风暴式医学教程——锥体外系疾病.doc

23Parkinsons Disease, Other Extrapyramidal Disorders, and MyoclonusExtrapyramidal conditions cause disorders of movement which can be broadly divided into two categories.l Those where there is diminished movement with an increase in tone -akinetic-rigid syndromes. l Those where there are added movements outside voluntary control-dyskinesias.These conditions involve lesions of the basal ganglia and their connections.AKINETIC-RIGID SYNDROMESParkinsons diseaseParkinsons disease was first described by James Parkinson in 1817, who named it the shaking palsy. It is the commonest of all the movement disorders. The disease is seen worldwide, with increasing incidence with age. The prevalence is 1 in 200 in those over 70 years. It is more common in men than in women.PathologyThere is progressive degenerations of cells within the pars compacta of the substantia nigra in the midbrain, with the appearance of eosinophilic inclusions (Lewy bodies). Minor changes may also be seen in other brainstem nuclei (striatum and globus pallidas). As a result, there is a reduction in dopamine in the striatum, disrupting the normal dopamine:acetylcholine ratio.AetiologyThe cause of Parkinsons disease is unknown. Discordance in identical twins suggests that genetic factors are not paramount. However, a consistent environmental factor has not been elucidated. Increased interest in exogenous toxins as a cause arose with the finding that drug addicts taking heroin contaminated with 1-methyl-4 phenyl-1,2,3,6-tetrahydropyridine (MPTP) developed similar condition, with selective destruction of the nigral cells and their striatal connections. A distinction must be made between idiopathic Parkinsons disease and parkinsonism. Parkinsonism denotes a syndrome that appears clinically similar to idiopathic Parkinsons disease but has a different pathological or aetiological basis. Causes of parkinsonism include:l Drugs-especially dopamine antagonists, e.g. phenothiazines, reserpine, haloperidol. l Trauma-especially repetitive head injury, e.g. boxing.l Cerebrovascular disease-especially lacunar infarcts of the basal ganglial Toxins such as MPTPClinical featuresClinical features of Parkinsons disease comprise the classical triad of tremor, rigidity, and bradykinesia, in association with important changes in posture and a mask-like, expressionless face. There is usually striking asymmetry in tremor and rigidity, such that a symmetrical onset should make one doubt a diagnosis of idiopathic Parkinsons disease.TremorThis is a characteristic coarse resting tremor (4-7 Hz), which is usually decreased by action, increased with emotion, and disappears during sleep. The tremor is often pill-rolling, the thumb moving rhythmically backwards and forwards of the palmar surface of the fingers.RigidityThere is stiffness of the limbs which can be felt throughout the range of movement and equally in the flexors and the extensors. This is termed lead-pipe rigidity. When combined with the tremor, there is a jerky element, which is termed cog-wheel rigidity. The increase in tone can be felt most easily when the joint is moved slowly and steadily, and can be made more apparent when the patient is asked to voluntarily move the opposite limb (synkinesis). The rigidity is often asymmetrical and may be very marked in the trunk (axial rigidity).Differences between spasticity and rigiditySpasticityRigidity lesion in upper motor neuronlesion in basal ganglia and connectionsincreased tone more marked in flexors in arms an extensors in legsincreased tone equal in flexors and extensorsincreased tone most apparent early during movement (clasp-knife reflex)increased tone apparent throughout range of movementreflexes brisk with extensor plantarsnormal reflexes with flexor plantarsBradykinesia (akinesia)Slowing and paucity of movement also occurs in addition to the limbs, this affects the muscle of facial expression (mask-like facies), the muscle of mastication, speech, and voluntary swallowing, and the axial muscles. There is difficulty in initiating movements and alternating movements.Posture changesThe posture is characteristically stooped, with a shuffling, festinant gait with poor arm swing. Falls are common, as the normal righting reflexes are affected. The patient falls stiffly, like a telegraph pole.Other featuresSpeech is altered, producing a monotonous, hypophonic dysathria, due to a combination of bradykinesia, rigidity, and tremor. Power is normal, however in advanced disease, the slowness (akinesia) and rigidity makes testing power difficult. Sensory examination is also normal, although patients describe discomfort in the legs. Handwriting reduces in size and becomes spidery (micrographia). Constipation is usual and urinary difficulties are common, especially in men. Depression is common. Cognitive function is preserved in the early stages, although dementia may occur late (to be differentiated from lewy body dementia, in which lewy bodies are found profusely in the cerebral cortex).Natural historyParkinsons disease progresses over a period of years. The rate of progression is very variable, with the mildest forms running over several decades. Usually the course is over 10-15 years, with death from bronchopneumonia.Differential diagnosisThe diagnosis of Parkinsons disease is a clinical one. It must be differentiated from the other akinetic-rigid syndromes (see later), secondary causes of parkinsonism (drugs, cerebrovascular disease, trauma), hypothyroidism, depression (especially in the elderly), and diffuse multifocal brain disease that may have some of the feature of parkinsonism.TreatmentDrug treatment is aimed at restoring the dopamine:acetylcholine balance caused by the dopamine deficiency and therefore either involves restoring dopamine or reducing acetylcholine.Levodopa (L-dopa)Levodopa forms the mainstay for the treatment of most patients with Parkinsons disease. It is given in a combined form with a peripheral decarboxylase inhibitor (benserazide-as Madopar; carbidopa-as sinemet) to prevent peripheral breakdown of the drug and to reduce the peripheral side effects (nausea, vomiting, hypotension). Treatment is commenced gradually and increased slowly until either an adequate effect is achieved or side effects limit further increases. Levodopa improves bradykinesia and rigidity, but has a lesser effect on tremor. The majority of patients with Parkinsons disease (but not other Parkinsonian syndromes) initially improve with L-dopa. However, with time the effect becomes diminished, the duration of action of the drug contracts, there are marked fluctuations in symptoms, and patients experience the on-off syndrome. In the latter, there are marked swings between dopa-induced dyskinesias (chorea, dystonia) and severe and often sudden periods of immobility (freezing), which may bear no relationship to the timing of the L-dopa dose. Consequently, L-dopa therapy should not be started until necessary.Dopamine agonistDopamine agonists are analogues of dopamine and directly stimulate the dopamine receptors. The most effective antiparkinsonian dopamine agonists stimulate D2 receptors predominantly. Dopamine agonists have varying selectivity and include bromocriptine, pergolide, ropinirole, and apomorphine. The latter is administered as individual subcutaneous injections or as a subcutaneous infusion. These can be used alone, especially in younger patients (aged less than 60 years) or to delay L-dopa use, or as an adjunct to L-dopa.Anticholinergic drugsAnticholinergic drugs include benzhexol and bentropine, which are antimuscarinic agents that penetrate the central nervous system. They are most effective in reducing tremor, though not so effective for rigidity and bradykinesia. Side effects (dry mouth, constipation, urinary retenition, visual blurring, hallucinations, and confusion) often prevent their use, especially in the elderly.SelegilineSelegiline is an inhibitor of monoamine oxidase B, so blocking the metabolism of central dopamine. Early use can delay the need for L-dopa, but there may be an increased risk of cardiovascular morbidity in advanced cases.COMT (catechol-O-methyltransferase) antagonistsCOMT antagonists are a new group of drugs. Dopamine is breken down peripherally by both decarboxylase and COMT. The rationale of these drugs is therefore to prevent the additional COMT-mediated breakdown and thus allow greater dopamine availability centrally. They are used in conjunction with L-dopa in order to reduce the L-dopa dose. Entacapone has currently the only drug in use in this group, as tolcapone has been withdrawn due to reports of death due to hepatic failure.SurgerySurgery is not extensively carried out but does have a place in severe cases and young patients. The techniques used include stereotactic thalamotomy for severe tremor, pallidotomy, transplantation of fetal substantia nigra, and subthalamic neurostimulators.Parkinsons plus syndromesParkinsons plus syndromes have some or all of the features of idiopathic Parkinsons disease plus other features.Progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome)Progressive supranuclear palsy may mimic Parkinsons disease in the early stages. There is marked axial rigidity, dementia, and a striking gaze palsy that initially affects vertical gaze but subsequently all the eye movements. Pseudobulbar palsy develops insidiously with dysarthria and swallowing impairment. There is usually little response to L-dopa. There is relentless progression, with a median survival of less than 6 years.Multisystem atrophyThere are three main variants of multisystem atrophy:l Striatonigral degeneration: this produces a picture similar to Parkinsons disease but without the tremor. There is usually no response to medication.l Shy-Drager syndrome: this comprises parkinsonism combined with severe autonomic failure. The parkinsonian features may respond well to L-dopa, but the resulting postural hypotension often forces withdrawal of the drug.l Olivopontocerebellar atrophy (OPCA): there is a variable presentation with this condition-in some patients parkinsonian features predominate, whereas in others cerebellar features are more prominent.Other parkinsonian syndromeDrug-induced parkinsonismAll drugs that have dopamine antagonist effects can cause a parkinsonian syndrome, usually with bradykinesia and rigidity but little tremor. The neuroleptics (phenothiazines) are a common cause. Other drugs include reserpine, butyrophenones, metoclopramine, and prochlorperazine.Cerebraovascular diseaseThe pathogical basis of cerebrovascular disease causing parkinsonism is usually multifocal small-vessel disease, particularly subcortical lacunar infarcts.Wilsons diseaseWilsons disease is an inherited autosomal recessive disorder of copper metabolism which causes copper depositon in the brain (particularly the basal ganglia), in the cornea (Kayser-Fleischer rings), and in the liver (causing cirrhosis). This is a treatable disease and the neurological damage is reve