SEMINAR -SEP 29/2006
• CEREBELLAR DISEASES
• 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
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
• Fastgial nucleus,nucleus globose, nucleus emboli form
and dentate (lateral cerebellar) nucleus.
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
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
- Each nucleus controls a different type of mode of
• inferior and superior cerebellar peduncles are afferents and efferents.
• Inferior cerebellar peduncle connects cerebellum to medulla oblongata.
dorsal spinocerbellar tract (T1-L2) , cuneocerebellar tract ,
vestibulocerbillar tract , reticulo cerebellar tract , trigeminocerebellar tract
Middle cerebellar pudncle:cotcopontocerebellar tracts
Superior cerebellar pud-cerebellum to midbrain
CLINICAL MANIFSTATIONS OF CEREBELLAR DYSFUNCTION
- accompanies acute, less often in chronic
- more noticeable in the upper limbs- proximal muscles
- decreased resistance to passive stretch of muscles
- Occurs in neocerebellar lesions.
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
- ataxia may affect limbs, trunk, gait, may be acute onset
,episodic or progressive - ataxia includes asynergia
(dysdiadokinesia, past pointing, excessive rebound
- 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
abnormality in articulation and prosody
described as scanning, slurring, staccato,
explosive, hesistant, garbled.
specially lesion of dentate nucleus gives
kinetic (intention) tremor. because intrupt
static (postral) tremor also may ccur.
• gaze evoked, upbeat, rebound
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
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
• - 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.
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
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,
Chronic symmetric inherited ataxia metabolic
disorder hypothyroidism, chronic infections
acute focal- ischemic infarction, cerebellar
- 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
- 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)
Focal and and Progressive Signs
SymmetricIpsilateral Cerebellar Signs
Acute (Hours to Subacute (Days to Chronic (Months to Acute (Hours to Subacute (Days to Chronic (Months to
Days) Weeks) Years) Days) Weeks) Years)
Intoxication: alcohol, Intoxication: Paraneoplastic Vascular: cerebellar Neoplastic: cerebellar Stable gliosis
lithium, mercury, solvents, syndrome infarction, glioma or metastatic secondary to vascular
diphenylhydantoin, gasoline, glue; Anti-gliadin antibody hemorrhage, or tumor (positive for lesion or
barbiturates (positive cytotoxic syndrome subdural hematoma neoplasm on demyelinating plaque
history and chemotherapeutic Hypothyroidism Infectious: cerebellar MRI/CT) (stable lesion on
toxicology screen) drugs Inherited diseases abscess (positive Demyelinating: MRI/CT older than
Acute viral Alcoholic-nutritional Tabes dorsalis mass lesion on multiple sclerosis several months)
cerebellitis (CSF (vitamin B1 and B12 (tertiary syphilis) MRI/CT, positive (history, CSF, and Congenital lesion:
supportive of acute deficiency) Phenytoin toxicity history in support of MRI are consistent) Chiari or Dandy-
viral infection) Lyme disease lesion) AIDS-related Walker
Postinfection multifocal malformations
syndrome leukoencephalopathy (malformation noted
(positive HIV test on MRI/CT)
and CD4+ cell count
Abbreviations: CSF, cerebrospinal fluid; CT, computed tomography; MRI, magnetic resonance imaging.
- result of insult to the cerebellum and its connecting pathways.
- - Acquired, Inherited, Sporadic ataxia
• - 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
Hypoxia damages Purkinje cells-ataxi ,myoclonus may result
Hyperthermia damage purknije cells
Hyperammonia in child
Wilsons dx-tremor,dystonia; Rx is copper restriction ,chelation
-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)
- Adverse effect of 5- FU (used in breast and GI
- Conventional dose of 5-FV may cause cerebellar
ataxia if there is an abnormality of pyrimidine
- 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.
Organic mercury contamination from
mercury -containg fungicides.
- Mercury toxic cerebellar granule cells and
- causes parasthesia, ataxia, restricted visual
Manganese- Parkinson + ataxia
Bismuth- gait ataxia, confusion. mycoclonus
- chronic solvents abuse (esp. toluene)
- spray paint
- paint thinners
- 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
- avoid phenytoin in an epileptic patient if ataxia
/cerebellar atrophy present.
• 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
- Many neurologic syndrome - ataxia
- Most pts have focal lesions, like
lymphoma, chronic meningeal
infection, PML or toxoplasmosis.
- 30% ADC - have ataxia prior
- MRI - cerebellar atrophy
- Pathology - marked granule cell
- 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
- 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
• 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
MRI- typically-cerebellar atrophy and high density signal in deep
CSF- mononuclear pleocytosis and oligoclonal bands.
The syndrome results from autoimmune process triggered by the
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.
Ataxia with Gluten Sensitivity
• Seen as neurological complication in celiac disease 68% had
• 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.
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
• In some lipid malabsorption eg. In cystic fibrosis,cholestatic dx
• - clinical feature other CNS involvement CSF findings
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%)
• 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.
• notorious for paucity and variability of signs,may present with
• infections are in or near adjacent structures(OM,mastoditis)
• Autosomal dominant, autosomal recessive or maternal (mitochondrial)
• 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
Autosomal Dominant Ataxia
• - Onset usually in 3rd - 5th decade but variable onset of
• - 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.
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
- 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.
Imaging and other lab studies in dominat
• 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
Neuropathology: SCA1, SCA2, SCA7 wide spread
pathology loss of Purkinje cells pontine neurons,
• +/- 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
• CAG repeats - polyglutamine disorders (ataxin
• Nuclear accumulation of these proteins (normally
• Ataxins with >40 glutamines toxic to the neurons.
• EA1 –potassium channel gene mutation on
• EA2-calcium channel mutaton on chromosmome
• In some chromosomes or the loci not known
Autosomal Recessive Ataxia
• Most common form of inherited ataxia
• Most of disease begin in childhood or early
• 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.
Some of autosomal recessive ataxia
Ataxia with isolated vit E deficiency
ARA of Charlovox-Sanguenay
• 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
• ECG abnormality and HCMP- 50% pts,
• Diabetis (10-20%)- insulin resistance and B cell dysfunction,
• skeletal and spinal deformity common. pescavus, pes equinovarus,
• 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.
• 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)
presence expanded GAA sequence-
reduced transcription and translational efficiency
leading to partial deficiency of the protein
• the exact function of ftataxin not clear- is
mitochondrial iron availability heme synthesis.
• 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
• 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
• Each mitochondrion contains several copies of circular
• mtDNA –small and encodes 13 proteins component of
respiratory chain in oxidative phosphorylation& ATP
• 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
• Clinical spectrum involves cardiomyophathy and
Sporadic/ Idiopathic Ataxia
• No primary cause known or no gene
• Progressive cerebellar ataxia resemble IA
• Etiopathogenesis not well known
• Dx is by exclusion of other genetic or
Eg.sporadic cortical cerebellar atrophy
spradic ataxia with added noncerebellar
Most important goal in management of Pts with
ataxia is to identify treatable disease entities;
Mass lesions should be ruled out and treated
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
A number of single case reports improvement after
tumor removal, plasma exchange, IVIG,
cyclophosphamide or glucocoticoids.
• 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)
• Avoid Exposure to metals or chemotherapy
• Gluten free diet
• Vit E therapy.
• Vit B1 and Vit B12 Supplementation in
• Replace hypothyroidism.
• CSF VDRL (CNS syphilis) Rx
• Ab titer to Leigionella and Lyme- appropriate
• Surgery-thalamic stimulation for tremer and brain
• chemotherapy and radiation for other neoplasms
• Chelating agents,hemodialysis
• THANK YOU!!