Download Parkinson`s disease and other movement disorders

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
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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
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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 (cobeneldopa, 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-Omethyltransferase (COMT), inhibitors of which will shortly be available, allowing lower doses of Ldopa 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 sideeffects 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.
•Chronic tardive dyskinesias. These disabling disorders consist of mouthing and smacking of the
lips, grimaces with contortion of the face and neck. They tend to occur several years after
commencing neuroleptic therapy and may be made temporarily worse when the dose of the drug
is reduced. Improvement occurs in fewer than half the cases if the neuroleptic can be stopped.
Postencephalitic parkinsonism
An epidemic of encephalitis lethargica, a condition of unknown cause, last occurred between
1918 and 1930. This disease causes an encephalitis which evolves over several weeks, with
intense sleepiness as a prominent feature, and sometimes psychosis. Some of the survivors left
in its wake remained permanently disabled by a severe parkinsonian syndrome with dystonic
movement disorders. Levodopa produced a dramatic but temporary improvement in some of
these survivors. Occasional sporadic cases of the disease are seen.
MPTP-induced parkinsonism
MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) is an impurity produced inadvertently when
opiates are synthesized illicitly. A severe and largely irreversible parkinsonian syndrome follows
ingestion of minute quantities of MPTP. The relevance of this to idiopathic Parkinson’s disease is
not clear.
Parkinsonism-plus
This term describes rare disorders in which there is parkinsonism and evidence of a separate
pathology. Progressive supranuclear palsy is the most common disorder, and consists of axial
rigidity, dementia and signs of parkinsonism together with a striking inability to move the eyes
vertically or laterally.
Other examples of parkinsonism-plus are the rare multiple system atrophies, such as
olivopontocerebellar degeneration and primary autonomic failure (Shy–Drager syndrome).
Akinetic–rigid syndromes in children
A group of extremely rare disorders cause an akinetic– rigid syndrome primarily in those under 20
years of age. The most important are Wilson’s disease and athetoid cerebral palsy.
Wilson’s disease
This is a rare and treatable disorder of copper metabolism that is inherited as an autosomal
recessive. There is deposition of copper in the brain, particularly in the basal ganglia, in the
cornea and in the liver (see p. 326), where it causes cirrhosis. It is most important that all young
patients with cirrhosis are screened for this condition, as the neurological damage is irreversible
unless early treatment is instituted.
Children with the disease have an akinetic–rigid syndrome and/or dyskinesias followed by
progressive intellectual impairment.
Diagnosis and treatment with the chelating agent penicillamine is mentioned on p. 327.
Athetoid cerebral palsy
Writhing movements of the limbs, sometimes with dystonia, are seen in cerebral palsy following
kernicterus. The dystonia tends to progress. The condition is now much less common following
the prophylactic treatment of rhesus haemolytic disease.