DEGENERATIVE DISEASES OF THE NERVOUS SYSTEM 2

MOVEMENT DISORDERS

PARKINSONS 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%

PARKINSONS DISEASE
CLINICAL FEATURES
1. Infrequency of eye blinking (normal: 12-20/min) 2. Slight widening of the palpebral fissures, creating a stare; 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 stages of the disease

TRIAD
1. Tremors 2. Bradykinesia 3. Rigidity

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, pronationsupination of the hand and foream; flexion-extension or abduction-adduction of the hand (pill-rolling tremor) Frequently involves the face-area of the mouth: upand-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 Rest tremors: complete relaxation reduces or abolishes the tremor

PARKINSONS DISEASE
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

PARKINSONS DISEASE
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

PARKINSONS DISEASE
CLINICAL FEATURES
As 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 to avoid falling (festination) Patient freezes in place

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 the bridge of the nose or glabella (Myerson sign) 4. Drooling of saliva 5. Cognitive decline mild and late 6. Depression, visual hallucinations 7. Complicated by dementia in 10-15%

PARKINSONS DISEASE
ETIOLOGY
1. Idiopathic: paralysis agitans 2. Encephalitis 3. Drugs/Toxins
Phenothiazines: Thioridazine, Chlorpromazine Butyrophenones: Haloperidol Metoclopromide Reserpine Toxic substances: manganese, carbon disulfide

PARKINSONS DISEASE
DIFFERENTIAL DIAGNOSIS
1. 2. 3. 4. 5. 6. 7. 8. Progressive supranuclear palsy Striatonigral degeneration Lewy-Body disease Corticobasal ganglionic degeneration Encephalitis: Japanese B encephalitis Pseudobulbar palsy from lacunar infarctions Normal pressure hydrocephalus Senile tremor

PARKINSONS DISEASE
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 2060% 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

PARKINSONS DISEASE
PATHOLOGY AND PATHOGENESIS
A neurotoxin (known as MPTP- 1-methyl-4 phenyl1,2,5,6 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 Parkinsons disease caused by this environmental toxin is common in industrial countries and agrarian areas Ingested by persons who self-administer an analogue of meperidine

PARKINSONS DISEASE
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

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 the peripheral 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 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)

PARKINSONS DISEASE
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; ropinirole: 0.25 mg TID up to 3 mg/day 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 concomitantly reduced by 50%) A dose of 5-10 mg bromocriptine has about the equivalent effect of 100/25 mg levodopa/carbidopa

PARKINSONS DISEASE
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

PARKINSONS DISEASE
TREATMENT
Another 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 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

PARKINSONS DISEASE
TREATMENT 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)

PARKINSONS DISEASE
TREATMENT
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

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 be discontinued abruptly in advanced cases: patient may become totally immobilized by a sudden and severe increase in tremor and rigidity

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 and hallucinations 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

PARKINSONS DISEASE
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

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 subthalamic nucleus produced impressive improvement in all features of the disease

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

 Extensive loss of neurons in the substantia nigra but no Lewy bodies or neurofibriallry 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

2. STRIATONIGRAL DEGENERATION AND MULTIPLE SYSTEM ATROPHY

2A. SHY-DRAGER SYNDROME

CLINICAL FEATURES
1. Orthostatic hypotension: loss of intermediolateral horn cells and pigmented nuclei of the brainstem 2. Combined Parkinsonism and autonomic disorder 3. Impotence, loss of sweating, dry mouth, miosis, urinary retention or incontinence 4. Vocal cord palsy: dysphonia, stridor and airway obstruction

2B. MULTIPLE SYSTEM ATROPHY

CLINICAL FEATURES
1. One or more symptoms of autonomic failure (postural hypotension, urinary urgency or retention, urinary or fecal incontinence, impotence, dysphonia or stridor) 2. Babinski signs, cerebellar ataxia 3. Males more than females; tremors are rare 4. The illness, on the whole, is more severe than Parkinsons disease 5. 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 Parkinsons disease

2B. MULTIPLE SYSTEM ATROPHY

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

3. PROGRESSIVE SUPRANUCLEAR PALSY

CLINICAL FEATURES
1. Seen during the 6th decade 2. Combination of difficulty in balance, abrupt falls, visual and ocular disturbances, slurred speech, dysphagia, vague personality changes 3. The commonest early complaint is unsteadiness of gait and unexplained falling 4. Characteristic syndrome: supranuclear ophthalmoplegia, pseudobulbar palsy, axial dystonia

3. PROGRESSIVE SUPRANUCLEAR PALSY

CLINICAL FEATURES
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 Bells 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

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 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

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

3. PROGRESSIVE SUPRANUCLEAR PALSY

1. 2. 3. 4. DIFFERENTIATED FROM PARKINSONS DISEASE Facial expression in PSP more of tonic grimace than lack of movement in PD Absence of tremors in PSP Erect rather than stooped posture Prominence of ocular abnormalities in PSP

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

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

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 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

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

4. CORTICAL-BASAL GANGLIONIC SYNDROMES

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

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 and limbs 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

5.DYSTONIC DISORDERS
5A. DYSTONIA MUSCULORUM DEFORMANS
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

5A. DYSTONIA MUSCULORUM DEFORMANS

CLINICAL FEATURES
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

5A. DYSTONIA MUSCULORUM DEFORMANS

CLINICAL FEATURES
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

5A. DYSTONIA MUSCULORUM DEFORMANS

PATHOLOGY: brain is grossly normal, ventricle size is not increased GENETICS
1. 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

5B. 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

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 respiratory muscles 3. Graphospasm: hand as in writers cramp or musicians dystonia 4. Proximal leg and pelvic girdle muscles where dyskinesia is elicited by walking 5. Dyskinesias involving the neck combined with facial muscles

5. DYSTONIA
TREATMENT
1. 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

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

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

6A1. FRIEDREICH ATAXIA

CLINICAL FEATURES
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 (+) 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 be so incoordinate that the patient chokes while speaking Facial, buccal and arm muscles display tremulous and sometimes choreiform movements

6A1. FRIEDREICH ATAXIA

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 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

6A1. FRIEDREICH ATAXIA

PATHOLOGY
1. Spinal cord is thin; posterior columns, corticospinal and spinocerebellar tracts are all depleted of medullated fibers 2. Large neurons of the dorsal root ganglia are reduced in number 3. Nuclei of cranial nerves VIII, X, XII exhibit a reduction of cells 4. Neuronal loss in the dentate nuclei 5. Middle and superior cerebellar peduncles reduced in size 6. Purkinje cells in the superior vermis and neurons in the inferior olivary nuclei depleted

6A1. FRIEDREICH ATAXIA

TREATMENT
1. Oral 5-hydroxytryptophan significantly modifies cerebellar symptoms 2. The drug is serotoninergic and is known to suppress posthypoxic action myoclonus 3. No other known therapeutic measures 4. Surgery for scoliosis and foot deformities may be helpful

6B. 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 6B1. PURE CEREBELLAR CORTICAL ATROPHY
Onset in later life Insidious, slow progression (survival 15-20 years)

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 rare 3. 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

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 bulbar muscles

Hereditary pattern
1. Autosomal dominant 2. One or more long tracts in the spinal cord degenerate 3. Half the cases develop parkinsonian symptoms 4. Pathology: extensive degeneration of the middle cerebellar peduncles, pontine, olivary and arcuate nuclei

6C1. OLIVOPONTOCEREBELLAR ATROPHY

Sporadic pattern
1. More common; in older age than the familial ones 2. Nystagmus, optic atrophy, retinal degeneration, ophthalmoplegia 3. Urinary incontinence not present 4. Variants: mild extrapyramidal and neuropathic signs, slow eye movements, dsytonia, vocal cord paralysis, deafness 5. Occurs most often independent of extrapyramidal degeneration

6C2. DENTATORUBROPALLIDUYSIAN ATROPHY

CLINICAL FEATURES
1. Cerebellar ataxia with choreoathetosis and dystonia 2. May include myoclonus, parkinsonism, epilepsy or dementia 3. Main diagnostic consideration when chorea is present is Huntington disease 4. Gene defect: unstable CAG trinucleotide repeat on chromosome 12 5. Autosomal dominant

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 dentate nucleus with degeneration of the superior cerebellar peduncles

7. 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

7. HUNTINGTON CHOREA
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)

7. HUNTINGTON CHOREA
CLINICAL FEATURES MENTAL CHANGES
Diminished work performance, inability to manage household responsibilities and disturbances of sleep Difficulty in maintaining attention, in concentration and in assimilating a new material Loss of fine manual skills; mental flexibility lessens Memory is relatively spared; elements of aphasia, agnosia and apraxia are observed (subcortical dementia) only rarely

7. HUNTINGTON CHOREA
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 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)

7. HUNTINGTON CHOREA
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)

7. HUNTINGTON CHOREA
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

7. HUNTINGTON CHOREA
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

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