movement disorders nov 2011

8/2/2019 Movement Disorders Nov 2011

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Movement disorders

Bogdan O. Popescu, MD, PhDAssistant Professor

Department of Neurology

University Hospital

Medical School Bucharest


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Lecture plan

Pathology of basal ganglia diseases

Symptoms of basal ganglia diseases

Huntingtons disease

Chorea of other types

Dystonia

Wilsons disease


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Pathology of basal ganglia diseases

Extrapyramidal syndrome first delineatedpathologically by S.A.K. Wilson, 1912

hepatolenticular degenerationbilateralsymmetrical degeneration of the putamen

Tretiakoff 1919cell loss in the SN in paralysis

agitans


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Clinicopathologic correlations ofextrapyramidal motor disorders

SYMPTOMS LOCATION OF LESIONS

Rigidity with rest tremor (PD) Substantia nigra plus other brainstemstructures

Hemiballismus and hemichorea STN or luysial-pallidal connections

Chronic chorea (HD) Caudate nucleus and putamen (corpusstriatum)

Athetosis and dystonia Caudate nucleus and putamen (corpusstriatum)

Cerebellar incoordination, intention tremor Cerebellar hemisphere (ipsi), medium or

inferior cerebellar peduncle

Decerebrate rigidity (extension of arms andlegs, opisthotonus)

Upper brainstem (midbrain - red nucleus)

Diffuse myoclonus Neuronal degeneration, usually diffuse orpredominating in cerebral or cerebellar

cortex


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Symptoms of basal ganglia diseases

Hypokinesia / bradykinesia

Disorders of posture and equilibrium

Rigidity and alterations in muscle tone

Involuntary movements in BG diseasesChorea

Athetosis

BallismusDystonia

Dyskinesia (encompasses all)


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Chorea

Greek word = dance Involuntary arrhythmic movements of a forcible, rapid,

jerky type

Movements may be simple or elaborate, of variabledistribution Movements are purposeless, but might be incorporated

into a deliberate act (exaggerated, bizarre character) Limbs are often hypotonic / knee jerks pendular Chorea differs from myoclonus:

speed of movements (myoclonic jerk faster) chorea is usually generalized / myoclonus affect individual

muscles or groups of muscles


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Diseases characterized by chorea Inherited disorders

Huntingtons disease (chromosome 4)

Benign hereditary chorea (chromosome 14) Neuroacanthocytosis Dentatorubropallidoluysian atrophy Wilsons disease

Rheumatic chorea(Sydenhams, chorea gravidarium)

Drug inducedchorea: Neuroleptics

Oral contraceptives Phenytoin Excess l-dopa and dopamine agonists Cocaine

Chorea symptomatic of systemic disease: Lupus erythematosus with antiphospholipid antibodies Thyrotoxicosis Polycythemia vera Hyperosmolar, nonketotic hyperglycemia AIDS Paraneoplastic syndromes

Hemichorea (rare): Stroke Tumor Vascular malformation


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Athetosis

Greek word = unfixed, changeable Inability to sustain fingers and toes, tongue or any part of the

body Posture interrupted by slow, sinuous, purposeless movements

Most pronounced in fingers, hands, face, tongue Flexion/extension of fingers, eversion/inversion of feet,

retraction/pursing of lips, twisting of neck Movements slower than in choreasometimes impossible to

separate them: choreoathetosis

Explanation: failure of basal ganglia to suppress the activity ofunwanted muscle groups

Combination of athetosis and chorea in all four limbs = cardinalfeature of HD


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Ballismus

Uncontrollable, poorly patterned, flingingmovement of the entire limb

Closely related to chorea and athetosis (frequentcoexistence)

Usually unilateral (hemiballismus) = acute lesion

of the contralateral STN (stroke, rarelydemyelinative)


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Dystonia

A persistent abnormal posture produced bycocontraction of agonist and antagonist muscles,placing the body segment in an unnaturalposition

Examples: overextension / overflexion of thehand, inversion of the foot, lateral flexion or

retroflexion of the head, torsion of the spine,frceful closure of the eyes


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Diseases characterized by dystonia Hereditary and degenerative dystonias

Huntingtons chorea

Dystonia musculorum deformans Juvenile dystonia-Parkinson syndrome (l-dopa responsive)

Parkinsons disease

Progressive supranuclear palsy

Drug-induced dystonia Neuroleptics

L-dopa excess in PD Symptomatic (secondary) dystonias Wilsons disease

Kernicterus

AIDS

Multiple sclerosis with spinal cord lesion

Basal ganglia calcificationFahrs disease

Toxic necrosis of lenticular nuclei (methanol) Idiopathic focal dystonias

Spasmodic torticollis Blepharospasm

Hemifacial spasm

Oromandibular dystonia

Spasmodic dysphonia Writers cramp and other occupational spasms


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Huntingtons disease

First symptoms of HDbetween ages 3545

Inexorably progressive, ultimately fataldegenerative disease (10-15 years total nursing

care)


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HD - pathogenesis

Pathology: generalized cerebral atrophy, especially of dorsalstriatum

Neurochemistry: marked deficiency of GABA and of glutamatedecarboxylase (enzyme involved in GABA synthesis)

Transmission: autosomal dominant with complete penetrance The gene: IT15 (huntingtin)end of the short arm of

chromosome 4 (4p16.3)contains CAG repeatscodes forglutamine

Healthy subjects: 11-34 CAG repeats, HD persons: > 40 repeats Paternal inheritance: associated with anticipation (not maternal)

Pathophysiological mechanismobscure: increased glutamatergictransmission / NMDA receptorsneuroexcitotoxicity

Now: a direct gene test on peripheral blood detects HD beforeonset of symptoms


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In hyperkinetic diseases suchas Huntington's, the projectionfrom the caudate and putamen to

the globus pallidus (externalsegment) is diminished (thinnerarrow). This effect increases thetonic inhibition from the globuspallidus to the subthalamic

nucleus (larger arrow), makingthe excitatory subthalamicnucleus less effective in opposingthe action of the direct pathway

(thinner arrow). Thus, thalamicexcitation of the cortex isincreased (larger arrow), leadingto greater and ofteninappropriate motor activity.(After DeLong, 1991.)


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HDsymptoms and signs (I)

Early stage Earlier onset: akinesia and cognitive impairment predominate

Later onset: choreiform movements predominate

Behavioral changes (depression, suicidal tendencies, paranoia,

irritability, impulsiveness, aggressive behavior, poor hygiene, loss ofinitiative, inappropriate sexual behavior)

Cognitive slowing

Diminished tolerance to stress

Impairment of memory and concentration

Unable to perform daily tasks at work or home Chorea (misdiagnosed as nervous agitation) disappears during sleep

Akinesia, dystonia, decreased voluntary motor control

Gait is impaired, poor balance, loss of motor postural control

Oculomotor disturbances


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HDsymptoms and signs (II)

Intermediate stage

Progressive dementiaLoss of drive

Generalized choreiform, dystonic and bradykineticmovements

Frequent falls


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HDsymptoms and signs (III)

Late stage

Patients become cachectic, with muscular atrophy(despite adequate caloric intake)

Chorea replaced by akinesia

General motor control greatly impaired

Urinary incontinence

Dementia

Need of full nursing care


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Huntingtons disease

Behavioral changes

Chorea

Dementia

Nursing dependence


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HD - treatment

Haloperidol (dopamine antagonist) 2-10 mgdailysuppress efficiently the movementdisorder and helps alleviate behaviorabnormalities

Chorea should be treated only if functionallydisabling (risk of tardive dyskinesiasuperimposed)

Juvenile formbest treated withantiparkinsonian drugs

Steadily progressive course, death 15-20 years

after onset


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Sydenhams chorea

Movement disorder associated with rheumaticfever (streptoccocal infection)one of the

major clinical signs

Striatal abnormalities demonstrated by MRI insome cases (usually transient)

Antibodies directed against cells of the basalganglia (autoimmune reaction)


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Sydenhams chorea

Involuntary, jerky, purposeless movements

Not rhythmic, sporadically in different muscle groups

Fine motor control difficult, handwriting change

Most frequently in prepubescent girls (possible but rarein boys)

History of sore throat preceding for several weeks

Emotional lability with bouts of inappropriate crying

and laughing Blood tests for rheumatic fever: ESR, CRP, ASO,

streptozyme test


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Sydenhams chorea - treatment

Antibiotics (penicillin)

Sedation (benzodiazepines, haloperidol, risperidone)

Corticosteroids

Anticonvulsivants (sodium valproate)

Plasmapheresis / IV IgG

Secondary prophilactic penicillin injections (benzathine

penicillin G) Prognosis: spontaneously resolve


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Dystonias

Forms of dystonia

Primary

Secondary Types of dystonias

Generalized

SegmentalFocal


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Dystonia genes

13 genes identified (DYT1-DYT13)

Early-onset generalized dystonia, dopa-responsivedystonia, X-linked dystonia-parkinsonism, myoclonic

dystonia, etc. DYT1 (1997)torsin A, similar to chaperone proteins

GAG deletion (glutamic acid)critical changes in thefunction of the proteinstill unknown function

Inheritance autosomal dominant, penetrance is variable(30-40% of the carriers develop disease)


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Generalized dystonia


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Spasmodic torticollis

Rotational Retrocollis

Laterocollis Anterocollis


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Blepharospasm


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Botulinic toxin treatment


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Writers cramp


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Occupational spasms


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Occupational spasms


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Occupational spasms


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Oromandibular dystonia


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Tardive dystonia

Complication of treatment with dopaminereceptor blocking agents (neuroleptiocs,antiemetics)


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Dystoniatreatment options

To lessen muscle contraction and pain and to alleviatedisturbed postures and muscle functions

Most therapiessymptomatic

Options: Oral medications

Botulinum toxin injections

Surgery

Physical therapy, speech therapy

No known cure


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Dystoniaoral medications

Anticholinergics (Trihexyphenidil = Artane)

BenzodiazepinesGABA-A receptormostused clonazepam

BaclofenGABA-B receptor

Dopaminesome respond

Anticonvulsivants (sodium valproate)


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Dystonia treatment

Botulinum toxin injections

Type A: Botox, Dysport

Type B: Myobloc (Neurobloc)

Surgery

Thalamotomy, pallidothomy

DBS (thalamus, pallidum)


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Wilsons disease (hepatolenticular

degeneration)


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The Menkes disease ATPase is expressed in alltissues except the liver while the Wilson disease

ATPase is expressed mainly in the liver, brain andplacenta

These patterns of gene exspression correlate wellwith the clinical manifestations observed

Both proteins are localized to the trans-golgimembrane where they are thought to transportcopper from the cytoplasm into the golgi lumen

where it is incorporated into newly synthesizedcopper containing proteins

Both proteins have also been shown to undergo acopper induced translocation from the trans-golgimembrane to both plasma membrane andvesicular compartments

The trans-golgi membrane localization of theproteins also explains the pathology of thediseases

If the Menkes protein is non-functional uptake of

copper from the intestines will not be possibleand a state of copper deficiency will result

If the Wilson disease protein is non-functional,copper cannot be transported into the golgi andout of the cell leading to the accumulation ofcopper in the liver and other organs.


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Wilsons disease

Are the patient's age, sex, and history

compatible with the diagnosis of Wilson's

disease?


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Wilsons disease

WD is an inherited disorder of hepatic copperexcretion

Clinical manifestations reflect injury to the

various tissues in which copper is deposited Symptomsnever apparent before 5 years of

age, almost always present by age 40

Fifty percent of patients are symptomatic by age15

Men and women are affected equally


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Wilsons disease - symptoms

Most of the early symptoms are hepatic, presenting at an averageage of 10-13 years, a decade earlier than onset of the neurologicsymptoms (accumulation of copper in the liver initially, before itsdeposition in other tissues)

A spectrum of hepatic injury occurs, as follows: (1) asymptomatic elevation of aminotransferases;

(2) acute hepatitis characterized by sudden onset of fatigue, abdominaldiscomfort, anorexia, nausea, and hemolytic jaundice, resolvingspontaneously in 1-2 weeks;

(3) chronic active hepatitis indistinguishable from autoimmune or viral

chronic active hepatitis; (4) fulminant hepatic failure manifested by marked jaundice, profound

nonimmune hemolytic anemia, coagulopathy, encephalopathy, andprogression to multiorgan failure;

(5) established cirrhosis with portal hypertension


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Wilsons disease

Neurologic symptoms - third or fourth decade of life Parkinsonian symptoms predominate, including bradykinesia,

rigidity and masked facies, resting tremor, and poor handwriting.The bulbar or facial muscles may be involved

Dystonic syndrome with involuntary choreatic movements WHY? - Degeneration of the basal ganglia with deposition of

copper Psychiatric symptoms can occur alone or in combination with

other symptoms impulsive or antisocial behavior depression frank psychosis

Other organ systems are involved less frequently


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Wilsons disease

Are the results of physical examination and

routine laboratory tests suggestive ofWilson's disease?

Wil di


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Wilsons disease

Many different organ systems can be involved inWilson's disease

abnormal physical findings in the skin(hyperpigmentation, acanthosis nigricans)

heart (cardiomyopathy, autonomic dysfunction)

skeletal (degenerative joint disease)

endocrine (amenorrhea, delayed puberty) systems

Wil di K Fl i h i


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Wilsons disease: Kayser-Fleisher ring Well-described ocular finding in Wilson's disease: Kayser-

Fleischer ring (a brownish-green discoloration in Descemet's

membrane in the limbic area of the cornea)results fromcopper deposition in this region

The ring begins forming at the superior and inferior margins ofthe cornea and may remain incomplete

Occasionally it can be seen with the naked eye, particularly in

individuals with light-colored eyes Usually visualization of the rings requires slit-lamp

examination performed by an ophthalmologist Kayser-Fleischer rings are seen in nearly all patients with

neurologic symptoms, but occur in 55% to 70% of patients with

hepatic disease only The rings are not entirely specific for Wilson's disease - can be

detected in conditions of prolonged cholestasis (primary biliarycirrhosis, sclerosing cholangitis, and chronic familial cholestaticsyndromes with impaired biliary copper excretion)


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Wilsons disease Kaiser-Fleisher ring


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Wilsons disease

Hepatic failure associated with Wilson's disease: 2atypical characteristics noted in routine laboratory

values:

Serum aminotransferase levels are less elevated (often 3:1 or 4:1

Alkaline phosphatase level is inappropriatelylow, with analkaline phosphatase:total bilirubin ratio of < 2


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Wilsons disease

What additional tests should be done to

either confirm or rule out the diagnosis ofWilson's disease?


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Wilsons disease ancillary examination

Currently no single, readily available diagnostic gold standard forWilson's disease

A constellation ofbiochemical and histologic abnormalities, inthe context of the clinical presentation, determines the diagnosis

In a study of 55 patients with Wilson's disease, 12 patients had

normal ceruloplasmin levels and no Kayser-Fleischer rings Therefore, multiple testing is usually required

Slit-lamp examination for Kayser-Fleischer rings

MRI of the liver to assess metal content

Copper assays of blood, urine, and liver - serumceruloplasmin, serum copper, 24-hour urinary copper, andhepatic copper concentration

Liver histology

Tests performed for the diagnosis of Wilson disease


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TEST COMMENTS

Urinary Copper24 hour copper excretion >100g in 65% of WDpatients

Urinary copper penicillamine challenge with two

dosages of 500mg 12 hours apart and measure urine

copper

24 hour copper excretion > 1600g in patients withactive liver disease

Serum CopperSerum copper may be low in asymptomatic cases

(because caeruloplasmin is low) or high in cases withactive liver disease (because free copper is raised)

Serum "free" copper

Calculated on the basis that caeruloplasmin contains

0.3% copperFree Copper >25g/dl

Serum Caeruloplasmin < 20 mg/dl (in 95% of WD patients)

KF ringsIdentification in most patients requires an experienced

observerLiver Copper >250 g/gm of dry weight liver

Coombs negative haemolytic anaemia

Biochemical indices Abnormal liver function tests

MRI scan Abnormal

Molecular diagnosis Over 200 mutations are known


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Wilsons disease ancillary examination

Imaging studies of the liver - often only nonspecificchanges of chronic liver disease (eg, fatty infiltration,heterogeneous liver parenchyma suggesting fibrosis,splenomegaly, ascites, and varices)

Hepatocellular carcinoma is uncommonly associatedwith Wilson's disease

Brain imaging usually is nonspecific - copper doesaccumulate in the basal ganglia and the MRI may showa hyperintense signal in the lenticular, thalamic, andcaudate nuclei as well as in the brain stem and whitematter


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Wilsons disease pathology


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movement disorders nov 2011

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