degenerative diseases of the brain 2

8/3/2019 Degenerative Diseases of the Brain 2

1/66

DEGENERATIVE DISEASES OF

THE NERVOUS SYSTEM 2

MOVEMENT DISORDERS


2/66

PARKINSONS DISEASE

Degenerative disorder characterized by loss ofpigmented cells in the substantia nigra and otherpigmented nuclei (locus ceruleus, dorsal motornucleus of the vagus)

Prevalence of about 1-2/1000 population

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

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

occurrence might be as high as 5%


3/66

PARKINSONS DISEASE

CLINICAL FEATURES1. Infrequency of eye blinking (normal: 12-20/min)

2. Slight widening of the palpebral fissures, creating astare; reduction in movements of the small facial

muscles imparts the characteristic expression(masked) appearance

3. Tremors at rest: usually the initial sign

4. Rigidity and hypertonus in the more advanced stagesof the disease

TRIAD1. Tremors

2. Bradykinesia

3. Rigidity


4/66

PARKINSONS DISEASE

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 orabduction-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 thetongue when protruded may move in and out of themouth

Rest tremors: complete relaxation reduces or abolishesthe tremor


5/66

PARKINSONS DISEASE

RIGIDITY Less impressive finding; appears in the more advanced

stages of the disease

When the examiner passively moves the limb, a mildresistance appears from the start and it continuesevenly throughout the movement, in both the flexor andextensor groups, being interrupted only by thecogwheel phenomenon

Cogwheel rigidity: ratchetlike interruptions of passivemovement

Postural hypertonus predominates in the flexormuscles of trunk and limbs and confers upon thepatient the characteristic flexed posture


6/66

PARKINSONS DISEASE

BRADYKINESIA Slowness of voluntary movement and a reduction in

automatic movement (swinging the arms whenwalking)

Slow and ineffective in attempts to deliver a quick hardblowAlternating movements, at first successful, become

progressively impeded and finally are blockedcompletely

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 whenwalking


7/66

PARKINSONS DISEASE

CLINICAL FEATURESAs the disorder of movement worsens, all customary

activities show the effects 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 loses

balance In walking forward or backward, he must chase the

bodys center of gravity with a series of short steps toavoid falling (festination)

Patient freezes in place


8/66

PARKINSONS DISEASE

OTHER FEATURES

1. Blepharospasm: involuntary closure of the eyelids

2. Blepharoclonus: fluttering of the closed eyelids

3. Inability to inhibit blinking in response to tap over thebridge of the nose or glabella (Myerson sign)

4. Drooling of saliva

5. Cognitive decline mild and late

6. Depression, visual hallucinations7. Complicated by dementia in 10-15%


9/66

PARKINSONS DISEASE

ETIOLOGY

1. Idiopathic: paralysis agitans

2. Encephalitis

3. Drugs/Toxins

Phenothiazines: Thioridazine, Chlorpromazine

Butyrophenones: Haloperidol

Metoclopromide Reserpine

Toxic substances: manganese, carbon disulfide


10/66

PARKINSONS DISEASE

DIFFERENTIAL DIAGNOSIS

1. Progressive supranuclear palsy

2. Striatonigral degeneration

3. Lewy-Body disease

4. Corticobasal ganglionic degeneration

5. Encephalitis: Japanese B encephalitis

6. Pseudobulbar palsy from lacunar infarctions

7. Normal pressure hydrocephalus

8. Senile tremor


11/66

PARKINSONS DISEASE

PATHOLOGY AND PATHOGENESISA loss of pigmented cells in the substantia nigra, locus

ceruleus and dorsal motor nucleus of the vagus

Remaining cells of the pigmented nuclei contain Lewybodies: congophyllic cytoplasmic inclusions with a fainthalo

Total number of pigmented neurons reduced by 20-60%

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

Normal balance between dopamine and acetylcholineis disturbed because of dopamine depletion in thenigrostriatal system


12/66

PARKINSONS DISEASE

PATHOLOGY AND PATHOGENESISA neurotoxin (known as MPTP- 1-methyl-4 phenyl-

1,2,5,6 tetrahydropidine) can produce irreversible signsof parkinsonism

This toxin binds with high affinity to an extraneuralenzyme, monoamine oxidase, which transforms it to atoxic metabolite, pyridinium MPP+

The latter is bound by the melanin in the dopaminergicnigral neurons in sufficient concentrations to destroythe cells

Parkinsons disease caused by this environmentaltoxin is common in industrial countries and agrarianareas

Ingested by persons who self-administer an analogueof meperidine


13/66

PARKINSONS DISEASE

TREATMENT No known treatment that will halt or reverse the

neuronal degeneration; only considerable relieffrom symptoms

1. L-dopa (L-dihydroxyphenylalanine) Theoretical basis: the remaining nigral cells are

capable of producing dopamine by taking up itsprecursor, L-dopa

Over time, the number of remaining nigral neurons

that convert L-dopa to dopamine becomesinadequate and the receptivity to dopamine of thestriatal target neurons becomes excessive

This results in both a reduced response to L-dopaand to paradoxical and excessive movements

(dsykinesias) with each dose


14/66

PARKINSONS DISEASE

TREATMENT 1. L-dopa

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 theperipheral side effects (nausea, hypotension, etc)

Initial dose: 100 mg/25 mg tab 3X a day up to a

maximum of 2 tablets 4X a day, or a similar dose of of250/25 mg combination

Long-acting preparations reduce dyskinesias in somepatients (morning rigidity and tremors); long-actingdrug is broken in half or a small dose of conventional

L-dopa is given at the same time)


15/66

PARKINSONS DISEASE

2. Bromocriptine, pergolide Direct stimulating effect on D2 receptors located oncorticostriate neurons, bypassing the depleted nigralneurons

Newer nonergot dopamine agonists, ropinirole and

pramipexole are well tolerated and have a a durationof effectiveness similar to that of other D2 agonists;ropinirole: 0.25 mg TID up to 3 mg/day

Very helpful in supplementing L-dopa and are nowincreasingly popular as the sole therapeutic agentbefore l-dopa is instituted

Bromocriptine: 7.5 to 10 mg/day (3-4X a day) up to40-60 mg/day (L-dopa concomitantly reduced by50%)

A dose of 5-10 mg bromocriptine has about the

equivalent effect of 100/25 mg levodopa/carbidopa


16/66


17/66

PARKINSONS DISEASE

TREATMENTAnother approach is to initiate the treatment of new

cases of PD with the monoamine oxidase inhibitor,selegeline 5 mg bid or rasageline 1 mg/day

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 notconfirmed this view and selegeline is infrequently used

2/3 of patients on L-dopa tolerate the drug initially withfew side effects; 1/3 will show dramatic improvement inhypokinesia and tremor


18/66

PARKINSONS DISEASE

TREATMENT

Coincident psychiatric symptoms and depression maybe present: trazodone and selective serotonin reuptakeinhibitors (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-dopaare end-of-dose failure, the on-off phenomenon andthe induction of involuntary movements (restlessness,head wagging, grimacing, lingual-labial dyskinesia,choreoathetosis and dystonia of the limbs, neck andtrunk)


19/66

PARKINSONS DISEASE

TREATMENT On-off phenomenon: unpredictable change in the

patient, in a matter of minutes, from a state of relativemobility 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 beenhanced by the addition of pergolide, bromocriptine,ropinirole and pramipexole and to some extent,amantadine

Amantadine acts by releasing dopamine from striatalneurons and with L-dopa, may reduce the dyskinesias andmotor fluctuations with advanced disease


20/66

PARKINSONS DISEASE

TREATMENT

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 bediscontinued abruptly in advanced cases: patient may

become totally immobilized by a sudden and severe

increase in tremor and rigidity


21/66

PARKINSONS DISEASE

TREATMENT 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 andhallucinations

Titrate the dose of L-dopa and utilize more frequent

doses during the 24-h day, combining it with a D2agonist or use long-acting preparations

Sometimes temporarily withdrawing L-dopa and at thesame time substituting other medications will controlthe on-off phenomenon


22/66

PARKINSONS DISEASE

TREATMENT (Surgical Measures) Stereotactic surgery has best results in relatively young

patients with unilateral tremor or rigidity, rather thanakinesia as the predominant symptoms

Least well responsive: postural imbalance andinstability, paroxysmal akinesia, bladder and boweldisturbances, dystonia and speech difficulties

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

Improvement in off-state bradykinesia is lost after 2 orso years and any betterment in axial rigidity andimbalance is lost within a year of operation


23/66

PARKINSONS DISEASE

TREATMENT (Surgical Measures)

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 subthalamicnucleus produced impressive improvement in all

features of the disease


24/66

2. STRIATONIGRAL

DEGENERATION AND MULTIPLE

SYSTEM ATROPHY Closely related to Parkinsons 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


25/66

2. STRIATONIGRAL

DEGENERATION AND MULTIPLE

SYSTEM ATROPHY Extensive loss of neurons in the substantia nigra

but no Lewy bodies or neurofibriallry tangles inthe remaining cells

Degenerative changes in the putamen and to alesser extent, in the caudate nucleus These structures are greatly reduced in size and

have lost most of their neurons more of thesmall than the large ones

Cell loss greater in the putamen than in thecaudate

Secondary atrophy of the globus pallidus


26/66

2A. SHY-DRAGER SYNDROME

CLINICAL FEATURES

1. Orthostatic hypotension: loss ofintermediolateral horn cells and pigmented

nuclei of the brainstem2. Combined Parkinsonism and autonomic

disorder

3. Impotence, loss of sweating, dry mouth,

miosis, urinary retention or incontinence4. Vocal cord palsy: dysphonia, stridor and

airway obstruction


27/66

2B. MULTIPLE SYSTEM

ATROPHY CLINICAL FEATURES

1. One or more symptoms of autonomic failure (posturalhypotension, urinary urgency or retention, urinary orfecal incontinence, impotence, dysphonia or stridor)

2. Babinski signs, cerebellar ataxia3. Males more than females; tremors are rare

4. The illness, on the whole, is more severe thanParkinsons disease

5. Relative symmetry of the signs and rapid course,lack of response to L-dopa and the absence oftremor and the presence of autonomic disordersdistinguish MSA from Parkinsons disease


28/66

2B. MULTIPLE SYSTEM

ATROPHY

Both MRI and CT scans show atrophy of the cerebellumand pons

Studies with PET disclose an impairment of glucosemetabolism in the striatum and to a lesser extent in thefrontal cortex

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

These cytoplasmic inclusions are a reliablehistopathologic hallmark of possible cases of MSA

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


29/66

3. PROGRESSIVE

SUPRANUCLEAR PALSY

CLINICAL FEATURES

1. Seen during the 6th decade

2. Combination of difficulty in balance, abrupt

falls, visual and ocular disturbances, slurredspeech, dysphagia, vague personalitychanges

3. The commonest early complaint is

unsteadiness of gait and unexplained falling4. Characteristic syndrome: supranuclear

ophthalmoplegia, pseudobulbar palsy, axialdystonia


30/66

3. PROGRESSIVE

SUPRANUCLEAR PALSY CLINICAL FEATURES

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

Later, both the ocular pursuit and refixation movementsdeteriorate and eventually, all voluntary eyemovements are lost

Bells phenomenon (reflexive upturning of eyes onforced closure of the eyelids) and ability to convergeare also lost; pupils become small

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

In the late stages, the eyes are fixed centrally


31/66

3. PROGRESSIVE

SUPRANUCLEAR PALSY

CLINICAL FEATURES Walking becomes more and more awkward

and tentative; patient has a tendency to totter

and fall repeatedly but has no ataxia of thelimbs or Romberg sign

Gradual stiffening and extension of the neck

The face acquires a staring, worried

expression with a furrowed brow and staringdemeanor

Some display mild dystonic postures of ahand or foot; limbs may be slightly stiff with

Babinski signs


32/66

3. PROGRESSIVE

SUPRANUCLEAR PALSY

CLINICAL FEATURES

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


33/66

3. PROGRESSIVE

SUPRANUCLEAR PALSY

DIFFERENTIATED FROM PARKINSONS

DISEASE

1. Facial expression in PSP more of tonic

grimace than lack of movement in PD2. Absence of tremors in PSP

3. Erect rather than stooped posture

4. Prominence of ocular abnormalities in PSP


34/66

3. PROGRESSIVE

SUPRANUCLEAR PALSY

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 colluculi, red nucleus, pallidum,

dentate nucleus, vestibular nuclei, oculomotor nuclei Cerebellar cortex usually spared

Neurofibrillay degeneration in residual neurons


35/66

3. PROGRESSIVE

SUPRANUCLEAR PALSY

ETIOLOGY

Autosomal dominant

Some cases were originally considered to be

instances of postencephalitic parkinsonism TREATMENT

1. L-dopa of slight but unsustained benefit

2. Combinations of L-dopa and anticholinergic drugs

also not effective

3. Zolpidem (Stilnox): GABAergic agonist of

benzodiazepine receptors; ameliorates akinesia and

rigidity


36/66

4. 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 movementsand changes in tone are more reminiscent of the alienhand

FEATURES: inappropriate movement of the limbs,apraxia, combinations of rigidity, bradykinesia,

hemiparesis, sensory ataxia, postural and action tremorand myoclonic jerks

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


37/66

4.CORTICAL-BASAL

GANGLIONIC SYNDROMES OTHER CLINICAL FEATURES

The most common early symptom is an asymmetrical

clumsiness of he 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


38/66

4. CORTICAL-BASAL

GANGLIONIC SYNDROMES PATHOLOGY

Cortical atrophy mainly in the frontal motor-premotorand anterior parietal lobes

Degeneration of the substantia nigra and

dentatothalamic fibersAffected neurons and adjacent glia are filled with tau

protein but no Pick bodies, Alzheimer fibrillarychanges, senile plaques or Lewy bodies

CT and MRI: asymmetrical cerebral and pontineatrophy

No family history

No organ other than the CNS is affected


39/66

5. DYSTONIC DISORDERS

5A. DYSTONIA MUSCULORUM DEFORMANS

Torsion dystonia

First seen on 3 siblings of a Jewish family with

progressive involuntary movements of the trunk andlimbs

2 patterns of inheritance

Autosomal recessive: early childhood, progressive over a

few years, restricted to Jewish patients, normal or even

superior intelligence

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


40/66

5.DYSTONIC DISORDERS

5A. DYSTONIA MUSCULORUM DEFORMANS In general, the more restricted types have a later onset

and a relatively milder, more slowly progressivecourse, with a tendency to involve the axial or the distal

musculature aloneAdult-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 istied to chromosome 9q begins early in life in one limb,followed by generalization of the dystonic movements

While in other types, the craniocervical or anotherregion is affected early and the condition does notspread


41/66

5A. DYSTONIA MUSCULORUM

DEFORMANS CLINICAL FEATURES

Patient is usually a child, 6-14 years old

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

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

Spasms become continuous and the body becomesgrotesquely contoured

Lateral and rotatory scoliosis are regular secondarydeformities

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


42/66


DEFORMANS CLINICAL FEATURES

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

Uncontrollable blepharospasm, dysarthria and

dysphagia (dystonia of the tongue, pharyngeal andlaryngeal muscles) Torticollis, action tremor, myoclonic jerks during

voluntary movement and mild choreoathetosis of thelimbs

Tendon reflexes are normal; corticospinal signs areabsent No ataxia, sensory abnormality, convulsions or

dementia In the Philippines, dystonia is sex-linked


43/66


DEFORMANS PATHOLOGY: brain is grossly normal,

ventricle size is not increased

GENETICS

1. Abnormal gene (DYT1) which codes for the proteintorsin A is mapped to the long arm of chromosome9q

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

3. Autosomal dominant PET SCAN: hypermetabolism in the

cerebellum, lenticular nuclei andsupplementary motor cortex


44/66

5B. TORTICOLLIS AND OTHER

RESTRICTED DYSTONIAS

Most frequent and familiar type is torticollis

An adult woman becomes aware of aturning of the head to one side while

walking Limited to scalene, sternocleidomastoid

and upper trapezius muscles

Occasionally combined with dystonia ofthe arm and trunk with tremor and facialspasms


45/66

5B. TORTICOLLIS AND OTHER

RESTRICTED DYSTONIAS

OTHER RESTRICTED DYSTONIAS

1. Blepharospasm/blephacroclonus: orbicularis oculi

2. Spastic dsyphonia, orofacial dyskinesia, respiratory

and phonatory spasms: throat and respiratorymuscles

3. Graphospasm: hand as in writers cramp or

musicians dystonia

4. Proximal leg and pelvic girdle muscles wheredyskinesia is elicited by walking

5. Dyskinesias involving the neck combined with facial

muscles


46/66

5. DYSTONIA

TREATMENT1. L-dopa, bromocriptine, carbamazepine, diazepamand tetrabenzene are helpful early in the course ofthe illness

2. Intrathecal baclofen is somewhat successful in

children3. High doses of Trihexyphenidyl (Artane), 30 mg/day

or more is advocated

4. Clonazepam is beneficial in patients with segmentalmyoclonus

5. Stereotactic techniques centered on the ventrolateralnuclei of the thalamus or in the pallidum-ansalenticularis regions have the most impressive results

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

6 SYNDROME OF PROGRESSIVE


47/66

6.SYNDROME OF PROGRESSIVE

ATAXIA

Chronic forms of cerebellar disease, familial and

more or less confined to the cerebellum

6A. EARLY ONSET SPINOCEREBELLAR

ATAXIAS (PREDOMINANTLY SPINAL) 6A1. 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


48/66

6A1. FRIEDREICH ATAXIA

CLINICAL FEATURES

1. Ataxia of gait always the initial symptom; usually

affects both legs; difficulty in standing steadily and

running

2. Clumsy hands, dysarthric speech; preserved

mentation

3. Pes cavus and kyphoscoliosis: high plantar arch with

retraction of the toes in the metatarsophalyngeal

joints and flexion at the interphalyngeal joints

(hammer toes)

4. Cardiomyopathy: hypertrophic myocardial fibers


49/66


CLINICAL FEATURES In fully developed state, abnormality of gait is of mixedsensory and cerebellar types (tabetocerebellar)

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

(+) Rombergs sign 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 beso incoordinate that the patient chokes while speaking

Facial, buccal and arm muscles display tremulous andsometimes choreiform movements


50/66


CLINICAL FEATURES 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 withcomplete absence of tendon reflexes (areflexiasensory in origin)

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

Sphincter control is preserved


51/66


PATHOLOGY1. Spinal cord is thin; posterior columns, corticospinal

and spinocerebellar tracts are all depleted ofmedullated fibers

2. Large neurons of the dorsal root ganglia are reducedin number

3. Nuclei of cranial nerves VIII, X, XII exhibit a reductionof cells

4. Neuronal loss in the dentate nuclei5. Middle and superior cerebellar peduncles reduced in

size

6. Purkinje cells in the superior vermis and neurons inthe inferior olivary nuclei depleted


52/66


TREATMENT

1. Oral 5-hydroxytryptophan significantly

modifies cerebellar symptoms

2. The drug is serotoninergic and is known tosuppress posthypoxic action myoclonus

3. No other known therapeutic measures

4. Surgery for scoliosis and foot deformitiesmay be helpful

6B PREDOMINANTLY


53/66

6B. PREDOMINANTLY

CEREBELLAR (CORTICAL)

FORMS OF HEREDITARYATAXIA

Degenerative changes in the cerebellum and

brainstem rather than the spinal cord Later age of onset; more definite hereditarytransmission (autosomal dominant); hyperactivityof tendon reflexes; frequent concurrence ofophthalmoplegia, retinal degeneration and optic

atrophy 6B1. PURE CEREBELLAR CORTICAL

ATROPHY Onset in later life

Insidious, slow progression (survival 15-20 years)

6B1 PURE CEREBELLAR


54/66

6B1. PURE CEREBELLAR

CORTICAL ATROPHY

CLINICAL FEATURES

1. Ataxia of gait, instability of the trunk, tremor of the

hands and head and slowed, hesitant speech

2. Intelligence is preserved; nystagmus rare3. Patellar reflexes are increased; extensor plantar

responses

PATHOLOGY: symmetrical atrophy of the

cerebellum, mainly the anterior lobe and thevermis; white matter slightly pale; cell loss in

the dorsal and medial parts of the inferior

olivary nuclei

6C CEREBELLAR ATROPHY


55/66

6C. CEREBELLAR ATROPHY

WITH PROMINENT BRAINSTEM

LESIONS 6C1. SPORADIC AND FAMILIAL

OLIVOPONTOCEREBELLAR ATROPHY Onset of symptoms at the 5th decade

Features: ataxia in the legs, arms, hands and bulbarmuscles

Hereditary pattern1. Autosomal dominant

2. One or more long tracts in the spinal corddegenerate

3. Half the cases develop parkinsonian symptoms

4. Pathology: extensive degeneration of the middlecerebellar peduncles, pontine, olivary and arcuatenuclei

6C1.


56/66

6C1.OLIVOPONTOCEREBELLAR

ATROPHY Sporadic pattern1. More common; in older age than the familial

ones

2. Nystagmus, optic atrophy, retinaldegeneration, ophthalmoplegia

3. Urinary incontinence not present

4. Variants: mild extrapyramidal andneuropathic signs, slow eye movements,dsytonia, vocal cord paralysis, deafness

5. Occurs most often independent ofextrapyramidal degeneration

6C2


57/66

6C2.

DENTATORUBROPALLIDUYSI-

AN ATROPHY CLINICAL FEATURES

1. Cerebellar ataxia with choreoathetosis and dystonia

2. May include myoclonus, parkinsonism, epilepsy ordementia

3. Main diagnostic consideration when chorea is

present is Huntington disease

4. Gene defect: unstable CAG trinucleotide repeat onchromosome 12

5. Autosomal dominant

6C3 DENTATORUBRAL


58/66

6C3. 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 dentatenucleus with degeneration of the superior cerebellar

peduncles


59/66

7. HUNTINGTON CHOREA

Triad of dominant inheritance, choreoathetosisand dementia Overall frequency estimated at 4-5 per million Initial age of onset at 4th-5th decade

Young patients usually inherit the disease fromtheir fathers and older patients from theirmothers

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

Gene abnormality is an excessively long repeatof trinucleotides (CAG), the length of whichdetermines the presence of the disease and theage of onset


60/66


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 orsexual promiscuity

Disturbances of mood: depression Invariably sooner or later, the intellect begins to fall;

becomes less communicative and more sociallywithdrawn; virtual psychosis (delusions andhallucinations)


61/66


CLINICAL FEATURES MENTAL CHANGES

Diminished work performance, inability to manage

household responsibilities and disturbances of sleep

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

Loss of fine manual skills; mental flexibility lessens

Memory is relatively spared; elements of aphasia,

agnosia and apraxia are observed (subcorticaldementia) only rarely


62/66


CLINICAL FEATURES ABNORMALITY OF MOVEMENT Initially: fidgety, restless or nervous Slowness of movement of the fingers and hands,

reduced rate of finger tapping and difficulty in

performing a a sequence of hand movements Increased frequency of blinking (opposite of

parkinsonism); voluntary protrusion of tongue isconstantly 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)


63/66


ABNORMALITY OF MOVEMENT (CHOREA)

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)


64/66


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


65/66


PATHOLOGY AND PATHOGENESIS

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


66/66


TREATMENT Dopamine antagonist haloperidol (2-10 mg) is probablythe most effective agent to suppress the movementdisorder but may cause tardive dyskinesia

The chorea should be treated only if it is functionally

disabling (smallest possible dosages and providingdrug holidays) Drugs that deplete dopamine or block dopamine

receptors (reserpine, clozapine) may suppress thechorea to some degree but side effects (drowsiness,akathisia and tardive dyskinesia) outweigh theirdesired effects

Juvenile form best treated with antiparkinsonian drugs Supportive therapy, genetic counseling Death in 15-20 years

degenerative diseases of the brain 2

Documents