cerebellar diseases (1)

8/7/2019 Cerebellar Diseases (1)

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NEUROLOGY SUBSPECIALTY

SEMINAR -SEP 29/2006


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CEREBELLAR DISEASES


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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 movementwith simultaneous inhibition of the agonist muscles thatinitiated the movement.

cerebellum is located in the posterior fossa of the skull,

dorsal to pons and medulla oblongata and separated fromthe occipital lobes by the tentorium cerebelli.

On coronal planes has two portions the midline, vermisand cerebellar hemispheres.

vermis - older- receives mainly spinocerebellar afferents

Hemispheres have more complex fiber connections


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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 molecularlayer: purkinjie cells arranged in a single row , granule

and Golgi cells in granule cell layer

- The white matter of the cerebellum is made up ofintrinsic, 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 cerebellarefferent.

Fastgial nucleus,nucleus globose, nucleus emboli formand dentate (lateral cerebellar) nucleus.


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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. Abnormalstance,gait,truncal titubation,disturbance of extraoccularmovement

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 ofmovement,dysdiaokinesia,dysarthria,tremer,hypotonia,excessiverebound

- Each nucleus controls a different type of mode ofmovements.


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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


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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.


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Ataxia or Dystaxia - result from defective timing of sequential contractions

of agonist and antagonist muscles. - due to disturbance in the smooth performance ofvoluntary motor acts.

- movements errantic in speed, range, force, and timing

- due to absence of cerbellar inhibitory and modulatinginfluences.

- ataxia may affect limbs, trunk, gait, may be acute onset,episodic or progressive - ataxia includes asynergia(dysdiadokinesia, past pointing, excessive reboundphenomenon.

- Wide based stance and gait characterized by staggeringand impaired tandem walking.

- Truncal instability -falls in any directions.

- Titubation or truncal ataxia suggest midline cerebellalesion


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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 intruptrubro-olivo-cerebellar circuit

static (postral) tremor also may ccur.

Nystagmus

frequently

gaze evoked, upbeat, reboundnystagmus


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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-spatialmemory, mild anomia, agrammatism anddysprosodia

macrographia


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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- infarcts, neoplasm and abscess

pancerbellar syndrome

- combination of all other cerebellar syndromes

- characterized by bilateral signs of cerebellar dysfunction affecting thetrunck, limbs, and cranial musculature.

etilogy - ifections, parainfections, hypogycemia, hyperthermia,paraneoplastic disorders, toxic metabolic disorder.


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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 orlabyrinthine disease- associated with dizziness or vertigo ,sensory disturbance (Roberg sign)

Rate and pattern of development of cerebellar symptoms helpto narrow ddx

Gradual, progressive, bilateral, symmetric - Biochemical,metabolic, immune, or toxic etiology.

Focal, unilateral Sx with headache and impaired level ofconsciousness with ipisilateral cranial nerve palsy andcotralateral weakness imply a space-occupying cerebellar

lesion.


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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 withalcohol, phenytoin, lithium, barbiturates.

subacute degeneration of cerebellar vermisdue to combined effect of alcoholism andmalnutrition. deficiency of B1 and B12vitamins, hyponatremia ,paraneoplastic,CJD,

Chronic symmetric inherited ataxia metabolicdisorder hypothyroidism, chronic infectionsmeningovascular syphilis


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Focal ataxiaacute focal- ischemic infarction, cerebellar

hemorrhage- ipsilateral to the injury

- may be associated with impaired level ofconsciousness due to BS compression or ICP

ipsilateral pontine sugns (CN, VI and VII palsy)

- posterior fossa subdural hematoma, bacterialabcess, primary or metastatic cerebellar tumor.

- CT or MRI

- most true neurologic emergencies / suddenherniation

- acute surgical decompression may be required

- acute or subacute focal cerebellar syndrome inAIDS are lymphoma or PML.

- chronic focal - MS, Chiari malfo, congenital cystof posterior fossa (Dandy -Walker syndrome)


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Symmetric and Progressive SignsFocal 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 B1

and B12

deficiency)

Lyme disease

Paraneoplastic

syndrome

Anti-gliadin antibodysyndrome

Hypothyroidism

Inherited diseases

Tabes dorsalis

(tertiary syphilis)

Phenytoin toxicity

Vascular: cerebellar

infarction,

hemorrhage, orsubdural hematoma

Infectious: cerebellar

abscess (positive

mass lesion on

MRI/CT, positive

history in support of

lesion)

Neoplastic: cerebellar

glioma or metastatic

tumor (positive forneoplasm on

MRI/CT)

Demyelinating:

multiple sclerosis

(history, CSF, and

MRI are consistent)

AIDS-related

multifocal

leukoencephalopathy(positive HIV test

and CD4+ cell count

for AIDS)

Stable gliosis

secondary to vascular

lesion ordemyelinating plaque

(stable lesion on

MRI/CT older than

several months)

Congenital lesion:

Chiari or Dandy-

Walker

malformations

(malformation notedon MRI/CT)

Abbreviations: CSF, cerebrospinal fluid; CT, computed tomography; MRI, magnetic resonance imaging.


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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


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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


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Toxic

Alcohol-

-The major exogenous agent causing ataxiasignificant proportion f alcoholics havemidline cerebellar degeneration at autopsy.

- characterized by progressive gaitdisturbance 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)


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Chemotherapy

- Adverse effect of 5- FU (used in breast and GIcancer)

- Conventional dose of 5-FV may cause cerebellarataxia if there is an abnormality of pyrimidinedehydrogenase deficiency.

- Higher dose 5-FU - pancerebellar syndrome(acute or sub acute coarse)

- cytosine arabinoside in high dose ( 3 gm/m2 for8-12 doses- conventional dose 1000-2000 mg/m2

for 5-7 days) significant pts develop cerebellarsyndrome. Pathologically characterized by loss ofPurkinje cells, gliosis , loss of dentate neurons,and spongiform changes.


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Metals

Organic mercury contamination frommercury -containg fungicides.

- Mercury toxic cerebellar granule cells andvisual cortex.

- causes parasthesia, ataxia, restricted visualfield.

Manganese- Parkinson + ataxiaBismuth- gait ataxia, confusion. mycoclonus

Solvents

- chronic solvents abuse (esp. toluene)

- spray paint

- paint thinners


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Anticonvulsants

- Issue of cerebellar atrophy and anticonvulsant

(phenytoin) is controversial.- Transient cerebellar signs in supratherapeticdose many anticonvulsants seen.

- Persistent ataxia and purkinje cell loss seenprolonged phenytoin use

- Pathogenesis is unclear - Hypothesis directtoxic effect of phenytoin, a result of repeatedhypoxia related seizures, the effect of seizurerelated electrical discharge on cerebellarPurkinje cells.

- avoid phenytoin in an epileptic patient if ataxia/cerebellar atrophy present.


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Infections

may be feature of post infectious encephalomyelitis butusually accompanies more diffuse cerebral process.

In children restricted cerebellar syndromes seen whenacute ataxic disorder that is not associated with a more diffuseprocess reflected by seizures, meningismus or obtundation.

In most children preceded by a non specific viral syndromeor varicella-peak incidence 5-6yr.

similar picture from EBV in teenage years.

Dx CSF protein elevation and modest mononuclearpleocytosis and MRI -signal density changes in the cerebellum.

Px - excellent.

Brain stem encephalitis - ataxia ophtalmoplegia and otherlower cranial nerve palsies- resemble MFS of GBS


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HIV

- Many neurologic syndrome - ataxia

- Most pts have focal lesions, likelymphoma, chronic meningealinfection, PML or toxoplasmosis.

- 30% ADC - have ataxia priordementia

- MRI - cerebellar atrophy

- Pathology - marked granule cellloss.


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CJD

- progressive ataxia.

- Rapidly progressive dementing illness.

- Due to accumulation of mutant prion protein (result frompost translational modification of normal prion protein)

- Among CJD - 17% early ataxia 60% cerebellar pathologyat 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 homozygosistytall-by ELISA


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Autoimmunecausesofataxia

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, hearingloss, dysphagia.

MRI- typically-cerebellar atrophy and high density signal in deepwhite 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.


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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 Tcelllymphocyte, posterior column degeneration

Variable proportion show celiac sprue on duodenal Bx.

Whether gluten -free diet or other immunomodulation willimprove gliadin Ab- associated ataxia is unclear.


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Ataxia and antiglutamate decarboxylase antibodies.

- Recently reported Anti GAD in progressive ataxia.

- Usually middle aged women - associated with peripheralneuropathy, slow saccades, stiff- person syndrome.

- Many pts had multiple organ specific Ab including Ab tothyroid cell, pancreatic islet cell,

Abs are seen in higher titers in adult onset diabetes andcerebellar purkinje cells.

Nutritionalvit E deficiency

Rare

In some lipid malabsorption eg. In cystic fibrosis,cholestatic dx

Demyelinating (ms)

- clinical feature other CNS involvement CSF findings


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Vascular Lesions cerebellum or pathways

Infarction - thrombotic or embolic occlusion of cerbellar vessels

clinical manifestation depends on specific vessels involved andextent of collateral circulation

main symptoms vertigo dizziness, nausea, vomitting gaitunsteadiness, limb clumsiness, headache dysarthria, diplopiaand decreased alertness, nystagmus.

2 clinical syndromes - cerebellar infarcts with fourthventricular and brainstem compression and those without.

Large cerebellar infarcts - cause brainstem compression withonset of occipital headache, vertigo, nausea, vomiting gait, anddysarthria impaired consciousness. Obstructivehydrocephalus, upward or down ward hernia tion.

small (border zone) infarcts specific boundaries causes cardiac

arrest4% atheroma or hypercoagulable 20% focal cerebellarhypo perfusion occlusion of vertebrobasilar occlusive disease(34%), brain embolism (23%)


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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 withheadache,nausae,vomitting,gait ataxia,vertigo arecommon but variable.

are emergency devastating.

Abscesses

notorious for paucity and variability of signs,may present withheadache alone

infections are in or near adjacent structures(OM,mastoditis)

Hydrocephalus


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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 ofthese structural abnormalities. Rarely dementia.

Homogenous in dominantly inherited family but different phenotypes mayoccur


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Autosomal Dominant Ataxia

- Onset usually in 3rd - 5th decade but variable onset of

age.

- Disease occurs in each generation of the pedigree, theoffspring 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 inparent, death of parent early, wrong paternity.


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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 formsthe core features of the Dx.

- ataxic gait, dysmetria, dysdiadokinesia, dysarhria, abnormal persuit andinaccurate saccades of the eyes, nystagmus.

- Many, not all Dx are associated with clinical signs referable to pathology in CNSstructures.

- Occulomotor abnormality - ptosis, gaze palsy, blepharospasm

- some- bulbar deficts- facial atrophy, facial fasciculation, toungue atrophy andfasciculation, 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.


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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


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Neuropathology: SCA1, SCA2, SCA7 wide spreadpathology 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 nucleotidesequences and point mutations seen (CAG repeatsinherited in heterozygous fashion)

CAG encodes for glutamine - polyglutamineprotein


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Pathogenesis.

CAG repeats - polyglutamine disorders (ataxinproteins)

Nuclear accumulation of these proteins (normallyin 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


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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 Sxbecause they are heterozygous for mutation.

Affects both males and females.


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Some of autosomal recessive ataxia

Frederichs ataxia

Ataxia telangectasia

Ataxia with isolated vit E deficiency

Abetalipoproteinemia

ARA of Charlovox-Sanguenay


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Friendreich'sAtaxia

Clinicla Features; prevalence 2/100,000 .

Age of onset


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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 diffusefashion 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.


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Mutation in FA is unstable expansion of arepeated 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 efficiencyleading to partial deficiency of the proteinfrataxin.

the exact function of ftataxin not clear- ismitochondrial iron availability heme synthesis.


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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 RESneoplasms.

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 andbasket 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


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MitochondrialAtaxias.

Each mitochondrion contains several copies of circular

chromosomes mtDNA small and encodes 13 proteins component of

respiratory chain in oxidative phosphorylation& ATPgeneration

Mt genome inherited maternally

30 pathogenic mtDNA point mutations and 60 differenttypes of mtDNA deletions are known, several of whichcause or are associated with ataxia

Alterations result in reduction in ATP supply,free radicalproduction,apoptosis

Clinical spectrum involves cardiomyophathy andenchephalopathy


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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


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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 anduncovering the primary cancer. (Usually refractorybut some may respond to tumor removal orchemotherapy)

A number of single case reports improvement aftertumor removal, plasma exchange, IVIG,cyclophosphamide or glucocoticoids.


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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 familyand 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 andcaring of the systemic complications are also important. (Skeletaldeformty, cardiomyopathy, and dialetes)


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Avoid Exposure to metals or chemotherapy

Gluten free diet

Vit E therapy.

Vit B1 and Vit B12 Supplementation indeficiencies

Replace hypothyroidism.

CSF VDRL (CNS syphilis) Rx Ab titer to Leigionella and Lyme- appropriate

Antibiotics

Surgery-thalamic stimulation for tremer and braintumor

chemotherapy and radiation for other neoplasms

Chelating agents,hemodialysis


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THANK YOU!!

cerebellar diseases (1)

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