Parkinson’s disease is a neurodegenerative condition which affects the basal ganglia and which presents with differing combinations of slowness of movement (bradykinesia), increased tone (rigidity), tremor and loss of postural reflexes. Parkinson’s disease has an annual incidence of about 0.2/1000 and a prevalence of 1.5/1000 in the UK. Prevalence rates are similar throughout the world, though lower rates have been reported for China and West Africa. Whilst 10% of the patients are under 45 years at presentation, the incidence and prevalence both increase with age, the latter rising to over 1% in those over 60. Sex incidence is about equal. It is less common in cigarette smokers. The outlook for patients with Parkinson’s disease is variable, and is related to age at onset. If symptoms start in middle life, the disease is usually steadily progressive and likely to shorten lifespan because of the complications of immobility and tendency to fall. Onset after 70 is unlikely to shorten life or become severe.

Pathophysiology

A small number of cases are familial in nature and mutations in several genes have now been identified as an underlying cause. However, in the majority the cause is unknown, and no strong genetic factors have been identified. The discovery that methyl-phenyl-tetrahydropyridine (MPTP) caused severe parkinsonism in young drug users suggests that the idiopathic disease might be due to an environmental toxin; many candidate toxins have been studied, but there is no strong evidence in favour of any of them. There are several features, including depletion of the pigmented dopaminergic neurons in the substantia nigra, hyaline inclusions in nigral cells (Lewy bodies), atrophic changes in the substantia nigra and depletion of neurons in the locus coeruleus. Reduced dopaminergic output from the substantia nigra to the globus pallidus leads to reduced inhibitory effects on the subthalamic nucleus, neurons of which become more active than usual in inhibiting activation of the cortex. This in turn results in bradykinesia.

Clinical features

The classical syndrome of tremor, rigidity and bradykinesia may be absent initially, when non-specific symptoms of tiredness, aching limbs, mental slowness, depression and small handwriting (micrographia) may be noticed. The presentation is almost always unilateral, a resting tremor in an upper limb being a common presenting feature. The tremor may eventually affect the legs, mouth and tongue. It may remain the predominant symptom for some years. Bradykinesia may develop gradually. Most patients have difficulty with rapid fine movements, and this manifests itself as slowness of gait and difficulty with tasks such as fastening buttons, shaving or writing. Rigidity, or increased muscular tone, causes stiffness and a flexed posture. Postural righting reflexes are impaired early on in the disease, but falls tend not to occur until later. As the disease advances, speech becomes softer and indistinct. There are a number of abnormalities on neurological examination, and these are listed below.

Although the features are initially unilateral, gradual bilateral involvement is the rule. Muscle strength and reflexes remain normal, and plantar responses are flexor. There is a paucity of facial expression (hypomimia) and the blink reflex may be exaggerated and fail to habituate (glabellar tap sign). Eye movements are normal to standard clinical testing, provided allowance is made for the normal limitation of upward gaze with age. Sensation is normal and intellectual faculties are not affected initially. As the disease progresses, about one-third of patients develop cognitive impairment.

Physical abnormalities in Parkinson’s disease General Expressionless face Greasy skin Soft, rapid, indistinct speech Flexed posture Impaired postural reflexes Gait Slow to start walking Shortened stride Rapid, small stride length, tendency to shorten (festination( Reduced arm swing Impaired balance on turning Tremor: Resting (4-6 Hz) Coarse, complex movements, usually first in fingers/thumb Flexion/extension of fingers Abduction/adduction of thumb Supination/pronation of forearm May affect arms, legs, feet, jaw, tongue Intermittent, present at rest and when distracted Diminished on action Postural (8-10 Hz) Less obvious, faster, finer amplitude Present on action or posture, persists with movement Rigidity Cogwheel type, mostly upper limbs Plastic (lead pipe) type, mostly legs Bradykinesia Slowness in initiating or repeating movements Impaired fine movements, especially of fingers

The diagnosis is made clinically, as there is no diagnostic test for Parkinson’s disease. Sometimes it is necessary to investigate patients to exclude other causes of parkinsonism if there are any unusual features. Patients presenting before the age of 50 are usually tested for Wilson’s disease, and imaging (CT or MRI) of the head may be needed if there are any features suggestive of pyramidal, cerebellar or autonomic involvement, or the diagnosis is otherwise in doubt.

Management

Drug therapy

Levodopa combined with a peripheral-acting dopa-decarboxylase inhibitor provides the mainstay of treatment in Parkinson’s disease but should only be started to help overcome significant disability. Other agents include anticholinergic drugs, dopamine receptor agonists, selegiline, COMT inhibitors and amantadine.

Levodopa

Although the number of dopamine-releasing terminals in the striatum is diminished in Parkinson’s disease, remaining neurons can be driven to produce more dopamine by administering its precursor, levodopa. If levodopa is administered orally, more than 90% is decarboxylated to dopamine peripherally in the gastrointestinal tract and blood vessels, and only a small proportion reaches the brain. This peripheral conversion of levodopa is responsible for the high incidence of side-effects if it is used alone. The problem is largely overcome by giving a decarboxylase inhibitor that does not cross the blood-brain barrier along with the levodopa. Two peripheral decarboxylase inhibitors, carbidopa and benserazide, are available as combination preparations with levodopa (as Sinemet and Madopar, respectively).

The initiation of levodopa therapy should be delayed until there is significant disability, since there is concern that its use makes long-term side-effects more likely. With this in mind, some authorities suggest that it is advisable to initiate treatment with a dopamine agonist (see below) or a slow-release preparation of levodopa in order to minimise or delay the onset of long-term side-effects, but evidence for this is not strong. The important point is to treat with as little medication as possible consistent with the patient being able to perform the activities of daily living. Levodopa is particularly effective at improving bradykinesia and rigidity. Tremor is also helped but rather unpredictably. The initial dose is 50 mg 8- or 12-hourly, increased if necessary. The total levodopa dose may be increased to over 1000 mg/day if necessary. Side-effects include postural hypotension, nausea and vomiting, which may be offset by the use of a peripheral dopamine antagonist such as domperidone. Other dose-related side-effects are involuntary movements, particularly orofacial dyskinesias, limb and axial dystonias, and occasionally depression, hallucinations and delusions. Unusual but important side-effects include change in personality with increased (sometimes pathological) gambling, hypersexuality and drug (levodopa)-seeking behaviour.

Late deterioration despite levodopa therapy occurs after 3-5 years in one-third to one-half of patients. Usually this manifests as fluctuation in response. The simplest form of this is end-of-dose deterioration due to progression of the disease and loss of capacity to store dopamine. More complex fluctuations present as sudden, unpredictable changes in response, in which periods of severe parkinsonism alternate with dyskinesia and agitation (the ‘on-off’ phenomenon). End-of-dose deterioration can often be improved by dividing the levodopa into smaller but more frequent doses, or by converting to a slow-release preparation. The ‘on-off’ phenomenon is difficult to treat, but sometimes subcutaneous injections of apomorphine (a dopamine agonist) are helpful to ‘rescue’ the patient rapidly from an ‘off’ period.

Involuntary movements (dyskinesia) may occur as a peak-dose phenomenon, or as a biphasic phenomenon (occurring during both the build-up and wearing-off phases). Management is difficult, but involves modifying the way levodopa is administered to obtain constant levels in the brain, and the use of alternative drugs, including amantadine and dopamine agonists. Continuous infusion of apomorphine may be particularly helpful in this situation.

Anticholinergic agents

These have a useful effect on tremor and rigidity, but do not help bradykinesia. They can be prescribed early in the disease before bradykinesia is a problem, but should be avoided in elderly patients in whom they cause confusion and hallucinations. Other side-effects include dry mouth, blurred vision, difficulty with micturition and constipation. Many anticholinergics are available-for example, trihexyphenidyl (benzhexol; 1-4 mg 8-hourly) and orphenadrine (50-100 mg 8-hourly).

Dopamine receptor agonists

Several of these drugs are now available. They all have slightly different activity at the various dopamine receptors in the brain. Apomorphine given alone causes marked vomiting and has to be administered parenterally. The vomiting can be overcome by the concomitant use of domperidone, and parenteral administration achieved through continuous subcutaneous infusion from a portable pump, or by direct injection as needed. This requires considerable nursing support but, used correctly, can be very useful.

More easily administered drugs include bromocriptine, lisuride, pergolide, cabergoline, ropinirole and pramipexole, which can all be taken orally, and rotigotine which can be administered as a transdermal patch. These drugs are less powerful than levodopa in controlling features of parkinsonism, but they are much less likely to cause dose fluctuations or dyskinesia, though they will certainly exacerbate the latter once these have developed. Side-effects include nausea, vomiting, confusion and hallucinations. The dose of bromocriptine is 1 mg initially, increased to 2.5 mg 8-hourly, and thereafter up to 30 mg/day. Pergolide dose starts at 50 μg, increased to 250 μg 8-hourly, and possibly to 3000 μg/day. Dopamine agonists derived from ergot (pergolide and cabergoline) have recently been associated with the development of fibrotic reactions and thickening of heart valves. For this reason, the use of these agents is not advised.

Amantadine

This has a mild, usually short-lived effect on bradykinesia, but may be used early in the disease before more potent treatment is needed. Amantadine can be particularly useful in controlling the dyskinesias produced by dopaminergic treatment later in the disease. The dose is 100 mg 8- or 12-hourly. Side-effects include livedo reticularis, peripheral oedema, confusion and seizures.

Selegiline

Selegiline has a mild therapeutic effect in its own right. An early suggestion that it slows the progression of the disease has been discredited, as has the suggestion that it might be associated with an increased risk of sudden death. The usual dose is 5-10 mg in the morning.

COMT (catechol-O-methyl-transferase) inhibitors

Entacapone (200 mg with each dose of levodopa) prolongs the effects of each dose and reduces motor fluctuations when used with levodopa. This allows the levodopa dose to be reduced and given less frequently.

Surgery

Stereotactic thalamotomy can be used to treat tremor, though this is needed relatively infrequently because of the medical treatments available. Other stereotactic lesions are currently undergoing evaluation, in particular the implantation of stimulating electrodes into the globus pallidus to help in the management of drug-induced dyskinesia. The implantation of fetal mid-brain cells into the basal ganglia to enhance dopaminergic activity remains experimental.

Physiotherapy and speech therapy

Patients at all stages of Parkinson’s disease benefit from physiotherapy, which helps reduce rigidity and corrects abnormal posture. Speech therapy may help in patients where dysarthria and dysphonia interfere with communication.

Recent Approaches for Parkinson’s Disease Therapy

Tags: treatment, sex incidence, decarboxylase <BR/>