion occlusion of vertebrobasilar occlusive disease (34%), brain embolism (23%)

29. Mass lesions • Most common is hemorrhage near dentate nucleus in HTN,edema in large infarct, tumors in children-medduloblastoma, astrocytoma, ependymoma and Adults,-Metastasis of tumor, hemangioblastoma, abscess, tuberculomas,other granulomas, toxoplasmosis • Cerebellar hemorrhages with headache,nausae,vomitting,gait ataxia,vertigo are common but variable. • are emergency devastating. Abscesses • notorious for paucity and variability of signs,may present with headache alone • infections are in or near adjacent structures(OM,mastoditis) • Hydrocephalus

30. INHERITED ATAXIAS • Autosomal dominant, autosomal recessive or maternal (mitochondrial) modes • Genomic classification superseded the previous clinical expression based • Even though cerebellar manifestations dominate, changes may occur in BS, SC, optic nerves, retina and peripheral nerves. • So manifestations range from purely cerebellar to mixed syndromes of these structural abnormalities. Rarely dementia. • Homogenous in dominantly inherited family but different phenotypes may occur

31. Autosomal Dominant Ataxia • - Onset usually in 3rd - 5th decade but variable onset of age. • - Disease occurs in each generation of the pedigree, the offspring of affected parents 50% risk. • - The progressive dominant ataxias are labeled SCA, followed by a number to denote the chromosomal locus. • Some differently named are MJD(SCA3), DRPLA (Dentatorubropallidolusysian atrophy),Episodic ataxias (EA1, and EA2) • - Absence of Sx in either parents is rare. • But possible because early onset in child and late in parent, death of parent early, wrong paternity.

32. Clinical Features of Dominant Ataxia • Overall have overlapping clinical features. • Genetic study is gold standard for Dx & classification - Gradually progressive ataxia associated with an array of cerebellar signs forms the core features of the Dx. - ataxic gait, dysmetria, dysdiadokinesia, dysarhria, abnormal persuit and inaccurate saccades of the eyes, nystagmus. - Many, not all Dx are associated with clinical signs referable to pathology in CNS structures. - Occulomotor abnormality - ptosis, gaze palsy, blepharospasm - some- bulbar deficts- facial atrophy, facial fasciculation, toungue atrophy and fasciculation, unable to cough. - UMN sign - DTR, spasticity, Babniski sign - Extrapyramidal sign- akinetic rigidity, chorea, athetosis, dystonia - PN- distal sensory loss and DTR , amyotrophy - In some cognitive decline and seizure, retinal disease and visual loss. - loss of ambulation over 10-15 yrs.

33. Imaging and other lab studies in dominat Ataxia • MRI/CT - to exclude many disorders causing ataxia - stroke, tumors, ms • atrophy of cerebellum, +/- atrophy of pons, medulla, middle cerebellar peduncles, and upper cervical cord. • Hyperintensity of middle cerebellar atrophy and SCA6 isolated cerebellar atrophy • NCS -axonal polyneuropathy

35. Neuropathology: SCA1, SCA2, SCA7 wide spread pathology loss of Purkinje cells pontine neurons, olivary neruons. • +/- dorsal root ganglion cell, cranial and LMN and tracts may be affected. • Both unstable expansions of repeated nucleotide sequences and point mutations seen (CAG repeats inherited in heterozygous fashion) • CAG encodes for glutamine - polyglutamine protein

36. Pathogenesis. • CAG repeats - polyglutamine disorders (ataxin proteins) • Nuclear accumulation of these proteins (normally in cytoplasm) • Ataxins with >40 glutamines toxic to the neurons. • Ataxin1,2,3,7,atrophin • EA1 –potassium channel gene mutation on chromsome 12 • EA2-calcium channel mutaton on chromosmome 19 • In some chromosomes or the loci not known

37. Autosomal Recessive Ataxia • Most common form of inherited ataxia (50%) • Most of disease begin in childhood or early adult life. • Late onset possible • Singleton pt- may occur in families. • Typically parents don't manifest any Sx because they are heterozygous for mutation. • Affects both males and females.

38. Some of autosomal recessive ataxia • Frederich’s ataxia • Ataxia telangectasia • Ataxia with isolated vit E deficiency • Abetalipoproteinemia • ARA of Charlovox-Sanguenay

39. Friendreich's Ataxia • Clinicla Features; prevalence 2/100,000 . • Age of onset <25 yr. typically early adolescent. • Onset ↑ing gait difficulty, gait ataxia, loss of proprioceptive sense in lower limbs, absent DTR (generalized or lower limb) because early involvement of dorsal root ganglion cell, dysarthria, UMN sign. • Pts loose ambulation by 9-15 yrs after onset. (at this stage increasing ataxia in both upper and lower extremities profound proprioceptive loss, areflexia, weakness of lower limb muscles, dystonia ,flexor spasm and increasing dysarthria, dysphagia. Optic athrophy, hearing loss in many

40. ECG abnormality and HCMP- 50% pts, • Diabetis (10-20%)- insulin resistance and B cell dysfunction, • skeletal and spinal deformity common. pescavus, pes equinovarus, scoliosis • Mean age at death 4th decade (cause- cardiac/ respiratory) • NCS early absence or reduction of sensory nerve potentials in diffuse fashion reflecting loss of large sensory axons of PN • Sural nerve Bx loss of myelinated fibers. • MRI upper cervical spinal cord atrophy nonmal cerebellum • Pathology- loss of Dorsal root ganglion cell, - degeneration of dorsal column, -degeneration of spinocerebellar and corticospinal tracts, -loss of dentate nuclei in cerebellum.

42. Mutation in FA is unstable expansion of a repeated trinucleotide(GAA) sequence within the first intron of the gene X25 on chromosome 9 • or point mutation of the gene (5% heterozygous) • Pathogenesis presence expanded GAA sequence- reduced transcription and translational efficiency leading to partial deficiency of the protein frataxin. • the exact function of ftataxin not clear- is mitochondrial iron availability heme synthesis.

43. Ataxia Telangiectasia • 3 in million frequency • Sx/Sn- Present in the first decade of life with progressive telangiectatic lesions associated with deficits in cerebellar function and nystagmus • neurologic manifestations correspond to FA so ddx. • High incidence of pulmonary infections and lymphatic and RES neoplasms. • Thymic hypoplasia (Cellular and humoral immunodefinciency) • Premature aging, endocrine disorders type 1 Dm. • Increased incidence of lymphomas, HD ,acute leukemias of T-cells, and breast cancer. • Most striking neurologic change: - loss of purkingje, granule and basket cells in the cortex and neurons in the deep cerebellar nuclei, neuronal loss in olive, loss of anterior horn cells, dorsal root ganglion. • Gene- ATM gene mutation product protein may result in DNA damage

44. Mitochondrial Ataxias. • Each mitochondrion contains several copies of circular chromosomes • mtDNA –small and encodes 13 proteins component of respiratory chain in oxidative phosphorylation& ATP generation • Mt genome inherited maternally • 30 pathogenic mtDNA point mutations and 60 different types of mtDNA deletions are known, several of which cause or are associated with ataxia • Alterations result in reduction in ATP supply,free radical production,apoptosis • Clinical spectrum involves cardiomyophathy and enchephalopathy

45. Sporadic/ Idiopathic Ataxia • No primary cause known or no gene identified • Progressive cerebellar ataxia resemble IA • Etiopathogenesis not well known • Dx is by exclusion of other genetic or acquired ataxias Eg.sporadic cortical cerebellar atrophy spradic ataxia with added noncerebellar deficits

46. Treatments • Most important goal in management of Pts with ataxia is to identify treatable disease entities; • Mass lesions should be ruled out and treated appropriately. • Paraneoplastic disorders can often be identified by the clinical patterns of the disease that they produce ,measurements of specific autoantibody and uncovering the primary cancer. (Usually refractory but some may respond to tumor removal or chemotherapy) • A number of single case reports improvement after tumor removal, plasma exchange, IVIG, cyclophosphamide or glucocoticoids.

47. Avoid phenytoin and alcohol. • No proven therapy for autosomal dominant ataxia (SCA1 - 22 ) - Preliminary evidences that idebenone a free radical scavenger, can improve myocardial hypertrophy in pts with classic FA. (Not known whether improves neuropathy) • Anticholinergic,serotoninergics,GABAergic tried but not effective • Acetazolamide - reduce the duration of Sx of episodic ataxia • Identifying at risk person's genotype together with appropriate family and genetic counseling can reduce the incidence of these cerebellar syndromes in future generations. • Supportive care of patients with FA include adequate rehabilitation efforts aimed at mobility using appropriate device and Monitoring and caring of the systemic complications are also important. (Skeletal deformty, cardiomyopathy, and dialetes)

48. Avoid Exposure to metals or chemotherapy • Gluten free diet • Vit E therapy. • Vit B1 and Vit B12 Supplementation in deficiencies • Replace hypothyroidism. • CSF VDRL (CNS syphilis) Rx • Ab titer to Leigionella and Lyme- appropriate Antibiotics • Surgery-thalamic stimulation for tremer and brain tumor • chemotherapy and radiation for other neoplasms • Chelating agents,hemodialysis

49. THANK YOU!!