neurology: degenerative diseases of the nervous system 2 - movement disorders

DEGENERATIVE DISEASES OF THE NERVOUS SYSTEM 2: MOVEMENT DISORDERSDr. OronceNeurology

PARKINSON’S DISEASE Degenerative disorder characterized

by loss of pigmented cells in the substantia nigra and other pigmented nuclei (locus ceruleus, dorsal motor nucleus of the vagus)

Prevalence of about 1-2/1000 population

Begins between 40-70 years of age; peak age in the 6th decade

Somewhat larger proportion of men Coincidence in a family on the basis

of chance occurrence might be as high as 5%

CLINICAL FEATURES Infrequency of eye blinking (normal:

12-20/min) Slight widening of the palpebral

fissures, creating a stare; reduction in movements of the small facial muscles imparts the characteristic expression (“masked”) appearance

Tremors at rest: usually the initial sign

Rigidity and hypertonus in the more advanced stages of the disease

TRIAD1. Bradykinesia2. Tremors3. Rigidity

TREMORS Coarse rhythmic tremor, 3-5 hz Localized in one or both hands and

forearms, and less frequently, feet, jaw, lips or tongue

Increased in times of emotional stress

Rhythmic flexion-extension of the fingers, pronation-supination of the hand and foream; flexion-extension or abduction-adduction of the hand (pill-rolling tremor)

Frequently involves the face-area of the mouth: up-and-down and pursing movement of the jaw and lips

Eyelids flutter rhythmically (blepharoclonus) or the tongue when protruded may move in and out of the mouth

Abolished or reduced by complete relaxation

RIGIDITY Less impressive finding; appears in

the more advanced stages of the disease

When the examiner passively moves the limb, a mild resistance appears from the start and it continues evenly throughout the movement, in both the flexor and extensor groups, being interrupted only by the cogwheel phenomenon

Cogwheel rigidity: ratchetlike interruptions of passive movement

Postural hypertonus predominates in the flexor muscles of trunk and limbs and confers upon the patient the characteristic flexed posture

BRADYKINESIA Slowness of voluntary movement and

a reduction in automatic movement (swinging the arms when walking)

Slow and ineffective in attempts to deliver a quick hard blow

Alternating movements, at first successful, become progressively impeded and finally are blocked completely

Difficulty in executing two motor acts simultaneously

Face is relatively immobile (mask-like facies)

Voice is of low volume with infrequency of swallowing and slowness of chewing; absence of arm swing when walking

CLINICAL FEATURES As the disorder of movement

worsens, all customary activities show the effects

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Handwriting becomes small (micrographia), tremulous and cramped

Voice softens and becomes less audible; finally the patient only whispers (hypokinetic dysarthria)

Speech seems hurried and monotonous

Walking is reduced to a shuffle; patient frequently lose balance

In walking forward or backward, he must “chase the body’s center of gravity” with a series of short steps to avoid falling (festination)

Patient ‘freezes” in place

OTHER FEATURES1. Blepharospasm: involuntary closure

of the eyelids2. Blepharoclonus: fluttering of the

closed eyelids3. Inability to inhibit blinking in

response to tap over the bridge of the nose or glabella (Myerson sign)

4. Drooling of saliva5. Cognitive decline mild and late6. Depression, visual hallucinations7. Complicated by dementia in 10-

15%

ETIOLOGY

1. Idiopathic: paralysis agitans2. Encephalitis3. Drugs/Toxins

o Phenothiazines: Thioridazine, Chlorpromazine

o Butyrophenones: Haloperidolo Metoclopromideo Reserpineo Toxic substances:

manganese, carbon disulfide

DIFFERENTIAL DIAGNOSISo Progressive supranuclear palsyo Striatonigral degenerationo Lewy-Body diseaseo Corticobasal ganglionic degenerationo Encephalitis: Japanese B encephalitiso Pseudobulbar palsy from lacunar

infarctionso Normal pressure hydrocephaluso Senile tremor

PATHOLOGY AND PATHOGENESIS A loss of pigmented cells in the

substantia nigra, locus ceruleus and dorsal motor nucleus of the vagus

Remaining cells of the pigmented nuclei contain Lewy bodies: congophyllic cytoplasmic inclusions with a faint halo

Total number of pigmented neurons reduced by 20-60%

Widespread depletion of cells in midbrain reticular formation near the substantia nigra is also noted

Normal balance between dopamine and acetylcholine is disturbed because of dopamine depletion in the nigrostriatal system

Lewy Bodies

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PATHOLOGY AND PATHOGENESIS A neurotoxin (known as MPTP- 1-

methyl-4 phenyl-1,2,5,6 tetrahydropidine) can produce irreversible signs of parkinsonism

This toxin binds with high affinity to an extraneural enzyme, monoamine oxidase, which transforms it to a toxic metabolite, pyridinium MPP+

The latter is bound by the melanin in the dopaminergic nigral neurons in sufficient concentrations to destroy the cells

Parkinson’s disease caused by this environmental toxin is common in industrial countries and agrarian areas

Ingested by persons who self-administer an analogue of meperidine

TREATMENT No known treatment that will halt or

reverse the neuronal degeneration; only considerable relief from symptoms

1. L-dopa (L-dihydroxyphenylalanine)• Theoretical basis: the

remaining nigral cells are capable of producing dopamine by taking up its precursor, L-dopa

• Over time, the number of remaining nigral neurons that convert L-dopa to dopamine becomes inadequate and the receptivity to dopamine of the striatal target neurons becomes excessive

• This results in both a reduced response to L-dopa and to paradoxical and excessive movements (dsykinesias) with each dose

• By combining with a decarboxylase inhibitor (carbidopa), the decarboxylation of L-dopa to dopamine is greatly diminished in peripheral tissues

• This permits a greater proportion of L-dopa to reach nigral neurons and at the same time, a reduction in the peripheral side effects (nausea, hypotension, etc)

• Initial dose: 100 mg/25 mg ½ tab 3X a day up to a maximum of 2 tablets 4X a day, or a similar dose of 250/25 mg combination

• Long-acting preparations reduce dyskinesias in some patients (morning rigidity and tremors); long-acting drug is broken in half or a small dose of conventional L-dopa is given at the same time)

2. Bromocriptine, pergolide Direct stimulating effect on D2

receptors located on corticostriate neurons, bypassing the depleted nigral neurons

Newer nonergot dopamine agonists, ropinirole and pramipexole are well tolerated and have a a duration of effectiveness similar to that of other D2 agonists

Very helpful in supplementing L-dopa and are now increasingly popular as the sole therapeutic agent before L-dopa is instituted

Bromocriptine: 7.5 to 10 mg/day (3-4X a day) up to 40-60 mg/day (L-dopa

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concomitantly reduced by 50%)

A dose of 5-10 mg bromocriptine has about the equivalent effect of 100/25 mg levodopa/carbidopa

TREATMENT Because of the side effects of L-

dopa and D2 agonists, some avoid all types of drugs if the patient is in the early stages and symptoms are not troublesome

When the symptoms become more annoying, initial therapy with either amantadine 100 mg bid or an anticholinergic agent may be advised

Only when the symptoms begin to interfere with work and social life or falling becomes a threat is a carbidopa/levodopa preparation introduced and then at the lowest possible dose - 10/100 mg bid or tid and slowly increased until maximal benefit is achieved

Another approach is to initiate the treatment of new cases of PD with the monoamine oxidase inhibitor selegeline 5 mg bid

Continue its use until the symptoms become disabling, at which point L-dopa or a D2 agonist is introduced

Selegeline slows progression of the disease in its early stages; subsequent observations, though, have not confirmed this view and selegeline is infrequently used

2/3 of patients on L-dopa tolerate the drug initially with few side effects; 1/3 will show dramatic improvement in hypokinesia and tremor

Coincident psychiatric symptoms and depression may be present: trazodone and selective serotonin reuptake inhibitors (SSRIs) like fluoxetine, sertraline are given

Confusion and outright psychosis: olanzapine, clozapine, risperidone and quetiapine in low doses

The most common and troublesome effects of L-dopa are end-of-dose failure, the “on-off” phenomenon and the induction of involuntary movements (restlessness, head wagging, grimacing, lingual-labial dyskinesia, choreoathetosis and dystonia of the limbs, neck and trunk)

On-off phenomenon: unpredictable change in the patient, in a matter of minutes, from a state of relative mobility to one of complete or nearly complete immobility: reduce dosage

If involuntary movements are induced by relatively small doses of L-dopa, the therapeutic effect may be enhanced by the addition of pergolide, bromocriptine, ropinirole and pramipexole and to some extent, amantadine

Amantadine acts by releasing dopamine from striatal neurons and with L-dopa, may reduce the dyskinesias and motor fluctuations with advanced disease

Anticholinergic agents have long been in use in conjunction with L-dopa: biperiden, trihexyphenydil, benztropine mesylate and amantadine

They should be given in gradually increasing dosage to the point where toxic effects appear (dry mouth, blurring of vision, constipation and urinary retention)

Anticholinergic drugs or L-dopa should not be discontinued abruptly in advanced cases: patient may become totally immobilized by a sudden and severe increase in tremor and rigidity

Long-term treatment with L-dopa or D2 agonists does not prevent the slow advance of the disease

With the end-of-dose loss of effectiveness and on-off phenomenon, the patient may experience pain, respiratory distress, akathisia, depression, anxiety and hallucinations

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Titrate the dose of L-dopa and utilize more frequent doses during the 24-h day, combining it with a D2 agonist or use long-acting preparations

Sometimes temporarily withdrawing L-dopa and at the same time substituting other medications will control the on-off phenomenon

TREATMENT (Surgical Measures) Stereotactic surgery has best

results in relatively young patients with unilateral tremor or rigidity, rather than akinesia as the predominant symptoms

Least well responsive: postural imbalance and instability, paroxysmal akinesia, bladder and bowel disturbances, dystonia and speech difficulties

Postoperatively, there is an enhanced responsiveness to L-dopa and a reduction of drug-induced dyskinesias

Improvement in “off-state” bradykinesia is lost after 2 or so years and any betterment in axial rigidity and imbalance is lost within a year of operation

With pallidotomy, surgical proponents have estimated that dyskinesias are reduced 50% contralateral to the operated side and that parkinsonian symptoms during the “off phase” are improved in 30-50%

These improvements do not persist indefinitely and in part due to the ability to reduce the dose of L-dopa

Recently, high frequency stimulation of the subthalamic nucleus produced impressive improvement in all features of the disease

STRIATONIGRAL DEGENERATION AND MULTIPLE SYSTEM ATROPHY

Closely related to Parkinson’s disease

Typical rigidity, stiffness and akinesia but with little or none of the characteristic tremor

Flexed posture of the trunk and limbs, slowness of all movements, poor balance, mumbling speech and a tendency to faint when standing

Intact mental functioning; no reflex changes; no suck and grasp reflexes

No cerebellar signs or involuntary movements

Extensive loss of neurons in the substantia nigra but no Lewy bodies or neurofibrillary tangles in the remaining cells

Degenerative changes in the putamen and to a lesser extent, in the caudate nucleus

These structures are greatly reduced in size and have lost most of their neurons – more of the small than the large ones

Cell loss greater in the putamen than in the caudate

Secondary atrophy of the globus pallidus

SHY-DRAGER SYNDROMECLINICAL FEATURES

Orthostatic hypotension: loss of intermediolateral horn cells and pigmented nuclei of the brainstem

Combined Parkinsonism and autonomic disorder

Impotence, loss of sweating, dry mouth, miosis, urinary retention or incontinence

Vocal cord palsy: dysphonia, stridor and airway obstruction

MULTIPLE SYSTEM ATROPHYCLINICAL FEATURES

o One or more symptoms of autonomic failure (postural hypotension, urinary urgency or retention, urinary or fecal incontinence, impotence, dysphonia or stridor)

o Babinski signs, cerebellar ataxia

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o Males more than females; tremors are rare

o The illness, on the whole, is more severe than Parkinson’s disease

o Relative symmetry of the signs and rapid course, lack of response to L-dopa and the absence of tremor and the presence of autonomic disorders distinguish MSA from Parkinson’s disease

Both MRI and CT scans show atrophy of the cerebellum and pons

Studies with PET disclose an impairment of glucose metabolism in the striatum and to a lesser extent in the frontal cortex

Presence of argyrophilic material in glial cells; most prominent in the cytoplasm of oligodendrocytes (oligodendroglial cytoplasmic inclusions)

These cytoplasmic inclusions are a reliable histopathologic hallmark of possible cases of MSA

Aggregates, however, are far from specific; they have been identified in practically every degenerative disease

PROGRESSIVE SUPRANUCLEAR PALSYCLINICAL FEATURES

Seen during the 6th decade Combination of difficulty in balance,

abrupt falls, visual and ocular disturbances, slurred speech, dysphagia, vague personality changes

The commonest early complaint is unsteadiness of gait and unexplained falling

Characteristic syndrome: supranuclear ophthalmoplegia, pseudobulbar palsy, axial dystonia

Difficulty in voluntary vertical movement of the eyes, often downward and sometimes upward is a characteristic and early feature

Later, both the ocular pursuit and refixation movements deteriorate and eventually, all voluntary eye movements are lost

Bell’s phenomenon (reflexive upturning of eyes on forced closure of the eyelids) and ability to converge are also lost; pupils become small

Upper eyelids may be retracted and the wide-eyed, unblinking stare, imparting an expression of perpetual surprise, is highly characteristic

In the late stages, the eyes are fixed centrally

Walking becomes more and more awkward and tentative; patient has a tendency to totter and fall repeatedly but has no ataxia of the limbs or Romberg sign

Gradual stiffening and extension of the neck

The face acquires a staring, “worried” expression with a furrowed brow and staring demeanor

Some display mild dystonic postures of a hand or foot; limbs may be slightly stiff with Babinski signs

Face becomes less expressive, speech is slurred, the mouth needs to be held open and swallowing becomes difficult

Focal limb dystonia, myoclonus, chorea, orofacial dyskinesias and disturbances of vestibular function are observed

Finally becomes anarthric, immobile and helpless and forgetful, apathetic and slow in thinking

Complaints of urinary frequency and urgency

Mild dementia

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DIFFERENTIATED FROM PARKINSON’S DISEASE

1. Facial expression in PSP more of tonic grimace than lack of movement in PD

2. Absence of tremors in PSP3. Erect rather than stooped posture4. Prominence of ocular abnormalities

in PSP

DIAGNOSIS MRI: atrophy of the mesencephalon,

superior colliculi, red nucleus (“mouse ears” configuration)

Normal CSF

PATHOLOGY Bilateral loss of neurons in the

periaqueductal gray matter, superior colliculi, red nucleus, pallidum, dentate nucleus, vestibular nuclei, oculomotor nuclei

Cerebellar cortex usually spared Neurofibrillay degeneration in

residual neurons ETIOLOGY

Autosomal dominant Some cases were originally

considered to be instances of postencephalitic parkinsonism

TREATMENT L-dopa of slight but unsustained

benefit Combinations of L-dopa and

anticholinergic drugs also not effective

Zolpidem (Stilnox): GABAergic agonist of benzodiazepine receptors that ameliorates akinesia and rigidity

CORTICAL-BASAL GANGLIONIC SYNDROMES

Progressive extrapyramidal rigidity with signs of corticospinal disease

Patients, though able to exert considerable muscle power, cannot effectively direct their voluntary actions

The disorder of limb function has some of the attributes of an apraxia but the hand postures, involuntary movements and changes in tone are more reminiscent of the “alien hand”

FEATURES: inappropriate movement of the limbs, apraxia, combinations of rigidity, bradykinesia, hemiparesis, sensory ataxia, postural and action tremor and myoclonic jerks

Apraxias of gaze, eyelid opening and closure, and stimulus-sensitive myoclonus appear

OTHER CLINICAL FEATURES The most common early

symptom is an asymmetrical clumsiness of the limbs, rigidity and tremor

Asymmetrical or unilateral akinetic-rigid syndrome, various forms of gait disorder and dysarthria

Limitations of vertical gaze and frontal lobe release signs become apparent in half of the patients

Mental deterioration is late In a few cases, there is some

involvement of lower motor neurons with resulting amyotrophy

PATHOLOGY Cortical atrophy mainly in the

frontal motor-premotor and anterior parietal lobes

Degeneration of the substantia nigra and dentatothalamic fibers

Affected neurons and adjacent glia are filled with tau protein but no Pick bodies, Alzheimer fibrillary changes, senile plaques or Lewy bodies

CT and MRI: asymmetrical cerebral and pontine atrophy

No family history No organ other than the CNS is

affected

DYSTONIC DISORDERS

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DYSTONIA MUSCULORUM DEFORMANS

Torsion dystonia First seen on 3 siblings of a Jewish

family with progressive involuntary movements of the trunk and limbs

2 patterns of inheritanceo Autosomal recessive: early

childhood, progressive over a few years, restricted to Jewish patients, normal or even superior intelligence

o Autosomal dominant: late childhood and adolescence, progresses more slowly and not limited to any ethnic group

Symptomatic (secondary) types: vascular, metabolic and other degenerative diseases

In general, the more restricted types have a later onset and a relatively milder, more slowly progressive course, with a tendency to involve the axial or the distal musculature alone

Adult-onset dystonias (both the restricted and the generalized forms) may be sporadic or familial in type

The general rule holds that the inherited variety that is tied to chromosome 9q begins early in life in one limb, followed by generalization of the dystonic movements

While in other types, the craniocervical or another region is affected early and the condition does not spread

Patient is usually a child, 6-14 years old

Patients begin to invert one foot, extend one leg and foot in an unnatural way or to hunch shoulder

Muscles of the spine and shoulder or pelvic girdles assume involuntary, spasmodic twisting movements

Spasms become continuous and the body becomes grotesquely contoured

Lateral and rotatory scoliosis are regular secondary deformities

For a time, recumbency relieves the spasms but later position has no influence

Cranial muscles do not escape; may present with slurring or staccato-type speech

Uncontrollable blepharospasm, dysarthria and dysphagia (dystonia of the tongue, pharyngeal and laryngeal muscles)

Torticollis, action tremor, myoclonic jerks during voluntary movement and mild choreoathetosis of the limbs

Tendon reflexes are normal; corticospinal signs are absent

No ataxia, sensory abnormality, convulsions or dementia

In the Philippines, dystonia is sex-linked

PATHOLOGY: brain is grossly normal, ventricle size is not increased

GENETICS1. Abnormal gene (DYT1) which codes

for the protein torsin A is mapped to the long arm of chromosome 9q

2. The gene probabaly accounts for the majority of inherited cases of dystonia

3. Autosomal dominant

PET SCAN: hypermetabolism in the cerebellum, lenticular nuclei and supplementary motor cortex

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TORTICOLLIS AND OTHER RESTRICTED DYSTONIAS

Most frequent and familiar type is torticollis

An adult woman becomes aware of a turning of the head to one side while walking

Limited to scalene, sternocleidomastoid and upper trapezius muscles

Occasionally combined with dystonia of the arm and trunk with tremor and facial spasms

OTHER RESTRICTED DYSTONIAS Blepharospasm/blephacroclonus:

orbicularis oculi Spastic dsyphonia, orofacial

dyskinesia, respiratory and phonatory spasms: throat and respiratory muscles

Graphospasm: hand as in writer’s cramp or musician’s dystonia

Proximal leg and pelvic girdle muscles where dyskinesia is elicited by walking

Dyskinesias involving the neck combined with facial muscles

DYSTONIA

TREATMENT1. L-dopa, bromocriptine,

carbamazepine, diazepam and tetrabenzene are helpful early in the course of the illness

2. Intrathecal baclofen is somewhat successful in children

3. High doses of Trihexyphenidyl (Artane), 30 mg/day or more is advocated

4. Clonazepam is beneficial in patients with segmental myoclonus

5. Stereotactic techniques centered on the ventrolateral nuclei of the thalamus or in the pallidum-ansa lenticularis regions have the most impressive results

6. Main risk of surgery: corticospinal tract lesion by damaging the internal capsule

SYNDROME OF PROGRESSIVE ATAXIA Chronic forms of cerebellar disease,

familial and more or less confined to the cerebellum

EARLY ONSET SPINOCEREBELLAR ATAXIAS (PREDOMINANTLY SPINAL)

FRIEDREICH ATAXIA Prototype of all forms of

progressive spinocerebellar ataxia Onset before 10 years old;

invariably and steadily progressive Within 5 years, walking is no longer

possible

CLINICAL FEATURES Ataxia of gait always the initial

symptom; usually affects both legs; difficulty in standing steadily and running

Clumsy hands, dysarthric speech; preserved mentation

Pes cavus and kyphoscoliosis: high plantar arch with retraction of the toes in the metatarsophalyngeal joints and flexion at the interphalyngeal joints (hammer toes)

Cardiomyopathy: hypertrophic myocardial fibers

In fully developed state, abnormality of gait is of mixed sensory and cerebellar types (tabetocerebellar)

The patient stands with feet wide apart, constantly shifting position to maintain balance

(+) Romberg’s sign

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Rhythmic tremor of the hand; both action and intention tremors are manifest

Speech Is slow, slurred, explosive and finally incomprehensible

Breathing, speaking, swallowing and laughing may be so incoordinate that the patient chokes while speaking

Facial, buccal and arm muscles display tremulous and sometimes choreiform movements

Mentation is preserved but emotional lability is prominent

Nystagmus, deafness with vertigo and blindness with optic atrophy

Tendon reflexes are abolished; plantar responses are extensor and flexor spasms may occur even with complete absence of tendon reflexes (areflexia sensory in origin)

Loss of tactile pain, and temperature sensation, vibratory and position sense

Sphincter control is preserved

PATHOLOGY Spinal cord is thin; posterior

columns, corticospinal and spinocerebellar tracts are all depleted of medullated fibers

Large neurons of the dorsal root ganglia are reduced in number

Nuclei of cranial nerves VIII, X, XII exhibit a reduction of cells

Neuronal loss in the dentate nuclei Middle and superior cerebellar

peduncles reduced in size Purkinje cells in the superior vermis

and neurons in the inferior olivary nuclei depleted

TREATMENT Oral 5-hydroxytryptophan

significantly modifies cerebellar symptoms

The drug is serotoninergic and is known to suppress posthypoxic action myoclonus

No other known therapeutic measures

Surgery for scoliosis and foot deformities may be helpful

PREDOMINANTLY CEREBELLAR (CORTICAL) FORMS OF HEREDITARY ATAXIA

Degenerative changes in the cerebellum and brainstem rather than the spinal cord

Later age of onset; more definite hereditary transmission (autosomal dominant); hyperactivity of tendon reflexes; frequent concurrence of ophthalmoplegia, retinal degeneration and optic atrophy

PURE CEREBELLAR CORTICAL ATROPHY

Onset in later life Insidious, slow progression (survival

15-20 years)

CLINICAL FEATURES Ataxia of gait, instability of the

trunk, tremor of the hands and head and slowed, hesitant speech

Intelligence is preserved; nystagmus rare

Patellar reflexes are increased; extensor plantar responses

PATHOLOGY: symmetrical atrophy of the cerebellum, mainly the anterior lobe and the vermis; white matter slightly pale; cell loss in the dorsal and medial parts of the inferior olivary nuclei

CEREBELLAR ATROPHY WITH PROMINENT BRAINSTEM LESIONS

SPORADIC AND FAMILIAL OLIVOPONTOCEREBELLAR ATROPHY

Onset of symptoms at the 5th decade

Features: ataxia in the legs, arms, hands and bulbar muscles

Hereditary pattern1. Autosomal dominant2. One or more long tracts in the

spinal cord degenerate

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3. Half the cases develop parkinsonian symptoms

4. Pathology: extensive degeneration of the middle cerebellar peduncles, pontine, olivary and arcuate nuclei

Sporadic pattern1. More common; in older age than

the familial ones2. Nystagmus, optic atrophy, retinal

degeneration, ophthalmoplegia3. Urinary incontinence not present4. Variants: mild extrapyramidal and

neuropathic signs, slow eye movements, dsytonia, vocal cord paralysis, deafness

5. Occurs most often independent of extrapyramidal degeneration

DENTATORUBROPALLIDUYSI-AN ATROPHY

CLINICAL FEATURES1. Cerebellar ataxia with

choreoathetosis and dystonia2. May include myoclonus,

parkinsonism, epilepsy or dementia3. Main diagnostic consideration when

chorea is present is Huntington disease

4. Gene defect: unstable CAG trinucleotide repeat on chromosome 12

5. Autosomal dominant

DENTATORUBRAL DEGENERATION

CLINICAL FEATURES AND PATHOLOGY Myoclonus combined with

progressive cerebellar ataxia Age of onset between 7-17 years

old Some signs of Friedreich ataxia

Degeneration of the posterior columns and spinocebellar tracts but not of the corticospinal tracts

Cerebellar lesion: atrophy and sclerosis of the dentate nucleus with degeneration of the superior cerebellar peduncles

HUNTINGTON CHOREA Triad of dominant inheritance,

choreoathetosis and dementia Overall frequency estimated at 4-5

per million Initial age of onset at 4th-5th decade Young patients usually inherit the

disease from their fathers and older patients from their mothers

A marker linked to the Huntington gene, localized in the short arm of chromosome 4

Gene abnormality is an excessively long repeat of trinucleotides (CAG), the length of which determines the presence of the disease and the age of onset

CLINICAL FEATURES MENTAL CHANGES Slight and annoying changes in

character, complain constantly and nag other members of the family

May be suspicious, irritable, impulsive, eccentric, untidy or excessively religious

Poor self-control: outbursts of temper, alcoholism or sexual promiscuity

Disturbances of mood: depression Invariably sooner or later, the

intellect begins to fall; becomes less communicative and more socially withdrawn; virtual psychosis (delusions and hallucinations)

Diminished work performance, inability to manage household responsibilities and disturbances of sleep

Difficulty in maintaining attention, in concentration and in assimilating a new material

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Loss of fine manual skills; mental flexibility lessens

Memory is relatively spared; elements of aphasia, agnosia and apraxia are observed (“subcortical dementia”) only rarely

ABNORMALITY OF MOVEMENT (CHOREA)

Initially: fidgety, restless or “nervous”

Slowness of movement of the fingers and hands, reduced rate of finger tapping and difficulty in performing a sequence of hand movements

Increased frequency of blinking (opposite of parkinsonism); voluntary protrusion of tongue is constantly interrupted by unwanted darting movements

In the advanced stage, the patient is seldom still for more than a few seconds

Muscle tone decreased until late in the illness

Some degree of rigidity, bradykinesia and tremors (parkinsonism)

Involuntary arrhythmic movements of a forcible, rapid type

Although purposeless, the patients may incorporate them into a deliberate act as if to make them less noticeable

Grimacing and peculiar respiratory sounds may be other expressions

Limbs often hypotonic; knee jerks pendular

Differs from myoclonic jerks (much faster and may involve single muscles, part or group)

PATHOLOGY AND PATHOGENESIS Gross atrophy of the caudate

nucleus and putamen bilaterally is the characteristic abnormality

Moderate degree of gyral atrophy in the frontal and temporal areas; ventricles diffusely enlarged

The first clinical manifestations are based on a biochemical marker

(decrease in glucose metabolism) without visible structural change)

Striatal degeneration begins in the medial part of the caudate; lost cells are replaced by fibrous astrocytes; large cells are relatively preserved

Aside from the impaired glucose metabolism, the abnormal movements of Huntington chorea represent a heightened sensitivity of striatal dopamine receptors

Disturbances in the metabolism of other neurotransmitters (norepinephrine, glutamic acid decarboxylase, choline acetyltransferase, GABA, acetylcholine and somatostatin)

Product of the Huntington gene locus is huntingtin which accumulates in the cells of the striatum and part of the cortex

TREATMENT Dopamine antagonist haloperidol

(2-10 mg) is probably the most effective agent to suppress the movement disorder but may cause tardive dyskinesia

The chorea should be treated only if it is functionally disabling (smallest possible dosages and providing drug holidays)

Drugs that deplete dopamine or block dopamine receptors (reserpine, clozapine) may suppress the chorea to some degree but side effects (drowsiness, akathisia and tardive dyskinesia) outweigh their desired effects

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Juvenile form best treated with antiparkinsonian drugs

Supportive therapy, genetic counseling

Death in 15-20 years

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neurology: degenerative diseases of the nervous system 2 - movement disorders

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