Parkinson’s disease and other movement disorders
Disorders of movement can be classified broadly into akinetic–rigid syndromes, where there is loss of movement with increase in muscle tone, and dyskinesias, where there are added movements outside voluntary control. Both are due to disorders of neurotransmitters of the extrapyramidal system.
Parkinson’s disease is much the most common of these conditions. A classification of movement disorders is given in Table 18.38.
Akinetic–rigid syndromes
· Idiopathic Parkinson’s disease
· PATHOLOGY
· CLINICAL FEATURES
· Symptoms
· Signs
o Tremor
o Rigidity
o Akinesia
o Postural changes
o Speech
o Gastrointestinal and other symptoms
· Natural history
· DIFFERENTIAL DIAGNOSIS
· TREATMENT
· Levodopa
· Unwanted effects of levodopa therapy
· Dopaminergic agonists
· Other agents
· Neurosurgery
· Physiotherapy and physical aids
· Psychiatric aspects
· Drug-induced parkinsonism
· Other movement disorders due to neuroleptic drugs
· Postencephalitic parkinsonism
· MPTP-induced parkinsonism
· Parkinsonism-plus
· Akinetic–rigid syndromes in children
· Wilson’s disease
· Athetoid cerebral palsy
Idiopathic Parkinson’s disease
In 1817, James Parkinson, a physician in Hoxton, London, published a monograph The Shaking Palsy, describing the clinical appearance of these patients. The disease is common and worldwide, with prevalence increasing sharply with age to about 1 in 200 in those over 70 years. The condition is clinically distinct from other parkinsonian syndromes.
There are few real clues as to its cause. The relatively uniform worldwide prevalence of the disease would suggest that an environmental agent is not responsible. Some factors possibly involved are the following.
Nicotine. Some epidemiological studies suggest the curious and unexplained fact that the disease is less prevalent in tobacco smokers than in lifelong abstainers.
MPTP. Minute doses of the pyridine compound, methylphenyltetrahydropyridine (MPTP) cause a severe parkinsonian syndrome. Any significance between this and idiopathic Parkinson’s disease is unclear. The suggestion has been made that environmental MPTP-like herbicides might be relevant.
Encephalitis lethargica. Survivors of encephalitis lethargica (see p. 1065), which is presumed to be a viral disease, develop parkinsonism. However, it is not thought that the idiopathic disease is related to this or to another infective agent.
Genetic factors. The condition is not usually inherited, though there is occasional clustering in families. It is postulated that a failure of dopamine synthesis, genetically programmed, could be responsible.
PATHOLOGY
In the pars compacta of the substantia nigra there is progressive cell degeneration and the appearance of eosinophilic inclusion bodies (Lewy bodies). Degeneration also occurs in other brainstem nuclei. Biochemically there is loss of dopamine (and melanin) in the striatum that correlates well with the areas of cell loss and also with the degree of akinesia. The underlying cause of the progressive changes in neurotransmitter profile (see p. 1030) remains obscure.
CLINICAL FEATURES
There is the combination of tremor, rigidity and akinesia, together with important changes in posture.
Symptoms
The most common symptoms are tremor and slowness of movement. Patients also complain that the limbs feel stiff and ache and that fine movements are difficult. The slowness of movement causes the characteristic symptoms of difficulty in rising from a chair or getting into or out of bed. Writing becomes small (micrographia) and spidery, with a tendency to tail off at the end of a line. Other evidence of the disease often comes from relatives who have noted slowness and an impassive facial expression. The disease is almost always more prominent on one side.
Signs
The diagnosis is often made immediately from the overall appearance of the patient.
Tremor
This is a characteristic 4–7 Hz rest tremor that is usually decreased by action and increased by emotion. Pill-rolling movements between the thumb and forefinger are seen.
Rigidity
Stiffness of the limbs develops that can be felt throughout the range of movement and is equal in opposing groups of muscles, in contrast to the selective increase in tone found in spasticity. This lead pipe-like rigidity is often more marked on one side and is also present in the neck and axial muscles, where it is difficult to examine.
The rigidity is usually more easily felt when a joint is moved slowly and gently. Simultaneous active movement of the opposite limb increases the tone of the side under examination. When combined with tremor, the smooth plasticity of the increase in tone is broken up into a jerky resistance to passive movement, a phenomenon known as cogwheeling, or cogging.
Akinesia
Poverty and slowing of movement (bradykinesia) is an additional handicap, distinct from rigidity. There is difficulty in initiating movement. Rapid fine finger movements, such as piano-playing, become indistinct, slow and tremulous. The immobility of the face gives a mask-like facies with the appearance of depression. The frequency of spontaneous blinking is reduced, producing a serpentine stare.
Postural changes
A stoop is characteristic and the gait is shuffling, festinant and with poor arm swinging. The posture is sometimes called ‘simian’ to describe the ape-like forward flexion, immobility of the arms and lack of facial expression. The patient sits with the trunk bent forward and motionless, without gesture or animation, while the limbs are tremulous. Balance is impaired, but despite this the gait remains on a narrow base. Falls are common as the usual corrective righting reflexes fail, the sufferer falling stiffly, like a falling tree.
Speech
Speech is at first monotonous, progressing to a characteristic tremulous slurring dysarthria, owing to the combination of akinesia, tremor and rigidity. Dribbling is frequent, and dysphagia develops as the disease worsens.
Power remains normal until advanced akinesia makes its assessment difficult. There is no sensory loss. Patients often complain of discomfort in the limbs and joints. The reflexes become brisk; their asymmetry follows the increase in tone. The plantar responses remain flexor.
Cognitive function is preserved, at least early in the condition. Dementia sometimes develops in the late stages.
Gastrointestinal and other symptoms
These include heartburn, dysphagia, constipation and weight loss. Urinary difficulties are common, especially in men. The skin is greasy and sweating is excessive.
Natural history
Parkinson’s disease progresses over a period of years, beginning as a mild inconvenience but slowly overtaking the patient. Remissions are unknown except for rare and remarkable short-lived periods of release. These tend to occur at times of great emotion, fear or excitement, when the sufferer is released for seconds or minutes and able to move quickly.
The rate of progression is very variable, with a benign form running over several decades. Usually the course is over 10–15 years, with death resulting from bronchopneumonia.
DIFFERENTIAL DIAGNOSIS
There is no laboratory test for the disease. The diagnosis is made by recognizing the clinical pattern. Imaging is unhelpful. The condition must be distinguished from other akinetic–rigid syndromes. Hypothyroidism and depression also cause slowing of movement.
Certain diffuse or multifocal brain diseases cause some features of parkinsonism, particularly the slowing, rigidity and tremor seen in idiopathic Parkinson’s. Examples are Alzheimer’s disease, multi-infarct dementia, and the sequelae of repeated head injury (e.g. in boxers, see p. 1114), or the late effects of severe hypoxia or carbon monoxide poisoning.
TREATMENT
Older treatments with anticholinergic drugs altered the disease little, and frequently caused mental confusion. Of these, benzhexol is still used in mild cases and as an adjunct to other therapy. Amantadine, originally introduced as an antiviral agent, is also sometimes helpful.
Levodopa
Levodopa is combined with an aromatic amino acid decarboxylase inhibitor – benserazide (co-beneldopa, as Madopar) or carbidopa (co-careldopa, as Sinemet). The drugs are interchangeable. This combined therapy reduces the peripheral side-effects, principally nausea, of levodopa alone and its metabolites. L-Dopa undergoes O-methylation by catechol-O-methyltransferase (COMT), inhibitors of which will shortly be available, allowing lower doses of L-dopa to be used.
Treatment is commenced gradually (co-beneldopa 125 mg or co-careldopa 110 mg, one tablet three times daily) and increased until either an adequate improvement has taken place or side-effects limit further increase in dose.
The great majority of patients with idiopathic Parkinson’s disease (but not other parkinsonian syndromes) improve initially with levodopa. The response in severe, previously untreated disease is sometimes dramatic.
Unwanted effects of levodopa therapy
Nausea and vomiting within an hour of treatment are the most common symptoms of the dose being too large. Confusion and visual hallucinations also occur with excessive doses. Chorea occurs in acute overdose.
There are difficult issues with long-term levodopa and therapy should not be started until necessary. Sometimes the drug becomes ineffective, even with increasing doses. As the disease progresses, the patient suffers from episodes of severe immobility, known as freezing, and falls. Fluctuation in the response to levodopa also develops, its effect apparently turning on and off. Dopa-induced dyskesias, chorea and dystonic movements appear. The duration of action of the drug shrinks, with dyskinesia becoming prominent at the end of the duration of action of the dose of levodopa (‘end-of-dose dyskinesia’).
The treated patient begins to suffer not only from Parkinson’s disease but also from a chronic levodopa-induced syndrome, fluctuating between dopa-induced dyskinesias and severe and sometimes sudden immobility (‘on-off syndrome’).
Levodopa therapy does not appear to alter the natural progression of the disease itself. After five years’ treatment, around half the patients with Parkinson’s are suffering from minor or major unwanted effects of therapy. These more distressing problems are difficult and often largely insoluble. Approaches to treatment of these complications include the following:
• The interval between levodopa doses is shortened; individual doses may need to be increased.
• Selegiline, a type B monoamine oxidase inhibitor, inhibits the catabolism of dopamine in the brain. This sometimes has the effect of smoothing out the response to levodopa. It has been suggested that there is an increased morbidity from cardiovascular disease in patients taking selegiline, but this remains unproven.
• Oral dopaminergic agonists (see below) are used, to add, or replace existing levodopa therapy.
• Apomorphine, a directly acting dopinergic agonist, given by daily subcutaneous infusion, is probably the best method of smoothing out the fluctuations in response. Skilled nursing help is required to train patients and their relatives to administer the drug. An unusual side-effect of apomorphine is severe haemolytic anaemia.
• Drug holidays – periods of drug withdrawal – are sometimes helpful. They require close supervision since severe rigidity and akinesia follow the withdrawal of levodopa.
Dopaminergic agonists
Bromocriptine, lysuride, pergolide are directly acting dopaminergic agonists, acting principally on D1 and D2 receptors, and also on other receptors D3–5. Additional drugs are being marketed. These are used as an alternative or an addition to levodopa therapy.
Dopaminergic agonists are in general less effective in treating the symptoms of Parkinson’s disease, but are associated with fewer late unwanted dyskinetic effects.
There is much variation in clinical practice between the different regimes of levodopa and dopaminergic agonists, either singly or in combination. Some neurologists tend to use dopaminergic agonists as a primary treatment, before levodopa. There is a trend towards delaying the start of drug treatment until this is clinically essential.
Other agents
Antioxidant compounds such as vitamins C and E possibly help the progression of the condition and are sometimes prescribed. Their role is uncertain.
Neurosurgery
Stereotactic placement of small lesions, usually unilaterally in the ventrolateral nucleus of the thalamus or globus pallidus, was used widely before the advent of levodopa. When successful the procedures still provide effective, if temporary improvement in severe tremor.
Attempts to transplant fetal or autologous dopamine-containing adrenal medulla to the cerebral ventricles or basal ganglia, though technically feasible, have not produced any major clinical improvement in the majority of patients with Parkinson’s disease despite some early promise, and compelling laboratory studies in rats with MPTP-induced parkinsonism. Experimental studies continue.
Physiotherapy and physical aids
Skilled and determined physiotherapy can improve the gait and help the patient to overcome particular problems. Practical guidance is of value about:
• clothing – avoiding zips, fiddly buttons and lace-up shoes.
• cutlery – using built-up handles.
• chairs – high, upright chairs are easier to rise from than deep, comfortable armchairs
• rails – should be fitted near the lavatory and bath
• shoes – should be easy to put on and have smooth soles
• flooring – patients complain that their feet sometimes stick to carpets and rugs, so they prefer to walk on vinyl or linoleum.
Walking aids are often a hindrance in the early stages, but later a frame or a tripod may be helpful. All attempts must be made to prevent falls, the effects of which may be catastrophic in these patients.
Psychiatric aspects
Depression is common in Parkinson’s disease as the symptoms become worse and unresponsive to treatment. It is particularly difficult to treat, since type A monoamine oxidase inhibitor antidepressants (e.g. phenelzine) are absolutely contraindicated with levodopa, and tricyclic antide-pressants (e.g. amitriptyline) have extrapyramidal side-effects.
All antiparkinsonian drugs, especially in high doses, can bring on confusion particularly with nocturnal visual hallucinations, which may exacerbate any cognitive impairment.
Drug-induced parkinsonism
Reserpine (a drug once used in the treatment of hyper-tension), phenothiazines and butyrophenones induce a parkinsonian syndrome, with slowness and rigidity but usually little tremor. Methyldopa and tricyclic anti-depressants also cause some slowing of movement. These unwanted effects tend not to progress. They respond poorly, if at all, to levodopa and usually disappear when the drug causing them is stopped.
Other movement disorders due to neuroleptic drugs
Neuroleptic drugs (i.e. phenothiazines and butyro-phenones) also produce other varieties of movement disorder. Three are described here.
•Akathisia. This is a restless, repetitive and irresistible need to move.
•Acute dystonic reactions. These sometimes follow, dramatically and unpredictably, single doses of neuroleptics, and related drugs used as antiemetics or vestibular sedatives (such as prochlorperazine and metoclopramide). Spasmodic torticollis, trismus and oculogyric crises (i.e. episodes of sustained upward gaze) occur. These acute dystonias respond promptly to the intravenous injection of an anticholinergic drug such as benztropine (1–2 mg) or procyclidine 5–10 mg. Both the offending drug, and all drugs from the same group, should be avoided subsequently.