Chapter 14: Movement Disorders
The movement disorders form a substantial part of neurological practice and have gradually attracted increasing psychiatric interest. This is partly on account of their psychiatric concomitants, for example a high incidence of depression in Parkinson’s disease and of behavioural disturbance in the opening stages of hepatolenticular degeneration. More than this, however, biochemical research, particularly in relation to dopamine metabolism, has revealed analogies between the changes thought to underlie certain movement disorders and those postulated to occur in major psychiatric illnesses. Basic research on such issues has been stimulated very considerably. We are, in effect, learning to value the lessons for psychiatry that can be gained from the study of extrapyramidal disease, and to appreciate the importance of subcortical activity in contributing to many aspects of mental life.
An additional spur to interest is the need to be conversant, in day-to-day clinical practice, with the wide range of movement disorders induced by neuroleptic medication. The management of the syndromes that result, and the unravelling of underlying mechanisms, have led neurologists and psychiatrists to areas of common endeavour.
Other movement disorders, such as spasmodic torticollis, writer’s cramp, blepharospasm and Gilles de la Tourette’s syndrome, reflect the striking influence that mental factors may bring to bear on motor dysfunction. So close is this interaction that psychogenic factors may appear to be solely responsible for causing such conditions, yet other evidence suggests that cerebral malfunction may be primarily to blame. Marked psychosensitivity need carry no implications for psychogenesis per se, yet attempts to discern the true situation can prove to be difficult. In the discussion of such disorders below the arguments advanced in both directions will be presented.
Soon after the introduction of phenothiazines to psychiatric practice it became apparent that extrapyramidal movement disorders ranked high among the unwanted effects of treatment. Until the introduction of clozapine, the successive development of new neuroleptics failed to solve the problem, in that all major tranquillisers appeared to share these side effects in some degree. Their propensity to disturb extrapyramidal function proved, indeed, to be roughly proportional to their antipsychotic effect, though earlier ideas that the two were necessarily linked to one another have not been upheld.
Among the phenothiazines, those with a piperazine side chain (e.g. trifluoperazine) show more marked extrapyramidal effects than those with aliphatic or piperidine side chains (e.g. chlorpromazine, thioridazine). The butyrophenones (haloperidol, benperidol, droperidol) are particularly potent in this regard. The thioxanthenes (e.g. flupenthixol) may induce the whole range of disorders considered below, whereas reserpine’s effects are usually limited to parkinsonism. Disturbance of dopaminergic mechanisms within the brain has been clearly incriminated as the major factor in leading to these effects, and clarification of the detailed mechanisms involved has had important consequences for the management of some of the more serious disorders.
Four main syndromes have been delineated, namely parkinsonism, akathisia, acute dystonic reactions and the group of disorders at present subsumed under the term ’tardive dyskinesia’. Tardive dystonia and tardive akathisia have been recognised more recently. Precise estimates of the incidence of all such conditions have been hard to obtain, on account of variations in prescribing practice and differences in the populations surveyed. It is now firmly established, however, that the drugs are to) be blamed rather than inherent aspects of the psychiatric disorders themselves. Exactly analogous movement disorders are induced whether the neuroleptics are given for schizophrenia, affective disorder, neurotic disability or for the control of chronic pain. It must be granted, however, that the stereotypies and mannerisms of chronic schizophrenia
can at times lead to diagnostic difficulty and even obscure for a while the development of the extrapyramidal symptoms.
The clinical pictures encountered are fully described in comprehensive reviews by Marsden et al. and Miyasaki and Lang , and may be summarised as follows.
Parkinsonian features usually develop insidiously, often within a week and almost always within the first month of treatment.
The development of parkinsonism is broadly dose dependent, increasing as higher levels of neuroleptics are achieved.
It emerges, however, in only some 20-40% of persons, individual susceptibility being important. The incidence increases with age, as with idiopathic Parkinson’s disease.
All of the features of idiopathic Parkinson’s disease (p. 646) may be induced.
Bradykinesia is the earliest and commonest sign, with muscular rigidity and disturbance of posture and gait developing later.
Tremor is a good deal less common than with the idiopathic disease, the exception being the occasional appearance late in the course of treatment of fine perioral tremor (’rabbit syndrome’). The latter generally sets in after months or years of therapy as with tardive dyskinesia.
With continuation of the drugs the parkinsonian features may gradually subside as tolerance develops. Short of this they will usually resolve over the course of several weeks when the drugs are stopped.
Marsden and Jenner stress, however, that occasional patients continue to show parkinsonism for as long as 18 months after cessation of therapy. In the rare examples that fail to recover thereafter one may usually presume that idiopathic Parkinson’s disease had already been present.
With the more severe extrapyramidal reactions provoked by potent neuroleptics, the clinical picture may occasionally come to resemble ’catatonia’.
Gelenberg and Mandel described a group of patients showing negativism, withdrawal, posturing and waxy flexibility, of gradual onset usually in the first few weeks of treatment.
Incontinence of urine was sometimes observed.
Behrman has described mutism, sometimes progressing to the full syndrome of akinetic mutism.
Such developments may easily be confused with worsening of schizophrenic symptomatology, leading to increase in dosage of the offending medication. Stopping the drugs, by contrast, can lead to slow resolution.
Akathisia consists of motor restlessness accompanied by subjective feelings of inner tension and discomfort referable chiefly to the limbs. It often coexists with parkinsonian features but is possibly even more common. The symptoms can be considerably distressing and are a frequent cause of poor drug compliance. The patient cornplains of being driven to move, of pulling sensations in the legs and an inability to keep them still. The disorder usually appears within the first few days of treatment but may only develop as higher dosage is achieved. Barnes has produced a rating scale for assessment of both the observable and subjective components of the syndrome. Sometimes the latter are lacking (pseudoakathisia), chiefly in patients with negative psychotic symptoms.
Braude et al. investigated motor restlessness in detail by ratings of subjective sensations and objective manifestations in a large group of patients on antipsychotic medication. A principal components analysis served to delineate the akathisia syndrome more precisely. Mild examples presented mainly subjectively; inner restlessness was a common and non-specific symptom, but complaints clearly referable to the legs characterised the akathisia group. Moderate akathisia showed in addition a tendency to rock from foot to foot or to walk on the spot, along with coarse tremor or myoclonic jerks in the feet. The severe akathisia group showed difficulty in maintaining their position, for example shuffling or tramping the feet when sitting, rising repeatedly when seated, or walking or pacing when attempting to stand still. In the most severe forms patients may be unable to tolerate any position, whether sitting, lying or standing, for more than a few minutes.
Continuation of the drugs may allow the symptoms to subside, but this is not invariable. An extrapyramidal origin is postulated, but the evidence for this is mainly inferential.
Akathisia must be distinguished from the restless legs syndrome (Ekbom’s syndrome) which may resemble it closely. This is seen in the absence of neuroleptic medication, usually in patients who are otherwise in normal health. However, associations have been noted with iron-deficiency anaemia, uraemia and pregnancy, and it is unusually common among patients with fibromyalgia or rheumatoid arthritis . Physical examination typically shows no neurological abnormality, though a small proportion of patients have peripheral neuropathy. The condition is sometimes familial.
An important difference from akathisia lies in the presence of marked leg discomfort, with creeping sensations, dysaesthesiae or sensations of cold or weakness, usually most pronounced in the calves . The desire to move arises directly from such discomforts which are temporarily relieved by getting up and walking about, whereas in akathisia the motor restlessness appears to derive directly from psychological impulses . The discomfort usually occurs while at rest in the evening or while trying to sleep, often leading to pronounced insomnia. Nocturnal myoclonus may be present. Among many treatments used clonazepam, carbamazepine, chlorpromazine and levodopa are perhaps the most effective.
1. Acute dystonic reactions are considerably rarer than the above reactions, affecting perhaps some 2% of patients.
2. They develop abruptly and early in the course of treatment, within a few days of oral treatment or within hours of intramuscular injection.
3. The more potent piperazine phenothiazines and the butyrophenones are chiefly responsible.
4. Young adults and children appear to be particularly susceptible, and males have outnumbered females in most surveys.
5. The patient is seized with strong sustained or intermittent muscular spasms which are frequently painful and deeply alarming. Deviation of the eyes, blepharospasm, trismus and grimacing are common. Severe examples show tongue protrusion, dysphagia and respiratory stridor. Extension to the neck and trunk can lead to torticollis, retrocollis, writhing and opisthotonos. Continuous slow writhing may affect the limbs, with dystonic postures of hyperpronation and adduction.
6. Marked examples may be mistaken for status epilepticus or tetanus by the inexperienced observer. Hysteria may be diagnosed when muscular spasms are remittent. The disorder is self limiting and usually of no more than several hours duration, though therapeutic intervention will often be indicated for the relief of acute distress.
As experience was gained of long-term neuroleptic medication it became apparent that a range of movement disorders make their first appearance only late in the course of treatment. These have attracted considerable attention, on account of their sometimes seriously disabling nature and because in a proportion of patients they can prove to be irreversible. The term ’tardive dyskinesia’ is used to refer to such late developments rather than to any phenomenologically distinct dyskinetic picture.
The commonest site of the abnormal movements is around the mouth and tongue, which become involved in a more or less continuous flow of choreiform activity (orofacial dyskinesia, bucco-linguo-masticatory dyskinesia). The tongue protrudes, twists and curls, along with incessant chewing, pouting and sucking movements of the lips, jaw and cheeks. In severe examples talking and eating can be hampered. The upper face tends typically to be spared, but may show tic-like blinking or blepharospasm. The neck may be affected with twisting dystonic movements.
Involvement of the trunk, arms, hands and legs may also be observed . The distal extremities show choreiform and athetotic movements, with finger twisting and spreading, tapping of the feet and dorsiflexion of the toes.
Abnormalities of gait and posture show as lordosis, rocking and shoulder shrugging.
Grunting and disturbance of the respiratory rhythm may be in evidence.
Factor analysis applied to ratings of involvement of different body regions has suggested that there may be relatively independent subvarieties, affecting, respectively, the jaws and tongue, the face and lips, and the extremities and trunk . These may possibly have differing aetiological and prognostic connotations.
Altogether the picture may come to involve a complex admixture of tics, chorea, athetosis, dystonia and myoclonic jerks. Rhythmic tremor is not, however, seen. It may worsen dramatically with emotional stress and it decreases with drowsiness. Choreiform movements appear to be commoner in the elderly, and dystonic pictures in the young. Age also influences the topography, orolingual movements being especially common in the elderly.
A similar disorder is known to occur spontaneously in the elderly, as the relatively rare ’senile chorea’. In patients on long-term neuroleptics, however, tardive dyskinesia is far from uncommon. Variable estimates have resulted from different surveys, depending among other factors on readiness to include very minor degrees of movement disorder. The working party appointed by the American Psychiatric Association (Task Force on Late Neurological Effects of Antipsychotic Drugs concluded that between 10 and 20% of people given antipsychotic drugs for a year or more could be expected to develop a clinically appreciable tardive dyskinesia, the rate probably being higher in the elderly. Disabling degrees are, however, rare. In the great majority of cases the patient will have been on neuroleptics for at least 2 years when the disorder makes its first appearance and often for considerably longer. A minimum period of exposure appears to be 3-6 months. In addition to neuroleptics, the condition may follow the prescription of antiemetics such as metoclopramide which also acts through dopamine receptor blockade.
Among the predisposing factors highlighted in certain surveys are age, sex and evidence of brain damage. There is a marked increase in incidence after the age of 40, and a female preponderance has repeatedly emerged among the elderly. The influence of pre-existing brain damage has been less uniformly upheld, but a history of exposure to electroconvulsive therapy or leucotomy has been found to increase the risk, likewise evidence of cognitive dysfunction or negative symptoms in schizophrenia .
In McClelland et al.’s long-term follow-up of hospitalised patients the development of facial dyskinesia was significantly associated with ventricular enlargement on computerised tomography (CT) scans. Patients with organic psychiatric disorders have shown an especially high prevalence.
The evidence that patients with affective disorders may be more at risk than patients with schizophrenia is reviewed by Barnes , likewise indications that depressive symptomatology in the course of schizophrenia may confer additional risk.
There is some evidence that prolonged exposure or exposure to high dosage of neuroleptics may increase the chance of developing the condition, but this is disputed.
The Yale study, in which a large cohort of patients was followed prospectively for evidence of developing the condition, has been exceptional in finding a clear positive relationship to neuroleptic dose .
It is clear, however, that most patients will have received large total quantities before tardive dyskinesia supervenes. The concomitant administration of anticholinergics appears to increase the severity of the disorder but probably does not alter the risk of its development. A noteworthy feature is that the first signs very often make their appearance when the drugs are discontinued or the dosage is lowered.
A disturbing aspect of the condition is its liability to persist despite stopping the medication. A majority of patients will improve substantially, usually within months but sometimes taking 1 or 2 years for complete resolution. Between a quarter and a half of patients may be expected to improve markedly within a year .
In children complete recovery can be predicted, but in some 30% of adults the condition seems destined to be permanent, especially in the elderly. It may, however, pursue a fluctuating course, and some patients experience spontaneous remission.
Important aspects of differential diagnosis include schizophrenic stereotypies and mannerisms, senile chorea, Huntington’s disease, Wilson’s disease and rheumatic chorea.
Burke et al. have described a syndrome of ’tardive dystonia’ which appears to be attributable to antipsychotic medication. As with tardive dyskinesia it typically follows several years of treatment with the drugs, and once established it tends to be persistent. The nature of the movement disorder is, however, quite different. The dystonia consists of sustained slow twisting movements affecting the limbs, trunk, neck or face. Among younger patients generalised dystonia is the usual picture, whereas in older patients the movements are often confined to the face, neck or arms. Unlike tardive dyskinesia it typically causes severe distress to the patient and can result in significant neurological disability.
Among Burke et al.’s 42 examples the age of onset varied from 13 to 60 years, after an average duration of exposure to drugs of 3-7 years. The onset was usually insidious, progressing over some months or years then becoming persistent and static. One patient was sufficiently disabled to be chronically confined to bed. All classes of antipsychotic medication could be incriminated-phenothiazines, butyrophenones and thioxanthenes.
The picture in generalised cases was indistinguishable from idiopathic torsion dystonia (p. 670, though all lacked a family history of such a condition. The possibility that they simply represented a chance association of this disorder appearing while on antipsychotic medication was considered to be remote, especially since a proportion showed the oral choreic movements of tardive dyskinesia along with their dystonia. Focal cases could present pictures identical to torticollis, blepharospasm or oromandibular dystonia. Pharmacological differences from tardive dyskinesia were shown in that anticholinergic agents, rather than causing exacerbation, could sometimes be observed to improve the dystonic movements. Treatment was, however, mostly disappointing. An increase in the offending medication could lead in some cases to temporary amelioration but this was short-lived.
Further experience has been reported by Kang et al. and Burke and Kang . Among 67 patients the median duration prior to onset was 5 years. However, 20% had developed relatively early within 1 year of starting neuroleptic drugs, the shortest exposure being 3 weeks. Two-thirds began with a focal onset in the face and neck, 15% remaining confined there and the others extending elsewhere. Only one patient showed generalised dystonia from the start. Most progressed to a plateau after several months, and by the time of maximal severity 15% were focal, 72% segmental and 13% generalised in distribution. Sustained postures could sometimes be seen in addition to the slow twisting movements, sometimes relieved by small tactile manoeuvres as in dystonia generally (pp. 670 and 673. Strange paradoxes could be seen, with some activities alleviating the condition while other movements aggravated it. The movements generally abated during sleep. Classic oro-bucco-lingual dyskinesia was present in 20% of patients and had featured at some point in the histories of rather more than half.
Follow-up for a mean of 2.5 years showed that half of the 67 patients had improved on various therapies, but the degree of disability remaining was often considerable. Five ofr the 42 withdrawn from neuroleptics had remitted completely, but only after substantial periods off the drugs (11 months to 5 years). Another eight could be considered as having successful results from therapy.
Davis et al. have extended the spectrum of disorders encountered, reporting three patients with laryngospasm as part of the clinical picture, sometimes developing abruptly and requiring tracheostomy, and two patients with spasmodic dysphonia.
In all cases differentiation must be made from Wilson’s disease by appropriate diagnostic studies, also from other symptomatic dystonias when there are abnormal neurological signs. A primary blepharospasm, oromandibular dystonia or torticollis must be considered when there are no dyskinetic movements. The distinction from classic tardive dyskinesia can at times be difficult and both may occur together; the distinction is chiefly important because of the different options presented for treatment (p. 645). Finally, it is important to beware of mistaking the picture for a psychogenic disorder, particularly when the movements are bizarre or influenced transiently by emotion, suggestion or an amytal interview.
A syndrome of ’tardive’ or ’chronic’ akathisia has been distinguished from the acute form, usually developing after some years on neuroleptics. It may coexist with features of tardive dyskinesia, including orofacial dyskinesia and choreoathetoid movements of the limbs; and like tardive dyskinesia it may worsen on dose reduction whereas acute akathisia tends to be aggravated by increase in dosage.
Burke et al. have presented the features seen in 52 cases. The condition had developed after a mean of 4.5 years on dopamine antagonists, but in a third had developed within a year. Complex stereotyped movements consisted of marching on the spot, frequent crossing and uncrossing of the legs, trunk rocking, grunting, moaning and face rubbing or scratching. Half of the patients managed to stop neuroleptics, and the symptoms then persisted for a mean of 2.5 years. The younger patients did better than the old. Attempts at therapy were frequently disappointing (p. 645). The condition can be profoundly disabling, leading to inner torment, irritability and inability to concentrate.
The pathophysiology of the neuroleptic-induced movement disorders appears to lie with various aspects of the dopamine-acetylcholine balance within the brain, more particularly within the corpus striatum. Earlier views have, however, become progressively more complex, with the discovery of both inhibitory and excitatory dopamine receptors in the striatum, and the demonstration of feedback striatonigral pathways which may be mediated in part by cholinergic or GABA-ergic mechanisms. The maintenance of correct dopamine and acetylcholine levels in the striatum is clearly under highly complex control and stands to be disturbed in a multitude of ways. Hence, no doubt, the variety of movement disorders encountered when this balance is altered by drugs. Discussions of the theories put forward in attempts at explanation are provided by Marsden and Jenner , Baldessarini and Tars and Miyasaki and Lang.
Among their many pharmacological actions, all neuroleptics have powerful effects on cerebral dopamine mechanisms. These correlate highly with their antipsychotic potency. It is clear, however, that the induction of extrapyramidal motor disorder is not a necessary prerequisite for benefit to psychosis, the latter conceivably hinging on effects within the mesolimbic dopamine projections (arising in the legmen turn of the midbrain and terminating in limbic forebrain structures) rather than on actions within the nigrostriatal system. The phenothiarines, butyrophenones and thioxanthenes act specifically to block cerebral dopamine D2 receptors. Reserpine and tetrabenazine operate differently, interfering with the intraneuronal granular uptake and storage of dopamine. Clozapine differs from the typical antipsychotics, in that it has weak effects on striatal dopamine D2 receptors, a high affinity for D4 and Dt receptors, and a relatively strong blocking effect on serotonin S2 receptors .
Drug-induced parkinsonism appears to be chemically closely analogous to naturally occurring Parkinson’s disease. The blockade of dopamine receptors within the striatum amounts to ’chemical denervation’, resulting in relative dopamine deficiency. Anticholinergic drugs can accordingly be of benefit by helping to restore the correct dopamine-acetylcholine balance.
The genesis of akathisia is little understood, but may rest on dopamine receptor blockade in brain areas other than the striatum. It is interesting that this is the only form of movement disorder which may develop within a few hours of starting treatment, i.e. within the time frame of dopamine receptor blockade with neuroleptics. It is clear, however, from pharmacological responses that other neurotransmitters must also be involved, including central adrenergic systems (p. 644).
The mechanisms underlying acute dystonic reactions also remain obscure. Their peak incidence at 24-48 hours from the initiation of therapy is well after the peak onset) of dopamine receptor blockade. They may reflect interference with presynaptic dopamine mechanisms; or there may be a mismatch between excess release of dopamine and coincident hypersensitivity of dopamine receptors. Neuroleptics principally occupy D2 receptors, and the increased dopamine turnover may be expressed through overactivation of unblocked D( receptors. Again, however, it is likely that other neurotransmitter systems are also implicated.
There is probably not a unitary pathophysiology for tardh e dyskinesia; various patterns of movement emerge after varying lengths of treatment and differ in their persistence. It has been especially difficult to explain why drugb which block striatal dopamine receptors should eventually produce forms of dyskinesia known to be associated with dopamine overactivity in the striatum. Thus the choreiform movements of tardive dyskinesia resemble those seen as a complication of levodopa therapy in Parkinson’s disease, and the administration of levodopa or of anticholinergic drugs exacerbates the condition. The prolonged blockade may have led to this end result by virtue of increased dopamine turnover coupled with upregulation of receptor numbers, possibly with an imbalance between the Dj and D2 receptors. Alternatively, hypersensitivity of D2 receptors may cause them to respond abnormally to the dopamine reaching them. Hypersensitivity of this nature probably accounts for the worsening of the condition on withdrawal of neuroleptics and the success of their reintroduction in ameliorating the condition. However, attempts to demonstrate dopamine receptor supersensitivity by positron emission tomography (PET) or at autopsy have been relatively unsuccessful.
Animal studies have indicated that over the course of prolonged neuroleptic administration, dopamine receptor blockade may actually slowly disappear, giving way to supersensitivity in its place. The latter, moreover, can be shown to persist for many months after withdrawal, providing an analogy to the possible situation in tardive dyskinesia in humans .
It remains difficult, nevertheless, to reconcile the very late appearance of tardive dyskinesia with the supersensitivity known to develop soon after starting neuroleptics, and it is likely that complex interactions with other neurotransmitters are also in part responsible. A role for GABA neurones in the striatum has been suggested .
No convincing pathology has been described in the brain to account for those tardive dyskinesias which become irreversible. Structural or neurotoxic changes in the neurones, affecting their membranes or the cell respiratory mechanisms, must nevertheless be postulated in such cases.
Anticholinergic drugs are of value in controlling drug-induced parkinsonism. It often transpires, however, that once parkinsonian features have come under control, the antiparkinsonian medication can then be withdrawn without recrudescence of the motor disorder. It should therefore be tapered off after 3 months for a trial period. Certainly if the risk of producing a severe tardive dyskinesia is to be minimised it would seem important to give anticholinergic medication as sparingly as possible, and only when the parkinsonism causes definite disability. Long-continued anticholinergic administration as a routine adjunct to neuroleptic treatment is now considered to be contraindicated. Levodopa should theoretically help drug-induced parkinsonism, but has been little used to date, perhaps because of adverse effects on the psychosis.
When akathisia is a persisting and disabling complaint the most decisive remedy is reduction of drug dosage .
Benzodiazepines may help in some degree, also anticholinergic agents when drug-induced parkinsonism is present as well. The most encouraging results, however, appear to be obtained with beta blockers such as propanolol, which can reduce both subjective and objective manifestations of the syndrome . If the above procedures are without effect and the symptoms are very disabling it may be necessary to change the neuroleptic to clozapine.
For acute dystonic reactions anticholinergic drugs are best given parenterally. Benztropine (Cogentin), diphenhydramine (Benadryl) and procyclidine (Kemadrin) can be administered intravenously and are often dramatically effective. Intravenous diazepam can also help. For milder reactions it is important to remember the efficacy of nonspecific calming of the patient, or simple sedation with diazepam. The previous occurrence of dystonic reactions constitutes one of the few indications for the prophylactic prescription of anticholinergic drugs from the start of a course of neuroleptic medication.
The management of tardive dyskinesia must take into account every effort at prevention. There is no firm evidence that any particular phenothiazine, butyrophenone or thiothanxene is less hazardous than others in this regard, though some think the risk is less with thioridazine, oxypertine or sulpiride. Dosage and duration of neuroleptics should be kept to a minimum, and long-term maintenance therapy strictly reserved for patients in whom definite benefit can be expected. In practice this usually means patients with chronic schizophrenia of a type liable to manifest on-going positive symptoms in the absence of medication. The task force of the American Psychiatric Association recommended that all patients on long-term treatment should be reviewed at 6- or 12month intervals (Task Force on Late Neurological Effects of Antipsychotic Drugs 1980). Whenever considered safe and feasible at these reviews the drugs should be gradually reduced until stopped completely for a 2-week period.
Such ’drug holidays’ have not been shown to be helpful in themselves in preventing tardive dyskinesia, and there have even been suggestions that they may increase the risk.
Nevertheless they allow assessment of continuing responsiveness to the drug and facilitate detection of the earlier stages of the disorder. Mild and early examples are perhaps most likely to subside, but even if they do not the patient will be left with less severe disability. Anticholinergic drugs as an adjunct to treatment should be avoided whenever possible.
Once tardive dyskinesia is detected anticholinergic drugs should be discontinued immediately. The next step is to reduce the dosage of neuroleptics gradually and if possible stop them altogether. This may lead to an initial worsening of the condition, but in favourable cases it will be a temporary exacerbation. Some 30-50% of patients will improve as a result, but this may occur only gradually over a number of months or years. If the mental state does not permit total withdrawal it may be possible to settle for a lower dose, or a change to a less potent neuroleptic such as thioridazine or sulpiride. In severely psychotic patients a change to clozapine may be indicated.
When the movements persist other treatments may be tried, but the number advocated indicates that none is universally successful. Drugs which deplete striatal dopamine such as reserpine or tetrabenazine are probably the treatments of first choice, but should be avoided in patients with pre-existing depression. Cholinergic agents such as physostigmine and lecithin, or GABA-enhancing drugs such as baclofen and sodium valproate may sometimes help. Benzodiazepines may be useful by virtue of their sedating effect. Propanolol, clonidine and the calcium channel blocker diltiazem have occasionally produced success . More recent treatments evaluated by double-blind comparisons include clonazepam and vitamin E used as a free radical scavenging agent .
Quite often, however, it will be found that no available therapy ameliorates the condition and one must merely hope for spontaneous resolution. The temptation to control the dyskinesia by reintroducing neuroleptics at increased dosage is strictly to be avoided, except in those rare cases where life is threatened by the severity of the involuntary movements. While it may be highly efficacious in producing short-term relief, this merely postpones the problem by reinstating the original pathogenesis and can be expected to worsen the ultimate disability. Clozapine in high dosage is perhaps an exception in this regard, preliminary studies showing that when given long term it can be effective in suppressing the condition.
Tardive dystonia presents equally severe management problems and the results of treatment are often disappointing. The first step should be to taper or discontinue the causative drugs or change to alternative therapy. Anticholinergic drugs such as benzhexol can help, though at the expense of worsening any coincident tardive dyskinesia. Reserpine or tetrabenazine are probably the most effective treatment, producing improvement in twothirds of Kang et al patients. Diazepam, lorazepam or baclofen may also be successful on occasion, different patients responding to different drugs.
Rarely it may be necessary to continue with the offending neuroleptic drug, for example when severe dystonia is causing pain or muscle damage as indicated by raised levels of serum creatine phosphokinase; or it may be necessary to reintroduce it when a drug-free period of 4-5 years has not achieved remission and all other treatments have failed . Clozapine holds special promise and has been reported to help after fruitless attempts with other drugs, leading to slow improvement over several months . It would certainly appear to be the drug of choice in patients whose psychosis requires the continuation of neuroleptics . The combination of clozapine and clonazepam has sometimes proved to be particularly effective .
Treatment of tardive akathisia can be particularly difficult, not least because discontinuation of neuroleptics may lead to transient worsening. This should nevertheless be attempted, even though few cases will benefit substantially. Burke et al. found that reserpine and tetrabenazine were the most successful drugs to try, though only a third of their patients achieved complete resolution of symptoms. Anticholinergics and beta blockers were without effect, though lorazepam improved occasional patients markedly. Sometimes the reintroduction of neuroleptic at higher dosage may need, ultimately, to be tried.
Parkinson’s disease and the parkinsonian syndrome
The cardinal neurological deficits which make up the syndrome of parkinsonism are tremor, muscular rigidity, bradykinesis and postural abnormality. A large number of other associated features are also characteristic as described below.
By far the commonest form is idiopathic parkinsonism or paralysis agitans, as described by James Parkinson in 1817. This owes its origin to a specific degeneration of pigmented cells in the brain stem, particularly those of the substantia nigra. An hereditary tendency towards the disease has recently been newly reconsidered ; in certain very rare families it has followed the pattern of autosomal dominant inheritance . Environmental ’toxins’ are also possibly operative (p. 648). Idiopathic parkinsonism is usually diagnosed when no evidence can be found from the history or examination for the presence of other diseases which could be aetiologically relevant.
The same clinical picture may be induced by certain medications such as reserpine, phenothiazines, butyrophenones and methyldopa (’drug-induced parkinsonism’). This tends to remit slowly over several weeks or months when the offending drug is withdrawn. A similar syndrome, ’postencephalitic parkinsonism’, was a common aftermath of the pandemics of encephalitis lethargica which occurred almost 80 years ago (p. 352). Cases could appear up to 20 years after the original infection which was sometimes very mild. An early age of onset suggested the postencephalitic variety, also oculogyric crises, abnormal pupil reactions or continuing marked sleep disturbance.
Many other conditions that affect the basal ganglia may cause akinetic rigid syndromes along with other features resulting from diffuse brain damage, for example repeated head injuries in boxing, cerebral syphilis, anoxia due to cardiac arrest, or poisoning with carbon monoxide or manganese. Such a syndrome may appear as part of other degenerative disorders such as progressive supranuclear palsy, multiple system atrophy, Alzheimer’s disease, Lewy body dementia, Wilson’s disease or cerebral arteriosclerosis. The latter, however, is no longer recognised as a cause of Parkinson’s disease per se, and the category of ’arteriosclerotic parkinsonism’ has fallen into disrepute . Certainly the clinical features that were used to delineate this form of the syndrome were variable from one observer to another. An arteriosclerotic origin tended to be blamed when the onset had been acute or progression had occurred in a step-like manner, when progressive dementia coincided with or preceded the parkinsonism, or when pseudobulbar palsy or pyramidal deficits were present. Marche a petit pas seemed also to be characteristic of the variety. It is hard, however, to establish a causal relationship to cerebral arterial disease when this exists, and the two disorders probably simply occur together by coincidence. In Eadie and Sutherland’s study no more clinical evidence of arterial disease could be found in a large group of parkinsonian patients than among equivalent agematched controls.
Hoehn and Yahr reviewed 802 patients from a neurological clinic and considered 84% to be idiopathic, 15% secondary (mostly postencephalitic but also ’arteriosclerotic’, toxic and metabolic in origin) and 1% to show uncertain evidence of being either primary or secondary.
The idiopathic disease is slightly commoner among men than women. The mean age of onset is 55 years with twothirds of cases beginning between 50 and 59 . Excellent accounts of the clinical features and natural history are given by Selby and Pearce .
Tremor is the presenting feature in about three-quarters of the idiopathic cases, consisting of four to six per second alternating contractions of opposing muscle groups.
It is present at rest but ceases during sleep, and may become less marked when the limb is engaged in voluntary movement.
It is worsened by excitement, anxiety and fatigue. Most typically it appears in the hands as flexion extension movements affecting the metacarpophalangeal joints of the fingers and thumb.
It is common also in the jaw and tongue and may come to affect the head or the lower limbs.
In some cases it is predominantly or entirely unilateral.
Rigidity affects the large and small muscles of the limbs
trunk and neck
involving agonists and antagonists equally and through the whole range of passive movement. In these respects it is quite unlike the spasticity that results from corticospinal tract damage
and feels to the examining hand to have a ’lead pipe’ or ’plastic’ quality. When tremor is also present
the rigidity is broken up (’cogwheel rigidity’). Rigidity
can be predominantly unilateral. It persists during sleep and is unaffected by emotional factors.
Bradykinesia consists of poverty and slowness of movement. This is not due solely to rigidity since stereotactic surgery can relieve rigidity without improving bradykinesia. Bradykinesia is not always sufficiently emphasised in descriptions of the disorder yet can be the most disabling aspect to the patient. Sometimes it dominates the entire picture. It shows in slowness in the initiation and execution of motor acts, and poverty of automatic and associated movements such as the normal swinging of the arms when walking. Fleminger has shown that it can be distinguished by certain dual task performance tests from the motor retardation of depression. Bradykinesia probably accounts for many of the classic features of parkinsonism – the mask-like face, infrequent blinking, clumsiness of fine finger movement, crabbed writing and monotonous speech. The striking disorder of prosody evident in the speech of Parkinson patients has been shown to be related to motor control, not loss of linguistic knowledge or associated depression (Darkins et al.. The gait is affected in many characteristic ways with slowness, shuffling, difficulty in starting and turning and impaired equilibrium. It may show an episodic quality, causing periodic freezing of action or episodes of complete immobility.
More than any other feature bradykinesia can be profoundly affected by the patient’s mental state. There are numerous reports of severely disabled patients achieving surprising feats of motor behaviour in response to fear, excitement or other environmental stimulation.
Postural changes show as a characteristic flexion of the trunk and neck bringing the chin to the chest, with arms adduaed at the shoulders and flexed at elbows, wrists and knuckles. The typical ’festinant’ gait appears to be a produa of the abnormal posture along with difficulty in controlling the centre of gravity. Postural instability leads to frequent falls.
Other features include oculomotor abnormalities, excessive salivation, seborrhoea, constipation, urinary disturbance, subjeaive sensory discomfort and marked fatigue. Infrequent blinking is common in all forms of parkinsonism, and paresis of convergence may occur. The latter is particularly common in postencephalitic parkinsonism which may also show oculogyric crises (pp. 352-3). Sialorrhoea is mainly the result of difficulties in coping with normal quantities of saliva on account of dysphagia. Constipation is a major symptom of the disease and a cause of much distress. Urinary frequency and incontinence are frequent complaints. Sensory discomforts include feelings of tightness, pain and cramp in the limbs and back. The fatigue associated with the disorder is often particularly distressing and disabling. It has been found to correlate better with coexistent depression than with the severity of motor symptoms but is often independent of both .
In the deteaion of early cases the following observations can be useful. The patient shows difficulty when asked to maintain a steady rhythmic movement, as in tapping or making polishing movements. The handwriting often reveals changes at an early stage, as do attempts to draw parallel lines or spirals. The glabellar tap reflex is elicited by tapping over the root of the nose between the eyebrows; parkinsonian patients are said to blink in response to each tap no matter how often or at what frequency, and fail to habituate as normal subjeas do. Observation of the gait can also be revealing in early cases when attention is directed at the lack of arm swinging, difficulty in turning sharply or the exacerbation of tremor in the hands.
Course and outcome
Idiopathic parkinsonism is usually a progressive disease. Hoehn and Yahr found that a quarter of patients were severely disabled or dead within 5 years of onset and two-thirds within 10 years. A small number, however, show very slow progression and remain without severe disablement after 20 years or more. The mortality is estimated to be three times that of the general population of the same age and sex. Older treatments did not influence prognosis but it is possible that levodopa therapy has prolonged life expectancy. Common causes of death are cardiac and cerebral vascular disease, bronchopneumonia and neoplasia. The prognosis in terms of rate of progression and mortality is better for postencephalitic cases and worse for those labelled as arteriosclerotic.
Pathology and pathophysiology
Parkinson’s disease is associated with lesions in component parts of the extrapyramidal nervous system. The most striking finding is degeneration and loss of neurones in the pars compacta of the substantia nigra, seen macroscopically as nigral pallor. The surviving neurones characteristically show Lewy bodies within their cytoplasm which are the pathological hallmark of the condition. These are inclusion bodies with characteristic eosinophilic staining surrounded by a clear halo (Plate II. Gibb and Lees were able to demonstrate Lewy bodies in the remaining pigmented nuclei of the substantia nigra in every case that conformed to strict clinicopathological criteria for idiopathic Parkinson’s disease.
Neuronal loss and Lewy body formation are also found in other brain stem nuclei, especially the locus caeruleus, raphe nuclei and dorsal vagal nucleus, as well as in the hypothalamus and nucleus basalis of Meynert. In up to a third of cases they are also apparent in the parahippocampus pus and temporal neocortex . Glial scarring is seen in the brain stem in the islands from which neurones have disappeared. Cellular degeneration is often apparent in the globus pallidus, putamen and caudate, possibly by virtue of trans-synaptic degeneration. Diffuse conical atrophy has been reported to be common, and possibly greater than would be expected for healthy individuals of equivalent age (p. 655).
In postencephalitic parkinsonism the pigmented cells of the substantia nigra and locus caeruleus are similarly lost, but neurofibrillary changes rather than Lewy bodies are seen in those that remain.
The cardinal biochemical feature of parkinsonism is striatal dopamine deficiency, resulting from loss of dopaminergic fibres in the nigrostriatal tract which passes from the pars compacta of the substantia nigra to the caudate and putamen. In consequence dopamine concentrations in these regions may be reduced to 10-20% of normal levels. The net result is increased inhibitory striatal input to the globus pallidus, and thence changes in many parts.of the extrapyramidal system which conspire to the development of the parkinsonian picture .
The connections of the basal ganglia, and the neurotransmitters involved in these, are complex and probably as yet incompletely understood . Multiple parallel loops are present in the extrapyramidal system, two of which predominate. The striatum (i.e. the caudate nucleus and putamen) receives glutamatergic projections from all pans of the cortex which pass to their small spiny neurones. These neurones use GABA and a variety of peptides as their neurotransmitters. They project to the lateral globus pallidus and from there to the subthalamic nucleus. This in turn sends glutamatergic projections to the internal segment of the globus pallidus, which projects to the ventrolateral nucleus of the thalamus and back to the cortex.
The second major loop involves GABA-ergic projections from the striatum to the pars retioilata of the substantia nigra, and dopaminergic projections back from the pars compacta of the substantia nigra in the dense nigrostriatal pathway. The striatum also contains large cholinergic intemeurones; dopamine and acetylcholine appear to be antagonistic in their effects in the striatum, any condition which alters the balance in the direction of marked cholinergic dominance leading to parkinsonism. It is clear, however, that dopamine deficiency will also alter the balance of excitatory and inhibitory activity in many pans of the extrapyramidal system, and that the evolution of parkinsonian symptoms will depend on changes in several of its components.
The losses of dopamine in the striatum can be detected by brain imaging with PET. The presynaptic uptake of 18F dopa is reduced in the caudate and putamen in comparison with age-matched controls, the degree of decline correlating with severity of locomotor disability . The posterior part of the putamen is most severely affected with reductions averaging 45% of normal, the anterior putamen and caudate being less markedly involved (62% and 84% of normal levels, respectively). This pattern differs from that seen with progressive supranuclear palsy (p. 666) which shows equally severe reductions in all parts of the putamen and caudate. There is also evidence from studies with 11C raclopride that the density of D2-binding sites is slightly upregulated in the putamen in untreated Parkinson’s disease, but without change in the caudate .
In addition to the nigrostriatal pathway, other dopaminergic neurones in the ventral tegmental area of the brain stem project to the cortex and limbic structures. There is evidence that these ’mesolimbic’ and ’mesocortical’ pathways are also impaired in Parkinson’s disease, which may be relevant to some of the psychiatric complications discussed below.
Interesting evidence has recently been obtained concerning the possible origin of the selective degeneration of dopaminergic neurones in the substantia nigra in the disease. The discovery that MPTP (l-methyl-4-phenyl 1,2,3,6 tetrahydropyridine) taken by drug addicts could result in parkinsonism has led to the hypothesis that environmental toxins could conceivably play a part. MPTP induces neuronal death via its metabolite MPP+, which has been shown to inhibit NADH-CoQ! reductase (complex I), the first enzyme of the mitochondrial respiratory chain . Complex I was then shown to be selectively deficient in the substantia nigra of patients with Parkinson’s disease, with normal activities of this and other respiratory chain enzymes in other brain area.No such abnormality was present in patients with multiple system atrophy which also leads to parkinsonism, suggesting that it may be causally related to Parkinson’s disease rather than a consequence of the neuronal degeneration. Possible mechanisms by which MPP+ causes neuronal damage are discussed by Marsden . It is taken up and concentrated in mitochondria, leading to depletion of adenosine triphosphate (ATP) and alterations in cellular calcium content. It may also induce the formation of free radical species, resulting in oxidative stress and consequent lipid membrane peroxidation.
Additional evidence comes from the finding of abnormalities in sulphur metabolism and AT-methylation in the disease. Both reflect deficiencies in the metabolic pathways for removing toxins from the body, suggesting that patients with Parkinson’s disease may have been unusually susceptible to environmental toxins with MPPMike activity. Support for such an idea comes from the observation that several environmental toxins can cause parkinsonism, for example carbon monoxide and manganese. Genetic susceptibility to these or other widespread toxic agents could conceivably play a role in the genesis of the disorder.
The diagnosis is usually apparent once the disease is reasonably well advanced but mistakes can occur in the early stages, particularly if tremor is absent. In elderly patients the signs may be overlooked and complaints of back or limb pain may lead to a diagnosis of arthritis or osteoporosis. Alternatively, the presentation may be with unexpected falls which are attributed to vertebrobasilar insufficiency. Strictly unilateral rigidity in the absence of tremor can raise suspicion of a cerebral tumour. Marked bradykinesia may at first raise the question of myxoedema or depressive illness. In patients with evidence of intellectual deterioration the parkinsonian features may be overlooked in favour of a diagnosis of presenile or senile dementia. Marked parkinsonian features are indeed not uncommon in Alzheimer’s disease (pp. 433 and 438).
Rapid fluctuations in the early stages can suggest a psychiatric disorder by way of neurosis, hysteria or even malingering. Such suspicion will be increased if the family report that the patient can function entirely normally in the face of a stressful situation. In the presence of known psychiatric disorder under treatment with neuroleptic drugs, considerable difficulty may be encountered in distinguishing side effects of therapy from the ingravescent development of idiopathic Parkinson’s disease. Here it can be important to remember that the parkinsonian side effects of neuroleptic drugs usually make their appearance early in the course of therapy, then often tend to subside (p. 640). In cases of doubt withdrawal may be necessary for very long periods, sometimes for a year or more, before the true situation is clarified.
Benign essential tremor (juvenile, adult or senile Minor’s disease) may lead to difficulties with diagnosis. This can begin at any age, a positive family history is often forthcoming and improvement with alcohol is characteristic. The hands are principally affected, the tremor disappears when the limbs are inactive, and titubation of the head is commoner than in Parkinson’s disease. There is no bradykinesia or rigidity and the condition is static or perhaps very slowly progressive over several decades.
Other neurological diseases which must sometimes be considered include Huntington’s disease and Wilson’s disease. The rigid and akinetic forms of Huntington’s disease may at first resemble Parkinson’s disease. Wilson’s disease must be carefully excluded when parkinsonian symptoms begin in adolescence or early adult life. The rigidity of Wilson’s disease is similar to that of parkinsonism, but the involuntary movements are more varied including choreic jerking, athetoid and dystonic movements, or flapping tremor of the outstretched hands. Other degenerative conditions which must be borne in mind include progressive supranuclear palsy (p. 666), corticobasal degeneration (p. 668) and multiple system atrophy (p. 668). Diffuse Lewy body disease (p. 450) may sometimes present with parkinsonian features alone.
Quite surprisingly it has recently been found that almost a quarter of patients diagnosed as suffering from Parkinson’s disease are wrongly so labelled: out of 100 cases coming to autopsy 24 had been misdiagnosed, showing the pathological features of progressive supranuclear palsy, multiple system atrophy, Alzheimer’s disease or basal ganglia vascular disease .
The treatment of Parkinson’s disease has undergone dramatic changes. Anticholinergic drugs are still in use but a vogue for stereotactic operations has now largely given way to treatment with levodopa. Useful reviews of current management are provided by Bakheit (1990) and Quinn (1995). Treatment will be considered only briefly here, but certain aspects of drug treatment and stereotactic operation will be dealt with in more detail in the following sections on psychiatric aspects of the disease.
There is no clear evidence that modern therapy alters the underlying pathology of the disease as opposed to suppressing the clinical manifestations. Nevertheless a large proportion of patients can obtain a gratifying degree of relief from their more disabling symptoms, certainly during the earlier stages of the disorder. Some severely crippled patients are enabled to lead relatively independent lives. Specific therapies must be accompanied by general measures to keep the patient active for as long as possible, with physiotherapy or the use of simple mechanical aids. Psychosocial aspects often need attention, especially since the degree of physical disability may be considerably worsened by stress or concurrent depression.
Anticholinergic drugs are still used alone in mild cases and are usually continued thereafter when further measures need to be instituted. The best known are benzhexol (Artane, Pipanol), benztropine (Cogentin), orphenadrine (Disipal), procyclidine (Kemadrin) and biperiden (Akineton). Their effect is variable. Mobility is usually improved, with some decrease in rigidity and tremor. Bradykinesia fc usually little affected. Atropine-like side effects limit the dose that can be employed.
Oculogyric crises in postencephalitic parkinsonism are sometimes reported to diminish with anticholinergic drugs. Amphetamine and chlordiazepoxide have also been found to help in this regard. Prolonged crises can often be terminated by intramuscular ethopropazine (Lysivane).
Amantadme hydrochloride (Symmetrel) stimulates dopamine release in the central nervous system, and is indicated if anticholinergic drugs fail and the patient is only mildly disabled. Among the severely disabled it finds application in patients who cannot tolerate levodopa. Amantadine helps with bradykinesia and postural instability in addition to improving rigidity. Mobility may thereby be considerably improved.
Selegiline (Eldepryl, Deprenyl) inhibits monoamine oxidase B, one of the enzymes responsible for the breakdown of dopamine in the brain. It has limited antiparkinsonian action, but when used with levodopa can potentiate and prolong its action, sometimes helping with mild dose-related fluctuations of response. It may also allow the dose of levodopa to be reduced. However, it can sometimes worsen dyskinesias and aggravate psychiatric adverse reactions.
Selegiline became widely regarded as the treatment of first choice for newly diagnosed patients because it proved to be ’neuroprotective’ in animals, preventing damage to the nigrostriatal system when they were exposed to the toxin MPTP . Evidence was obtained, moreover, that Parkinson’s disease progressed more slowly in patients who started on treatment with selegiline, in that the need for levodopa was delayed for almost a year in relation to controls (Parkinson Study Group, though it remained unclear whether this reflected neuroprotection or merely mild symptomatic benefit. These results have, however, come under critical re-evaluation, and more recent evidence has even pointed to increased mortality among patients treated with the combination of levodopa and selegiline, casting doubts on the advisability of its longterm use in the disease .
Levodopa (L-dopa) is now well established as a highly effective drug with a wide range of activity on different parkinsonian symptoms. It is a logical form of treatment, L-dopa being the immediate precursor of dopamine which is known to be deficient in the brain. Approximately one third of patients can be expected to obtain marked relief, one-third moderate benefit, and the remainder show a modest or disappointing response. Perhaps some 15% do not respond at all; in such cases the possibility of some alternative diagnosis such as progressive supranuclear palsy or multiple system atrophy should be considered.
Levodopa is therefore widely regarded as the treatment of choice in patients who can tolerate it. A synergistic action is seen when given in conjunction with anticholinergic drugs and perhaps with amantadine as well. It may take several months before maximal benefit is obtained, and it cannot be said to have failed until it has been tried for 6 months or preferably a year. The variability of response seen from one individual to another cannot yet be accurately predicted.
Levodopa is now always given in combination with a peripheral dopa-decarboxylase inhibitor such as carbidopa (in Smemet) or benserazide (in Madopar). This prevents its metabolism in the gastrointestinal tract, reducing nausea and vomiting, and allows higher blood levels to be achieved with smaller doses. Moreover the combined preparations increase the turnover of dopamine in the nigrostriatal system more selectively than does levodopa alone, and maximal benefit is obtained earlier.
Rigidity is helped and tremor also improves but less consistently. Propanolol or some other beta blocker may further help the latter. Outstanding benefit is seen where bradykinesia and postural instability are concerned, both of which are rarely responsive to anticholinergic drugs. Thus facial mobility is improved, salivation lessened and the voice strengthened. Gait, handwriting and ability to do fine manipulative tasks all improve. The overall result can be dramatic with the patient able to do such things as shaving, knitting or getting out of bed unaided when these have not been possible for some considerable time.
Unfortunately as time goes by the efficacy of levodopa may diminish. In general, over a 5-year period a third of those who responded initially retain their benefit, a third lose some and a third lose all their gains becoming worse than they were before. This is most probably due to progression of the underlying disease. Variations in benefit may emerge for hours or days at a time, or the effects of each dose may become shorter-lasting. The first sign of fluctuation may be early morning bradykinesia when the effects of the previous day’s dose have worn off. ’End dose deterioration’ then appears, with bradykinesia or tremor returning as each dose is due. In time this shows as the ’on-off effect, with swings from complete relief to total immobility, often occurring with startling rapidity and sometimes many times a day . By this time peak dose dyskinetic movements have also usually developed. In extreme form the patient may be precipitated within minutes, or even seconds, from a state of dyskinetic mobility to one of profound rebound p^rkinsonism .
Tests carried out serially during on and off phases have shown some mild impairment of cognition and adverse swings of affect during the latter phases . In a detailed study of nine patients experiencing severe on-off phenomena, Nissenbaum et al. found that four had clear-cut depression and anxiety when ’off, one also showing features of elation and disinhibition when ’on’. In a questionnaire survey two-thirds of 31 such patients reported some degree of parallel mood change, usually towards depression when akinetic but also with feelings of irritability, aggressiveness and frustration. In rare cases hallucinations and delusions may accompany the transient depressions:
A 69-year-old woman on treatment with Sinemet progressed after 7 years to severe and abrupt changes characteristic of the on-off phenomenon. One year later she began to experience parallel fluctuations in mood. In the ’off condition she showed depressed mood, agitation, hypochondriacal and nihilistic delusions, and an unshakable belief that something dreadful was about to happen. She had ideas of guilt, and auditory and visual hallucinations. Although agitated she remained fully orientated and could retain information provided her attention could be sustained. In this condition she was chair-bound. When mobile and ’on’ she had a mildly depressed mood, but was not agitated, deluded or hallucinated, and had partial insight into the psychotic phenomena experienced when immobile.
A 35-year-old man who had taken Sinemet for 4 years developed manic features during ’on’ phases alternating with depression when ’off. During ’on’ phases he showed choreoathetoid movements and became overactive and talkative. He was extremely elated and expressed grandiose ideas that he would marry several women and live for 100 years. On reverting to severe immobility he showed profound depression and nihilistic thought content and expressed the wish to be dead. Between the fluctuations in mood and movement he improved, exhibiting neither mood abnormalities nor dyskinesias. There was no past or family history of affective disorder. His condition was ameliorated by giving smaller doses of medication more frequently.
Considerable improvement may be obtained by giving the drug in small divided doses, even 2- or 3-hourly through the day, or by the use of sustained release preparations. Other approaches are to add selegiline, or to partially substitute an agonist drug such as bromocriptine or pergolide. Apomorphine can find a special place in the treatment of refractory on-off oscillations as described below.
Adverse effects commonly include anorexia, nausea, vomiting and hypotension. These can usually be overcome by starting with low dosage and increasing very gradually. The gastrointestinal effects can be largely avoided by the use of combined preparations of levodopa with a selective extracerebral decarboxylase inhibitor (Sinemet or Madopar). Tremors, tachypnoea, flushing and cardiac dysrhythmias may also be troublesome, but the commonest dose-limiting factor is the appearance of dyskinetic movements. Such dyskinesias can take any form, including orofacial dyskinesia, chorea, dystonia or athetosis of the limbs, analogous in form, and probably in pathophysiology, to the movements seen in tardive dyskinesia (p. 641). Three main varieties are recognised: ’peak dose dyskinesia’ with choreic or dystonic movements, ’diphasic dyskinesia’ occurring at the beginning and end of the dose and often being ballistic in character, and ’off period dystonia’ with fixed, often painful, spasms mainly involving the feet. A compromise quite often has to be sought between the severity of such adventitious movements and the degree of relief of parkinsonian disability. The psychiatric effects of levodopa are considered on p. 658 et seq.
Bromocriptine (Parlodel) acts as a direct stimulant of dopamine receptors. Only about a third of patients obtain a response to bromocriptine alone, but when given along with levodopa it allows a smaller dose of the latter to be employed. Some prefer to use it initially on its own in order to defer the introduction of levodopa with its attendant long-term risks of fluctuation in response and dyskinesias. Early combination therapy with levodopa and bromocriptine has some advocates. It finds a special place in the management of patients who experience fluctuations in response to levodopa as described above.
Bromocriptine must be used with caution in the presence of peripheral vascular disease since it is derived from ergot, and it is contraindicated in the presence of ischaemic heart disease. Postural hypotension can be a problem when starting treatment, also nausea and vomiting which are helped by domperidone. Psychiatric side effects are similar to those seen with levodopa (p. 658 et seq.).
Other dopamine agonists include lisuride (Revanil) and pergolide (Celanace), the latter with a longer duration of action and effects on Dl as well as D2 dopamine receptors. Both are again ergot derived, and similar contraindications apply. Indications for their use parallel those for bromocriptine, some patients appearing to derive more benefit from one drug than another. A high incidence of psychiatric complications, particularly hallucinations, has again been reported.
Apomorphine has a special place in the treatment of latestage fluctuations in response to levodopa when other approaches have failed, and can on occasion be life-saving . It is also a D1- and D2-receptor agonist but must be given by subcutaneous injection. Oral domperidone is given concurrently to prevent vomiting. Patients and their relatives can be instructed to inject the drug when ’off periods occur, relief occurring within 15 minutes and lasting for up to an hour. Continuous daytime infusion can be achieved through a portable pump.
The injections work with high reliability and tolerance does not develop, but drowsiness and local reactions at the injection sites can be troublesome. Adverse psychiatric complications have been rare, in contrast to those encountered with continuous lisuride infusions.
Catechol 0-methyl transferase inhibitors are currently under trial. This is one of the enzymes that metabolise levodopa and dopamine. Entacapone acts peripherally and tolcapone both peripherally and centrally. Both appear to have a dose-sparing effect and to prolong the effects of levodopa.
Psychotropic drugs often have an important part to play in management. The relief of depression and anxiety can itself lead to a considerable improvement in physical disability, but over and above this the tricyclic antidepressants may have a more direct effect on parkinsonian symptomatology. Imipramine or amitriptyline are usually employed along with anticholinergic drugs or levodopa, but in mild cases may prove to be effective on their own. The antidepressant nomifensine was regarded as particularly appropriate by virtue of its dopaminergic activity, but has now been withdrawn on account of toxic effects. Diazepam is used when anxiety is the predominant manifestation. Monoamine oxidase inhibitor antidepressants must not be given in association with levodopa.
Stereotactic surgery declined abruptly in popularity after the introduction of levodopa, but still finds an occasional place in patients with tremor or rigidity which are predominantly unilateral and when bradykinesia is minimal. The optimal site for Stereotactic destruction has been extensively debated. Common targets have included the globus pallidus, the ventrolateral nucleus of the thalamus and the pallidofugal fibres in the ansa and fasciculus lenticularis.
The relief of tremor and rigidity can be impressive but the gains in terms of functional ability are often disappointing. This is probably because the bradykinesia of the disorder is unaffected. Thus the festinant gait, postural imbalance and mask-like face persist unaltered. Side effects of the operations further limit their usefulness occasional patients suffer speech disturbance, impairment of balance or some degree of paresis or mental deterioration.
Neural transplantation has been shown to be successful in restoring function in primates with lesions of the dopamine pathways, and limited experience has been obtained in patients with Parkinson’s disease . Despite occasional reports of striking success with autologous transplantation of tissue from the adrenal medulla this approach has proved disappointing, and the use of foetal dopaminergic cells appears to hold more promise. This, however, raises considerable ethical problems.
Adrenal medullary transplantation seems commonly to be followed by behavioural complications in the immediate postoperative period, including sleep disturbance, hallucinations, delusions, confusion and mood changes . Techniques of this nature may yet find a place in the management of younger patients whose disease is difficult to control by other means, but continuing improvements in drug therapy may overtake their further development.
Psychiatric aspects of parkinsonism
Interest in the psychiatric aspects of parkinsonism has increased as a result of advances in knowledge of the disease. The advent of Stereotactic surgery focused renewed attention on the problem of intellectual impairment in the disorder, and the demonstration of disturbance of amine metabolism has brought new interest to its association with depression.
There is a good deal of disagreement in different reports regarding the frequency of mental symptoms, depending no doubt upon the particular population under scrutiny. Thus behavioural disturbance is likely to be more common when a substantial number of postencephalitic cases are examined, and intellectual impairment will be more frequent when patients with ’arteriosclerotic parkinsonism’ are included in the sample. The difficulties of achieving anything like a reliable estimate are increased by the problems inherent in distinguishing these different varieties one from another.Mjones reviewed the earlier work in detail. Three main groups of mental disturbance gradually came to be recognised and were sometimes regarded as an integral part of the pathological picture-a change of personality towards suspicion, irritability and egocentricity, an impairment of memory and intellect, and psychotic developments with depression, paranoia and sometimes visual hallucinations. Some felt that there was a typical paralysis agitans psychopathy, others a characteristic psychosis. Some found a great excess of dementia, others of depression. Mjones’ own investigation of 262 cases of paralysis agitans revealed mental symptoms in approximately 40% of cases. ’Organic’ changes predominated over ’reactive’ changes, the former consisting of impaired memory and intellect, the latter of depression with irritability, egocentricity and hypochondriasis. .Transitional forms were also encountered in which the relative contributions of organic or reactive elements were uncertain.
More recent studies have served to underline the associations with depression and cognitive impairment, the latter chiefly in later-onset Parkinson’s disease. It now seems indubitable that the risk of dementia is increased above expectation and several theories have been advanced to account for this. A typical personality change, or a characteristic form of psychotic reaction, are no longer recognised. Those psychoses which do emerge are largely seen in the context of treatment with levodopa and other drugs. These matters are dealt with in detail in the sections that follow.
Cognitive impairment and dementia
The question of cognitive impairment in Parkinson’s disease has attracted a great deal of interest, particularly since the advent of treatments which may be effective in prolonging life. There is no doubt that some patients show impairment of cognitive function, sometimes severe and pervasive enough to amount to an easily recognised progressive dementia. Others by contrast remain intellectually intact despite gross physical disablement. The issue which has been hard to resolve is whether, as a group, patients with idiopathic Parkinson’s disease are more prone to develop such difficulties than would be expected by virtue of their age alone. The present consensus is that the risk of dementia is definitely increased, perhaps some two- or threefold. Possible reasons for this have turned out to be complex, and are gradually being disentangled as discussed below.
Brown and Marsden review the differing estimates of the prevalence of dementia in Parkinson’s disease, ranging from 10% to over 80%, and the possible reasons for such wide discrepancies:
Sampling errors are compounded by difficulties in excluding other causes of akinetic-rigid syndromes during life, in particular in separately idiopathic Parkinson’s disease from ’arteriosclerotic parkinsonism’ (p. 646). If some examples of parkinsonism merely reflect an accent of diffuse cerebral vascular disease on the basal ganglia, then the cognitive impairments encountered could be due to the widespread cerebral changes in this group. When, on the other hand, cognitive impairment is used as a criterion for separating arteriosclerotic from idiopathic parkinsonism, the idiopathic cases will tend to be reported as intact.
Problems with the definition and assessment of dementia are also considerable, and the criteria employed have varied from one study to another. Some have sought to identify the clinical syndrome of dementia, using behavioural criteria and brief mental state tests, whereas others have used batteries of psychological tests to look for specific cognitive deficits. With both approaches the assessment of parkinsonian patients can raise special difficulties. Behavioural criteria must allow for the curtailment of activities occasioned by the disease; psychological testing must take into consideration slowness of response which may be largely attributable to motor handicap. Care must be taken to allow for what is to be expected in any ageing group of persons, and to differentiate cognitive failure from the depression which is common with Parkinson’s disease. Drugs taken for treatment of the condition may further complicate assessments.
Earlier studies served mainly to focus attention on the problem. Riklan et al. examined 220 consecutive patients referred for stereotactic surgery, using a battery of measures for assessing cognitive and personality functioning. Duration of illness was unrelated to scores on any test, but muscular rigidity and autonomic dysfunction were associated with decreased intellectual productivity and perceptual difficulties. But the most striking relationships were between the degree of voluntary movement impairment and a wide range of psychological deficits loss of drive and energy, impairment of intellectual and perceptual functions, and pervasive personality and emotional disorders. This was thought to reflect not only central factors but also the psychosocial consequences of the disease.
Pollock and Hornabrook estimated that 20% of a large unselected series of patients showed significant mental deterioration, the majority being in the group labelled as arteriosclerotic but some being examples of idiopathic Parkinson’s disease. They stressed that intellectual impairment could exist alongside mild parkinsonism, many patients being a burden to their families on account of dementia rather than their motor disabilities. Mindham found that one-third of parkinsonian patients admitted to a psychiatric hospital showed cognitive impairments, this being equally frequent among idiopathic and arteriosclerotic cases. Celesia and Wanamaker claimed that 40% of 153 patients with idiopathic Parkinson’s disease showed some evidence of cognitive impairment, this correlating in frequency and severity with the duration of the disease.
An impressive early survey was carried out by Marttila and Rinne involving all traceable patients with Parkinson’s disease in a defined area of Finland. Of 144 patients, 29% were thought to be demented, 50% of these being mildly, 30% moderately and 20% severely affected. Patients with evidence of arteriosclerosis were more often demented than those without (56% and 18% of cases, respectively. There was a clear rise with age, from 20% among the under seventies to 65% among the over eighties. The severely physically disabled showed dementia more often than the mildly affected, increasing severity of rigidity and bradykinesia showing a positive correlation with the degree of intellectual decline. This association pointed to a role of subcortical structures in the pathophysiology of the dementia.
Lieberman et al. found moderate to marked dementia in one-third of 520 patients, this being 10 times the prevalence in spouses used as controls. The demented patients, in addition to a later onset, had become more physically disabled in a shorter time and had responded less well to levodopa.
Two distinct forms of Parkinson’s disease, with and without dementia, thus seemed a possibility. Lees and Smith restricted attention to mildly disabled patients, all under the age of 65 and with normal CT scans. Comparisons with age-matched controls showed no impairment on tests of intelligence or memory, but revealed significant deficits on the Wisconsin Card Sorting Test and a verbal fluency test. Frontal cognitive deficits were therefore highlighted.
More recent surveys have attempted to allow for the various sources of artefact outlined above, in particular adopting stringent criteria for the diagnosis of dementia. The great majority have confirmed an increased prevalence of dementia In the disease. Rajput et al. reviewed the Mayo Clinic records of all Parkinson patients seen over a 13-year period, charting dementia only when this had been diagnosed on at least two separate occasions. For every patient two sex- and age-matched controls were selected from residents in the area. Of the 138 new Parkinson patients seen, 13 (9.4%) were demented, compared with 2.9% of controls. When none of the three matched individuals showed dementia at the time the parkinsonism was first recognised these were followed further, and dementia emerged more frequently among the patients than the controls.
Mayeux et al. performed a similar review of records from a medical centre in New York. Among 339 patients with idiopathic Parkinson’s disease 10.9% were demented according to DSM-m criteria. The demented patients were significantly older than the remainder, had a later age of onset and a more rapid progression of physical disability. When the parkinsonism had begun after the age of 70 dementia was noted almost three times as often as when the onset had been earlier. Among patients over
60 years old the prevalence was judged to be almost four times that expected for a population of equivalent age.
Equivalent results were obtained from a register-based survey of patients in the Netherlands, incepted with a hospital discharge diagnosis of Parkinson’s disease and followed an average of 8 years later . In comparison with a reference group of patients with non-cerebral diseases the risk of developing dementia during this period was increased threefold.
The most clear-cut evidence, however, has come from Mindham’s group, who have reported the first truly prospective study of dementia in idiopathic Parkinson’s disease :
Serial assessments were made of cognition, mood and level of disability in a group of 87 patients and 50 healthy matched controls over a 4.5-year period, each subject being examined at 9month intervals. The mean age of the patients was 64 years. Patients were excluded if they had a history of stroke, hypertension or transient ischaemic attacks, or when there were indications of other neurological disorder. An extensive battery of psychometric tests was administered at each examination, along with rating scales for depression, anxiety and physical disability. The accumulated data sheets were reviewed at the end of the study, blind to whether the subject was a Parkinson patient or control, and diagnoses of dementia were made according to DSM-III criteria. Judgements were made as to the assessment at which these criteria were first satisfied.
Five of the 87 patients (6%) were considered to have been demented from the outset of the study, and 10 more became demented during the follow-up period. No control subject did so. After allowing for patients who dropped out during the course of the survey the cumulative incidence of dementia over this period was 19%. Comparisons between those who demented and those who did not showed that the former were older, older at onset of Parkinson’s disease, had a longer duration of illness, and lower initial performance on certain cognitive tests. This last might indicate that their dementia had already been present in milder form while not yet meeting DSM-III criteria.
It therefore seems clear that dementia, identifiable clinically, is increased above expectation in Parkinson’s ’ disease, even when care has been taken to exclude vascular and other pathologies which might have contributed towards it. Cognitive impairments, insufficient in themselves to lead to such a diagnosis, seem also to be common, though there is insufficient information to judge how often these may be a prelude to dementia.
Psychometric studies show a wide spectrum of deficits among cognitively impaired parkinsonian subjects, as reviewed by Ross et al. . In some the picture resembles ’subcortical dementia’ (p. 667), particularly with respect to memory functioning, and executive function deficits are often prominent suggesting disruption of frontal-subcortical connections. In others, however, there are language and other impairments which point to cortical dysfunction. Sometimes, indeed, the clinical picture appears to overlap with that of Alzheimer’s disease. Ross et al. conclude that the heterogeneity of the pictures seen suggests that there are multiple dementia syndromes in Parkinson’s disease, associated with varying structural and biochemical pathology.
The causation of these deficits remains uncertain and a number of possibilities must be considered. First, they may be due in part to the classic pathology of Parkinson’s disease and the dopamine deficiency that ensues. The subcortical nature of the dementia in many examples would fit with such a pathogenesis, especially since mesolimbic and mesocortical projections are known to be involved along with disruption of the nigrostriatal system. Such projections arise from the medial substantia nigra and the ventral tegmental area, and these have been found to be particularly severely affected in Parkinson patients with dementia . Neuronal
counts and noradrenaline levels have also proved to be reduced in the locus caeruleus in the presence of dementia, suggesting that diminished noradrenergic inputs to the cortex may make an additional contribution. Together these observations support a subcortical origin for the dementia.
To a notable degree, however, dementia is rare in younger patients with Parkinson’s disease, even though in all other respects the course and pathology of the disorder appears to be similar whatever the age of onset . Dementia has emerged as exceptional with onsets below the age of 50, even with disease of long duration, and it becomes commoner with later onsets, especially after 70 years. Indeed the factor of age of onset has emerged as one of the firmest risk factors for the development of dementia.
With age there is increasing likelihood of finding Alzheimer-type pathology in the cortex, and certain studies have suggested that this may play a major role in producing the dementia. Alvord etal. and Hakim and Mathieson found Alzheimer changes to be commoner in patients with Parkinson’s disease than in age-matched controls, and Boiler et al. found the prevalence of plaques and tangles in the cortex to rise as the severity of dementia increased. A cortical pathology of Alzheimer type might thus be accelerated in the presence of Parkinson’s disease and account for the cognitive deficits seen. However, further detailed studies have given conflicting results and this hypothesis is now regarded as uncertain .
A third possible explanation involves the nucleus basalis of Meynert. Perry et al. demonstrated marked cholinergic deficits in the cerebral cortex of Parkinson patients, which in the temporal neocortex correlated with the severity of mental impairment assessed prior to death. The cholinergic deficits were of a similar order to those seen in Alzheimer’s disease, despite the dementia being milder, but lacked correlation with the degree of tangle and plaque formation. Rather they correlated with the extent of neuronal loss in the nucleus basalis of Meynert. This was always pronounced with losses of up to 70% in the presence of parkinsonian dementia. Thus the cortical cholinergic deficits seemed not to be explicable in terms of cortical pathology, but more probably resulted from degeneration of cholinergic axons associated with the loss of cells in the Meynert nucleus. Such loss might itself be due to a pathological process analogous to that inducing changes in the substantia nigra.
This striking set of observations has been both confirmed and refuted in other studies, as reviewed by Ross et al. and Chui and Perlmutter . And it has become apparent that, at least in some cases, dementia can occur in Parkinson’s disease in the absence of either Alzheimer-type pathology in the cortex or cell loss in the nucleus basalis of Meynert.
These various possible contributions to dementia are discussed in detail by Dubois and Pillon . It seems probable that many of the cognitive changes are largely due to subcortical pathology, with dopamine deficiency being compounded by loss of inputs from noradrenergic and cholinergic nuclei. In the older patient with Parkinson’s disease and severe dementia, concomitant changes of Alzheimer type in the cortex are likely to make an additional contribution.
Structural brain imaging has not contributed substantially to this cortical/subcortical debate. Air encephalography and CT scanning have shown a high prevalence of cerebral atrophy in patients with Parkinson’s disease, and in several studies ventricular enlargement has correlated with the presence of cognitive impairment . Third ventricular width and the intercaudate distance have also shown such associations, whereas the contribution of conical atrophy usually disappears on controlling for age. To this extent structural imaging supports the relevance of subcortical pathology. Magnetic resonance imaging has not clarified the situation further .
PET and SPECT scans have by contrast tended to underline the importance of cortical pathology, showing deficits in metabolism in the frontal and parietal regions which are marked in the presence of dementia. Metter et al. , using FDG-PET, found essentially the same pattern of hypometabolism in parkinsonian dementia and Alzheimer’s disease, with global reductions in brain metabolism and an accent on the parietal regions. These could be observed to progress with worsening of the cognitive impairment. Peppard etal. (1992) showed widespread cortical and subcortical reductions in glucose metabolism in nondemented Parkinson patients, though with significant further reductions in the cortical regions in the presence of dementia. The temporoparietal regions were again particularly affected. It remains unclear, however, whether such patterns reflect intrinsic cortical pathology, or the cortical effects of deafferentation from subcortical structures.
Finally a fourth element has been added now that it is appreciated that Lewy bodies are often found in the cerebral cortex as well as in the brain stem nuclei. How far diffuse Lewy body disease (p. 450 et seq.) may make its own contribution to cognitive failure in patients with’ Parkinson’s disease remains to be determined, but no doubt this may operate as a substantial additional factor.
An association between parkinsonism and depression is well established. The depression is sometimes clearly reactive in nature, setting in immediately the patient is informed of the nature of the disease, or developing later as an understandable response to the limitations and discomforts imposed by the disablement. Mindham , for example, was able to show a significant correlation between the severity of the leading signs of parkinsonism and the severity of depression in a group of patients attending a neurological clinic. This relationship persisted during treatment with levodopa, those improving physically showing a fall in the severity of affective symptoms.
However, there are also indications that depression may sometimes bear a more integral relationship to the disease process itself, reflecting in some way the causative brain pathology. The high prevalence of depression has impressed many observers and it has seemed to be cornmoner than in equivalently disabling illnesses. In several investigations it has failed to show a proportionate relationship to the degree of disability, and quite often it has been found to respond to antidepressive treatment (including electroconvulsive therapy) while the physical disability persists unchanged. Rather strikingly, Fleminger showed that depression and anxiety were both commoner when unilateral Parkinson’s disease affected the left rather than the right side of the body, which is the reverse of what might have been expected if the symptoms were purely a response to functional disability. Schiffer et al. found that the depression was often atypical in form, frequently coexisting with panic disorder or generalised anxiety.
Warburton examined 140 parkinsonian patients referred for thalamotomy and compared them with matched controls suffering from a variety of surgical and medical conditions. Depression was significantly cornmoner among the parkinsonian patients, particularly among the females. Fifty-six per cent of the males and
71% of the females showed some degree of depression. No relationship could be observed to age, duration of illness or degree of physical handicap.
Mindham , in a retrospective survey of 89 parkinsonian patients admitted to a psychiatric hospital, found that in almost two-thirds the psychiatric diagnosis had been of an affective disorder. Several patients improved in mood with appropriate psychiatric treatment even though their physical condition remained unaltered.Celesia and Wanamaker found some degree of depression in one-third of 153 patients with idiopathic Parkinson’s disease, the severity again being independent of the degree of motor disability or duration of disease. Horn confirmed a significant relationship between parkinsonism and depression using an objective rating scale for mood disorder. This relationship was independent of age, duration or measures of severity of handicap, suggesting an integral association with the disease process itself.
Robins , in a carefully controlled study, supported such an interpretation. Forty-five patients with Parkinson’s disease were matched for age and sex with chronically disabled people drawn from the same institutions (patients with hemiplegia, paraplegia and arthritis. The groups resembled each other with regard to the frequency of a pre-illness history of depression or of neurotic symptoms. The duration of disablement was similar in both but the degree of handicap greater in the nonparkinsonian group. Nevertheless the patients with Parkinson’s disease were significantly more depressed than the controls as measured by the Hamilton rating scale. In neither group did the severity of disability affect the presence or absence of depression, suggesting that the latter was not solely reactive in nature. Mayeux et al. examined 55 patients using their spouses as controls. Forty-seven per cent of the patients were deemed depressed, compared with 13% of controls, the depression being mild in two-thirds and moderate to severe in the remainder.
In a large postal survey Gotham etal. were able to show that depression was related to the degree of impairment in activities of daily living, but even so much of the variability was left unaccounted for. Individual differences in coping style and the availability of social support were probably also influential. The symptom profiles observed included pessimism, hopelessness, decreased motivation and increased concern over health; by contrast guilt, self blame and worthlessness were usually absent.
With regard to treatment antidepressant medication can be highly effective in relieving both physical and mental symptoms . Electroconvulsive treatment is not contraindicated, and may result in pronounced motor benefit while alleviating the affective disorder . Sometimes, indeed, improvement in parkinsonian features has been observed to antedate the improvement in depression during a course of electroconvulsive therapy . Rasmussen and Abrams and Faber review the evidence that such treatment can improve the motor symptoms of Parkinson’s disease, at least temporarily, even in the absence of depression.
In the great majority of cases depression follows the onset of the disease, but patients are occasionally encountered where it is the presenting feature. Kearney reported two examples in whom the first symptom was depression combined with anxiety and agitation. In the first the depressive illness responded well to electroconvulive therapy, then returned 1 year later when it was apparent that parkinsonism was developing. The second patient became increasingly depressed over several months with complaints about his legs which he could not describe accurately; he thought he had Parkinson’s disease and sought many consultations with negative result until 6 months later when the definitive signs appeared.
To the extent that depression appears to be closely tied to the parkinsonian disease process it is tempting to suppose that common biochemical factors may be operative. In depressive illness, as well as in Parkinson’s disease, deficiencies of noradrenaline, dopamine and 5-hydroxytryptamine (5-HT) have been postulated to play a part. Fleminger’s finding that left-sided Parkinson’s disease is associated with greater depression than rightsided disease suggests that dopamine deficiency in the right cerebral hemisphere may be especially liable to provoke depression. Mayeux et al. suggest, however, that a reduction in brain 5-HT may be the important factor, showing that the cerebrospinal fluid content of its major metabolite (5-hydroxyindoleacetic acid) is significantly lower in depressed than nondepressed Parkinson patients. Oral administration of 5hydroxytryptophan, a serotonin precursor, was found to alleviate the depression in the absence of changes in motor symptoms or activities of daily living. It is possible therefore that serotonergic antidepressants such as fluoxetine may be particularly helpful in the disorder.
Finally, increased tearfulness has been found to be common in patients with Parkinson’s disease, sometimes with ’emotionalism’ as indicated by sudden weeping with loss of normal social control . Almost half of a group of patients with idiopathic Parkinson’s disease reported being more tearful since the onset, and 10% showed emotionalism of the type following cerebrovascular accidents (pp. 386-7). Such disturbances were sometimes evident in the absence of lowered mood or cognitive impairment.
Increasing disability may understandably lead to irritability, as in any disease which results in restriction of activities and dependence upon others. Egocentricity, querulousness and an exacting attitude towards those around have often been stressed, likewise a change towards suspiciousness or even frank paranoia. However, the prevalence of such changes is hard to assess. Obsessional traits in the premorbid personality may become exaggerated, and hypochondriasis can be marked. Euphoria by contrast appears to be distinctly rare, and when present is probably closely tied to intellectual deterioration.
There does not appear to be any form of personality change specific for parkinsonism. The majority of the features outlined above are generally held to be accountable in terms of individual vulnerability and the psychological and social stresses which operate upon the disabled person.
The commonest psychotic disorder in parkinsonism is affective in nature. This is almost always depressive, Mindham ( finding no examples of mania in a retrospective survey of 89 patients admitted to a psychiatric hospital. Only two had schizophrenic illnesses, one with postencephalitic and one with arteriosclerotic parkinsonism. Davison and Bagley note that reports of schizophrenia-like psychoses in association with idiopathic Parkinson’s disease are rare and review the occasional examples in the literature. Crow etal. report four further cases, two with postencephalitic and two with idiopathic parkinsonism.
Mjones could find no support for the idea of a special paralysis agitans psychosis. Many of the earlier examples, with florid delusions and auditory and visual hallucinations, were no doubt the product of overmedication with hyoscine, atropine or other solanaceous drugs. Even nowadays acute organic reactions in parkinsonian patients are most often due to medication as discussed below. Celesia and Wanamaker observed acute psychotic episodes in 12% of 153 patients, the majority being attributable to drugs and most occurring in patients who showed impairment of cognitive function. Bell et al. found a similar prevalence of psychosis-13% in 393 patients – with less than a third being unrelated to medication. On follow-up the non-drug-related psychoses proved usually to be transient and were frequently associated with the development of dementia. The psychoses which may develop in response to treatment with levodopa and dopamine agonists are discussed below.
Psychiatric complications of anticholinergic drugs
Anticholinergic drugs may produce an acute organic reaction which sometimes leads to diagnostic difficulty. Porteous and Ross reported mental disturbance in 20% of patients treated with benzhexol (Artane), sometimes in response to small doses. Symptoms included confusion, excitement, agitation, paranoid delusions, hallucinations and suicidal intentions, all rapidly disappearing when the drug was withdrawn. The disorder was usually evident
soon after starting the drug, but could sometimes be gradual in evolution with risk that the relationship to treatment would be overlooked. Stephens and rawshaw and Mullen have reported misuse of benzhexol in high dosage for its hallucinogenic properties, sometimes with outbursts ofsevere pathological excitement. Adverse reactions in parkinsonian patients are mostly seen in the elderly. They are also especially common when anticholinergics are added to levodopa, even in low dosage.
Duvoisin and Katz recommend treating such reactions with physostigmine, a parenteral anticholinesterase which gains access to the central nervous system. Symptoms such as confusion, agitation, hallucinations, ataxia and dysarthria were promptly reversed by the drug in patients who had developed toxic reactions to scopolamine, atropine and antiparkinsonian medications.
Amantadine in high dosage may likewise provoke acute organic reactions and sometimes epileptic fits.
Psychiatric aspects of treatrrient with levodopa and dopamine agonists
A great deal of psychiatric interest has centred on the psychiatric consequences of treatment with levodopa. Closely similar disorders have emerged with dopamine agonists such as bromocriptine, lisuride and pergolide. Adverse reactions range from acute organic reactions and affective disorders to psychotic developments. The latter may occur in conjunction with delirium or in clear consciousness. Beneficial effects include a feeling of increased well being and temporary improvements on tests of cognitive function
Goodwin reviewed reports to that date of adverse psychiatric reactions to levodopa, varying in incidence from 10% to 50% of patients treated. Mental cornplications were next only to gastrointestinal disturbances and movement disorders as side effects. Confusion and delirium had developed in 4% of patients treated, a similar proportion showing depression, restlessness and agitation, or delusions and paranoia. Hypomania had occurred more rarely, and hypersexuality had developed in occasional patients. Other reactions included lethargy, anxiety, impulsivity, insomnia and vivid dreaming.
Brief episodes of tension and restlessness may accompany the ingestion of each dose from the early phases of treatment, but the more severe reactions tend to set in only after many months on the drug. Jenkins and Groh emphasised the abrupt appearance, often with little warning, of the mental complications, and the rapid
worsening that could occur. As experience of long-term treatment has accrued it has become apparent that the prevalence of abnormal mental reactions increases as time goes by. Barbeau noted changes of intellect and behaviour in a fifth of patients maintained on the drug for over 2 years, and Sweet et al. found that agitation, hallucinations and delusions increased from 10% of patients initially to 60% after 6 years of treatment. Some of the more dramatic changes in mood accompany the swings of motility which develop as part of the ’on-off’ effect as described on pp. 650-1.
The psychoses that arise with levodopa are not uncommonly the reason for limitation of dosage. Klawans suggests that they are prone to occur in two situations – either during the early weeks of treatment in patients with a previous history of psychiatric illness, or after several years in patients who lack such a history. The commonest manifestation consists of visual hallucinations typically of relatives, neighbours or animals, recurring frequently and especially at night. These are usually preceded or accompanied by vivid dreams and sleep disturbances. Insight into their unreal nature may be preserved for a time. Auditory and tactile hallucinations also occur but are much less common. Such disturbances may be accompanied by confusion and agitation, amounting sometimes to frank delirium, but typically they occur in a setting of fully preserved consciousness.
Delusions are prone to develop only later, being rare before 2 years of treatment with levodopa have elapsed . They are typically persecutory in nature, often taking the form of a paranoiddelusional system. Again these usually emerge with a clear sensorium but are occasionally part of a confusional state. They are more frequently encountered in the elderly or in the presence of cognitive impairment.
Both hallucinations and delusions usually resolve with reduction of dosage, but if not low dosage of neuroleptics should be tried with caution. Clozapine has been especially commended for its effectiveness and lack of liability to aggravate extrapyramidal disturbance . It is especially valuable when antiparkinsonian medications cannot be adjusted downwards without compromising the patient’s functional status, and may even lead to improvement of parkinsonian symptoms. Risperidone can( be a useful alternative. Electroconvulsive therapy has also been shown to be effective with non-confusional psychoses, leading to sustained remissions despite the continuation of dopaminergic drugs .
Dopamine agonists are equally liable to provoke psychotic reactions, and may do so when they are added to levodopa on account of fluctuations in effect . Lisuride infusions appear to be accompanied by a particularly high incidence of visual hallucinations and paranoid delusions. Bromocriptine has been observed to induce paranoid psychoses when given to non-parkinsonian patients for the regulation of the menstrual cycle , also schizophreniform and- hypomanic psychoses when given to patients with acromegaly or prolactinomas . Again the psychotic symptoms usually resolve within a few days of partial or complete withdrawal.
Acute confusional states are mostly encountered in the context of intellectual impairment and treatment with multiple drugs. Severe delirious reactions may be accompanied by aggressive and even violent behaviour. Such reactions should be managed first by the withdrawal of any concurrent anticholinergic medication, then discontinuation of selegiline, amantadine and dopamine agonists . The dosage of levodopa should then be gradually tapered.
It is unclear whether long-term treatment with levodopa conspires towards cognitive decline, or merely enables patients to survive long enough for this to be revealed. Sometimes resolution of the parkinsonism may unmask a dementia not previously apparent. followed a large group of patients for several years; the prevalence of dementia, judged clinically, fell after starting levodopa, but with continuation over the years new cases appeared and established cases could be observed to worsen.
Patients with already-established dementia seem usually to show little change on instituting treatment . Some, however, deteriorate abruptly, with changes that may be transient or permanent. Sacks et al describe the alarming adverse reactions which may occasionally emerge in such a situation, with the abrupt appearance of agitated hallucinatory delirium accompanied by chorea, akathisia and motor unrest. Some patients proceeded to stupor or coma, with or without the preceding phase of excitement. The disturbances could persist for a week or more after withdrawal of levodopa. Those who had had severe confusional episodes showed worsened intellectual deficits for many months afterwards.
By contrast, patients who have been dulled from previous medication may show abrupt improvement on starting levodopa. Others, irrespective of previous medication, may appear to think more quickly and clearly. The effect has been construed as part of an overall alerting and activating effect of the drug, but usually proves to be evanescent. Nevertheless improvements on psychometric tests have been documented after starting on optimal regimens of treatment, independently of physical or affective changes, and persisting some years later.
Affective responses have proved to be variable, a proportion of patients experiencing improvement in mood but others developing severe depression, apprehension and anxiety. Many patients experience increased well being on levodopa, with renewal of interest in family life and the environment, replacing earlier feelings of depression and apathy. The mood elevation can sometimes extend to mania, with elation, overactivity and increased libido. Those who develop depression have sometimes failed to obtain motor benefit but have sometimes responded well. A depressive state prior to starting levodopa has emerged as the most important predisposing factor. Pre-existing anxiety may also be exacerbated, leading to feelings of impending disaster. Responses of this nature are also observed after starting treatment with dopamine agonists.
Sexual interest and activity may improve with levodopa or dopamine agonists, usually in the context of dramatic improvement in mobility. Among 19 patients Bowers et al. found activation of sexual behaviour in six; in the majority this seemed to be part of a general motor improvement, though occasionally there appeared to be a specific stimulation of the sexual drive. In one patient the increased sexual behaviour resulted from disinhibition associated with an acute toxic reaction to the drug. Hypersexuality has been reported in a minority of patients, sometimes in the presence of hypomania. Deviant sexual behaviour has very occasionally been unmasked, including episodes of sadomasochistic behaviour and exhibitionism .
These various psychiatric effects are clearly variable from one individual to another and no uniform set of mental changes has emerged. The factors responsible are likely to include genetic vulnerability, the pretreatment psychiatric state, the extent of neurological and central dopaminergic involvement, and perhaps the presence of diffuse brain damage. Older age, high dosage and the concurrent administration of anticholinergic and dopaminergic medication are clear risk factors. A previous history of psychiatric illness appears to constitute a special hazard where affective and some psychotic reactions are concerned. Some have proposed that levodopa is contraindicated in patients with prior severe mental illness, but in practice a cautious trial of this and other drugs will frequently be undertaken in patients with such a history.
Finally, mention must be made of the astonishing effects of levodopa observed among long-term survivor
of encephalitis lethargica . Institutionalised patients who had spent 20 years or more in states of ’trance’ or immobility due to advanced parkinsonism were often dramatically liberated, experiencing virtually a total return to physical and mental health for a time. Sooner or later, however, the majority encountered a variety of difficulties, with the reactivation of symptoms and behaviour patterns from an earlier stage of the disease. Profound motor blocking set in, or a great excess of tics and urges. States of mounting excitement and ecstasy gave way eventually to exhaustion, depression and a recrudescence of the parkinsonism. Sacks’ vivid case studies illustrate the profound and far-reaching effects which levodopa had on the mental life of his patients, in addition to its remarkable effects on the motor system.
Psychiatric consequences of stereotactic surgery
The vogue for stereotactic surgery in Parkinson’s disease provided an unusual opportunity for examining large numbers of patients before and after circumscribed lesions of the basal ganglia. Extensive psychological studies were pursued, usually with a view to exploring the functions of such regions in relation to intellect, mood or personality. The results were unfortunately often conflicting, though some interesting general findings emerged as reviewed b.
Transient deficits in certain cognitive functions were a common sequel, usually with a return to preoperative status in the months that followed. The side of the lesion was sometimes found to affect the nature of the immediate postoperative deficits. Riklan and Levita , for example, found verbal impairments after left-sided ventrolateral thalamic lesions, and spatial-perceptual impairments after right-sided lesions. Asso et al. showed transient impairments in auditory-verbal learning but found no convincing relationship to the laterality of the lesion. Samara et al. were able to examine the exact site of the lesion at autopsy in the brains of 27 patients and correlated the results with the language deficits which had resulted. They demonstrated convincingly that a lesion strictly confined to the ventrolateral thalamic nucleus could be followed by language deficits. When these occurred the lesion had almost always been in the left dominant hemisphere. Dysarthria could result from a lesion on either side but was usually associated with bilateral operations.
Riklan et al. showed changes in figure drawing, compared to preoperative performance, hi a group of patients having operations on the globus pallidus and thalamus. For several months postoperatively there was a significant decrease in the ’humanisation’ apparent in the drawings, involving such factors as facial expression, shape and body details. This was interpreted as reflecting the level of self or ego development, in turn related to conceptions of the body image. It seemed possible that the basal ganglia might play a role in the integration of the body image, perhaps through their interactions with the parietal lobes.
Discrepant findings emerged where emotional reactions were concerned. Hays et al. found that depression commonly improved after operations on the ventrolateral thalamic nucleus, with an elevation of mood that was largely maintained during the following year. This could not be attributed solely to improvement of motor function and appeared to be a specific consequence of the operation. By contrast Asso et al. found a high incidence of anxiety and depression in the first 9 months after operation and elevation of mood was rare. These differing results doubtless owed much to the preoperative or premorbid psychiatric status of the patients concerned, and perhaps also to the exact sites of the lesions involved.
Premorbid personality and psychological precipitation of Parkinson’s disease
As with certain other neurological diseases there have been occasional suggestions that the premorbid personality of patients with Parkinson’s disease has characteristic features. Closely associated is the proposition that psychological influences may be important in the development of the disorder. None of the observations in this area can be regarded as well founded, but neither can it be said that they have been decisively disproved.
Certain striking qualities in patients with Parkinson’s disease have been stressed – their industriousness, rigid moralistic attitudes and habitual suppression of aggression prior to the appearance of the disease. Sands and Booth championed the view that persons of a particular psychological make-up were at special risk of developing the disorder. Sands described what he called the ’masked personality’, finding a marked discrepancy between the outward appearance of coping and the turmoil within. Premorbid histories showed the patients to have been exemplary citizens, successful in their undertakings and externally calm, undemonstrative and stable. Close acquaintance, however, revealed a subjective state of tension which was suppressed and concealed from outsiders. With the development of parkinsonism a decompensation could often be observed, exposing the inner turmoil in the form of complaints, demands and self-centred behaviour. Sands suggested that the habitual suppression of emotion, doubtless involving intense physiological activity in many pans of the brain, may have led in some way to the degenerative changes responsible for the disease.
Booth developed such concepts further in a clinical study of 66 patients supplemented with Rorschach protocols. Some were postencephalitic and some ’senile degenerative’ in origin. He concluded that the personality structure had been more decisive for the development of parkinsonism than the immediately obvious pathogenic mechanism; the latter had merely served to precipitate or actualise the disorder. Features stressed by Booth included a habitual impulse to action and a striving for success, independence and authority. Tension was prone to arise between this and the equally strong drive towards social conformity. But such tensions, like other emotions and impulses, were firmly suppressed. Regarding their success in life, he found this to be usually the result neither of great intelligence nor of unusual vitality, but attributable to aggressive perseverance and instinctive social conformity. An externally virtuous and docile disposition concealed hostile and sadistic impulses of unusual strength.
Such a character structure would be vulnerable to frustration in a number of ways. In many examples the first clinical symptoms of parkinsonism were preceded by a situation which had imposed a serious handicap to the execution of self-willed strivings and activities – arthritis, exhaustion, economic losses or professional disappointments. In other patients psychological conflicts could be identified as precipitants. Booth saw the major symptoms of parkinsonism as reflecting the original personality and its conflicts-rigidity, for example, being the product of a balance between overcoming obstacles and submission to restrictive influences, and the parkinsonian posture being related to unconscious hostility. Psychotherapy, in conjunction with antiparkinsonian medication was claimed to meet with success in alleviating the symptoms.
There has been little support for these ideas from more recent studies. Diller and Riklan attempted an objective assessment of personality and background in a large number of patients referred for stereotactic surgery, but found nothing that could be regarded as characteristic for Parkinson’s disease. Smythies compared 40 consecutive patients referred for surgery with control groups on a questionnaire relating to childhood disturbance, premorbid neurotic symptoms and life adjustment. No excess of premorbid emotional disability could be discerned, and no unusual difficulties in life adjustment antedating the illness. Pollock and Hornabrook , however, were impressed with the high proportion of teetotallers among their large unselected series of parkinsonian patients, and found that many lacked hobbies and showed narrow intellectual horizons. Poewe et al. compared groups of patients with Parkinson’s disease and benign essential tremor with healthy controls, using Cattell’s personality inventory and a structured interview. Both patient groups were significantly more likely to be introverted, rigid, pedantic and self reproachful than the controls, confirming previous impressions of personality. However, the similarity between the parkinsonian and tremor patients suggested that such traits were merely the product of chronic disability.
More interesting findings have come from comparisons between pairs of monozygotic twins, one of whom had Parkinson’s disease and the other did not . The affected members tended to describe themselves as more nervous, quiet, serious and introspective, whereas their co-twins were more outgoing and light-hearted. Moreover a group of traits showed significant differences before the onset of the Parkinson’s disease-the affected twin was less commonly the leader, less aggressive, more self controlled and less confident. These differences in personality sometimes dated well back into adolescence and early adult life. It seemed possible therefore that neurochemical differences between the twins might have existed from early in their lives, or that there had been some error of foetal development in the member destined for the disease.
Twin studies have also been employed to detect risk factors for the illness. The only possible association that has emerged is that affected twins have smoked less often and less heavily than their co-twins, which is interesting in that animal studies have indicated a dopaminergic effect of smoking on the brain. Baron reviews the epidemiological evidence from many case-control studies which also suggest that smoking may be protective, though with occasional negative reports . It is possible, however, that differences in smoking habits reflect no more than differences in personality.
Hepatolenticular degeneration is a rare inherited disorder affecting both the liver and the central nervous system. Since its description by Wilson in 1912 understanding of the condition has advanced very considerably, and it is known to be linked to abnormalities of copper metabolism. This has led to treatment with penicillamine which meets with considerable success in the amelioration of symptoms. Familial concentrations of the disorder have always been recognised.
A high consanguinity rate is found among the parents, who are themselves unaffected, and it is now clear that the fundamental biochemical abnormality leading to the illness is inherited as an autosomal recessive.
The responsible gene has been mapped to the long arm of chromosome 13 .
The onset is usually in childhood or adolescence, but may be delayed as late as the fifth decade of life. Approximately half of patients are symptomatic by the age of 15. The presentation may be with hepatic disorder, neurological disorder or both together. In addition, as discussed below, a considerable proportion present initially with psychiatric disturbance.
Beam estimated that some 40% of cases first show hepatic dysfunction, 40% neurological symptoms, and perhaps 20% psychiatric illness or behavioural disorder. There is a marked tendency for the liver disorder to be the first to appear when the onset is in childhood.
Hepatic involvement is almost invariable but may sometimes be found only on liver biopsy or at autopsy. Jaundice or hepatosplenomegaly can be the presenting features, or later there may be ascites, ankle swelling or haematemesis from rupture of oesophageal varices.
The neurological disorder is confined to the motor system and takes the form of extrapyramidal disturbance with a characteristic accent on the facial and bulbar muscles . There may be rigidity, tremor, athetoid writhing movements and abnormal dystonic postures of the limbs. In the early stages the disabilities may be transient and sensitive to emotional influences, leading to an erroneous impression of conversion hysteria. A flapping tremor may be seen at the wrists, or characteristic ’wing beating’ at the shoulders when the arms are abducted and the elbows flexed. The facial expression is stiff and motionless, often with open mouth and a rigid silent smile. Bulbar symptoms take the form of spastic dysarthria and dysphagia
Occasional patients develop epileptic seizures, usually of Jacksonian type. Dening et al. found that seizures were 10 times as frequent as in the general population. Hemiplegia is not uncommon. Periods of coma or semicoma may develop, persisting for several weeks but not necessarily heralding a fatal outcome.
Variations in the clinical picture depend to some extent on the age at presentation . In young subjects dystonia or spastic rigidity tend to dominate the picture and tremor may be slight. The course is then liable to be acute and rapidly progressive. In adults tremor predominates and rigidity may be unobtrusive, with a milder course and slower progression. A good deal of overlap occurs, however, and mixed pictures are common In the earlier literature the term ’lenticular degeneration’ was used for cases showing spasticity, rigidity and dystonia, and ’pseudosclerosis’ for cases with marked tremor and dysarthria.
The Kayser-Fleischer ring is a diagnostic sign of great importance. It is situated at the margin of the cornea, brown or greyish-green in colour, and often evident to the naked eye. It is readily detected on slit-lamp examination. Absence of a Kayser-Fleischer ring makes the diagnosis of Wilson’s disease improbable in the presence of neuropsychiatric symptoms, but it may be absent in purely hepatic forms of the disease.
The CT and MRI scans have been found to show a characteristic picture .
Ventricular dilatation, cortical atrophy and enlargement of the cisterns around the brain stem are common, and may be accompanied by typical hypodense areas in the basal ganglia on CT. This combination is considered to be specific for Wilson’s disease. The hypodense areas are most frequent in patients with neurological disability, but can also be seen in those presenting with hepatic disorder or even in presymptomatic cases.
MRI characteristically shows symmetrical focal areas of increased signal, especially in the lenticular nuclei (i.e. putamen and globus pallidus) but also in the thalamus, caudate nuclei, dentate nuclei and brain stem . Focal white matter lesions may sometimes be observed. Rescanning after treatment with chelating agents (p. 664) may show resolution of the changes. PET scanning has shown diffusely reduced brain metabolism with a particular accent on the lenticular nuclei .
Other features include abnormalities of renal function, with aminoaciduria in a high proportion of cases. The urine may also contain sugar or protein, or unusual quantities of uric acid, calcium or phosphate. Degenerative changes around joints are commonly seen on X-ray examination, even in young persons, and fractures and fragmentations of the bones of the hands and wrists may be detected. Episodes of haemolytic anaemia may occur, presumably due to sudden release of copper from the tissues.
Course and outcome
Remissions may be seen in the earlier stages, and even thereafter marked fluctuations in severity can occur. Ultimately, however, severe crippling results from spasticity and dystonic contractions. Dysphagia is often profound, and intellectual deterioration is common in the later stages. The prognosis is worse the younger the age of onset. Formerly children rarely survived for more than 4 years, whereas adults might survive without severe disablement for 12 years or more. Death usually occurs from liver failure, rupture of oesophageal varices, inhalation or intercurrent infection.
With treatment this gloomy outlook has been altered as described below.
Smith describes the pathological findings as follows. The brain is usually normal externally, but on section the corpus striatum is found to be shrunken and brownish or brick red in colour. The putamen often shows cavitation. Microscopically neuronal loss is seen in the caudate and putamen, and the latter contains large numbers of astrocytic nuclei, many having a characteristic enlarged and vesicular appearance (’Alzheimer nuclei /. By contrast the globus pallidus often shows relatively little change. Pericapillary concretions which stain for copper may also be detected. Other abnormal elements include large phagocytic ’Opalski’ cells, possibly derived from histiocytes.
The thalamus, the subthalamic nuclei and the brain stem nuclei may also show Alzheimer nuclei and Opalski cells. Phagocytes containing iron pigment are commonly found in the substantia nigra. Degeneration of the dentate nuclei and superior cerebellar peduncles has occasionally been observed.
Foci of degeneration are not uncommon in the cerebral cortex, especially in the frontal lobes. Diffuse loss of neurones and fibres may occur, or status spongiosus involving both the cortex and the white centres of the convolutions. Astrocytic and oligodendrocytic proliferation may be seen.
The liver may be enlarged in the early stages but is usually smaller than normal at autopsy. It is coarsely cirrhotic, varying in colour from yellow to brown or brick red depending on the relative amounts of copper storage, fatty degeneration and bile staining. Microscopically the picture is of multilobular cirrhosis. The spleen is usually enlarged.
Abnormalities of copper metabolism appear to be fundamental to the development both of the hepatic and cerebral lesions, though the underlying defect of copper
homeostasis is still unclear . The liver and brain contain a marked excess of copper in the disease, the basal ganglia being particularly heavily affected. The Kayser-Fleischer ring in the cornea is due to deposition of copper there, and levels may be raised in the kidneys and other tissues. The total serum copper is usually low and the excretion of copper in the urine is high, though measurement of these is of little value for diagnosis.
Scheinberg and Gitlin showed that the caeruloplasmin content of the serum was low or even absent in the disease, and this has emerged as a finding of great importance. Caeruloplasmin is a globulin which is synthesised in the liver. Ninety per cent of the serum copper is normally bound to caeruloplasmin, the remainder being loosely attached to serum albumin. This free copper is the toxic pool, probably representing the part in transition to other body regions, and it is raised in the disease. While important as a screening test, low values of caeruloplasmin are not invariable, some 5% of patients having normal levels and 10-20% of heterozygotes showing a deficiency . Levels may also be reduced in protein-deficiency states and in the presence of liver disease. When the index of suspicion is high, and caeruloplasmin is normal, a radioactive MCu incorporation test can be valuable, revealing a lack of uptake of orally administered copper into newly synthesised caeruloplasmin. Definitive diagnosis can depend on liver biopsy which reveals elevated copper levels and the histological changes of nodular cirrhosis.
With the advent of effective treatment special attention must be directed towards the detection of asymptomatic but vulnerable individuals in the families of patients so that prophylactic treatment can be commenced. Once the disease has been diagnosed all siblings of the patient should be examined: 25% will be at risk and 50% will be heterozygote carriers. Discovery of a low caeruloplasmin should then lead to liver biopsy, which in the heterozygote may show a mild increase in liver copper, though not in the range of Wilson’s disease, and the liver histology is normal .
The exact pathogenesis of the disorder remains uncertain. The low caeruloplasmin is no longer thought to play a primary role, and there is not a close correspondence between the severity of the disease and the extent to which caeruloplasmin is lowered. There seems rather to be a defect in hepatobiliary copper excretion, allowing excessive accumulation of copper in the liver until free copper enters the blood stream and is deposited in other organs. There may additionally be an abnormal affinity of certain tissues for copper. The primacy of the liver abnormality in the disorder is supported by the success that may follow liver transplantation as described below. Whatever the precise pathogenic mechanism, the net consequence is a positive body copper balance which must be reversed if treatment is to be effective.
The aim of treatment is to eliminate excessive copper from the body and prevent its reaccumulation. It must begin as soon as the diagnosis is made and continue for life. Dimercaprol (BAL) was the first chelating agent to be tried. Results were encouraging but the injections were painful and liable to lead to toxic reactions.
D-penicillamine is now the treatment of choice, though sensitivity reactions can limit its use-fever, rashes, lymphadenopathy and bone marrow suppression. Prednisone cover may allow a restart to be made if bone marrow suppression has not occurred . During the early weeks of treatment the neurological , state may worsen as copper is mobilised from the tissues. This may occasionally extend over several worrying months. Late side effects can include skin changes, renal damage, systemic lupus erythematosus, myasthenia gravis, optic neuritis, bone marrow suppression and loss of the sense of taste. The treatment should ideally be combined with a low copper diet, avoiding such items as liver, shellfish, nuts, chocolate, mushrooms, dried fruits and whisky.
When problems arise with D-penicillamine a change may be made to the alternative chelating agent trientine (triethylene tetramine dihydrochloride), or to zinc acetate or sulphate which decrease copper absorption from the gut. Acutely ill patients may be unable to wait the 2-6 months necessary for chelating agents to work, and plasma exchange may then be indicated or peritoneal dialysis with albumin added to the dialysate.
Clinical improvement may not be obvious for 6 months or even a year in some patients, but with maintenance of treatment progressive gains can continue for several years . Most patients make an excellent recovery from both hepatic and neurological disorder; a small proportion, however, fail to respond to penicillamine or any other drug and follow a steady downhill course to death over several weeks or months .
Neurological improvement is often more rewarding than hepatic improvement, but all aspects of the picture can respond. Tremor, rigidity, dystonia, dysarthria and dysphagia may all gradually resolve and some patients become entirely symptom-free. In general improvement is more complete the earlier treatment has been cornmenced. Dramatic results have been reported from states of hopeless incapacity to relative independence, though such cannot always be achieved.
Psychiatric symptoms have been found to improve as well, some more impressively than others. This is discussed below.
Occasional patients will warrant liver transplantation, which effectively treats the Wilson’s disease as well as the liver failure, restoring copper excretion to normal. Poison et al. have reported its success in reversing severe neurological manifestations, this occurring with unusual rapidity in one of their patients:
A man of 30 had a 14-month history of hepatic and neurological impairment. Despite treatment with penicillamine he developed increasing dysarthria, dysphagia, akinesia and rigidity of the limbs, requiring continuous nursing care. After transplantation liver function became virtually normal from 4 weeks onwards, and neurological recovery began 2-3 months later. By 8 months postoperatively no neurological signs were detectable.
Psychiatric manifestations of Wilson’s disease
Psychiatric symptoms can form a prominent part of the clinical picture along with the neurological defects. On this account it is not uncommon for patients to present to psychiatrists before their disease is diagnosed, with a risk that treatment will be dangerously delayed. Dening and Berrios recommend that serum caeruloplasmin should be measured in all psychiatric patients who show personality change, especially towards disinhibited, bizarre or reckless behaviour, in those who show neurological signs not accounted for by medication, and in patients with unexplained hepatic disease. Dysarthria and other bulbar symptoms will be a strong indication for investigation in patients below middle age, likewise deterioration in school or work performance in children or young adults. The following case illustrates the diagnostic difficulties that can arise:
A 17-year-old girl developed emotional lability, nervousness, difficulty with handwriting and deterioration in school performance. She was at first thought to be suffering from adolescent adjustment problems. Chlorpromazine was prescribed, leading to increasing tremor, and she became withdrawn. Abnormal liver function tests were noted, likewise milcj extrapyramidal dysfunction, but both were ascribed to the drug. She was later hospitalised with a diagnosis of schizoaffective disorder. Finally she was noted to show excessive drooling, a mask-like face, dysphagia, choreoathetoid movements, dystonia, spasticity, splenomegaly and Kayser-Fleischer rings. A diagnosis of Wilson’s disease was confirmed 22 months after the first manifestations. Two years of treatment with penicillamine left her still dysphonic and with severe motor disability. ( Wilson stressed the prominence of psychiatric symptoms in his initial description and believed them to be a fundamental pan of the clinical picture. He noted psychotic and hysterical manifestations, later adding affective change and disordered behaviour (Wilson . Impairment of mental function seemed often to be more apparent than real, being to a large extent suggested by the patient’s appearance and dysarthria.
These various aspects have been reiterated in subsequent descriptions, though until recently it has been difficult to obtain a comprehensive picture. Most examples have been reported anecdotally by psychiatrists or in small series examined by neurologists. Scheinberg et al. found that more than a quarter of 49 patients had significant psychiatric disorder as the first indication of their illness, and almost two-thirds at some point in the course, mostly personality and emotional disturbance. Loss of impulse control could be marked, also depression, anxiety, irritability and excitability. Many patients showed evidence of cognitive impairment, but in general emotional and behavioural disorders predominated. Inose drew attention to fluctuating disturbances of consciousness with episodes of delirium, especially in the later stages. Knehr and Beam demonstrated intellectual impairment on psychological testing in all seven patients examined, with good preservation of language but substantial difficulties with conceptual thinking. More recently Medalia et al. have compared groups of patients with and without neurological impairment on a battery of psychological tests. The former were poorer on memory tests than the latter, but the deficits were mostly mild. Performance on tests reflecting motor impairment was also poor, but ability at naming and card sorting was intact. There were no indications of neuropsychological deficits in patients who had never shown neurological symptoms when compared with normal controls.
Particular attention has been given to psychotic phenomena, with reports of depressive, hypomanic and schizophrenic pictures, sometimes as transient episodes and sometimes as enduring accompaniments of the neurological deterioration. Beard felt that most reports of schizophrenia were probably incorrect, and should more properly be viewed as examples of acute or chronic organic reactions, but reported a convincing example of his own. Davison and Bagley considered that there was a more than chance association with schizophrenia, and that an organic basis was likely – in most reported cases the psychosis and the neurological abnormalities had appeared at about the same time, a family history of schizophrenia was uncommon, and the psychosis tended to progress towards dementia. ,
These impressions have been considerably refined by a series of publications on the large number of patients referred to Dr John Walshe at Cambridge, representing the largest series available in the UK. The careful documentation employed, and the application of operationally defined criteria for the assessment of psychiatric disorder increase the validity of the findings, even though matters of special selection cannot be excluded. The principal conclusions are that personality change and ’incongruous behaviour’ are undoubtedly common in Wilson’s disease, while psychotic phenomena are rare. Irritability, aggression and depression appear to be frequent, likewise cognitive impairment of mild degree. Many of these psychiatric features appear to have an organic cerebral basis.
Dening and Berrios first assessed 195 cases by retrospective case note review. Half were rated as showing some psychiatric disturbance at index admission and 20% had seen a psyhiatrist before the disease had been diagnosed. In half of these an organic condition had been suspected and appropriate action taken, but not in the remainder. Reasons for referra} included deterioration in school or work performance, outbursts of abnormal behaviour and strange disorders of movement.
Personality change, in terms of alterations in life style, relationships or behaviour, was judged as present or possible in a quarter of patients. A similar proportion showed incongruous behaviour by way of disinhibition, bizarre or reckless behaviour, often leading to forensic problems. Evidence of such behavioural abnormality was significantly associated with high scores on ratings of neurological symptomatology, especially dysarthria. Irritability emerged in 18% and showed similar associations, and aggression was noted in 14%. Cognitive impairment was present or suspected in almost a quarter, being generally mild, and depression in 21 %. Depression showed associations with long duration of admission and the presence of family problems but little relationship to neurological symptoms.
By contrast delusions and hallucinations occurred in less than 2% of patients, casting doubt on any significant relationship between psychotic illness and Wilson’s disease. Disorientation was relatively rare at 7% and closely associated with liver failure.
A more intensive prospective study was made of 31 consecutive> attenders at the clinic . These ranged in severity from patients who had never been symptomatic to patients who were mute and bedridden. More than half were rated as abnormal on the Personality Assessment Schedule, the main factor on factor analysis reflecting traits such as impulsiveness, irresponsibility and aggression. A third were ’cases’ as judged by scores on the General Health Questionnaire. No psychotic chotic symptoms were observed. Only four patients scored below the threshold for cognitive impairment on the MiniMental State Examination, and in general such impairment was not severe.
Disorders of personality and behaviour were again significantly related to the presence of neurological symptoms, especially dysarthria, bradykinesia and rigidity, strongly suggesting that they had an organic basis. Depressive symptoms were related to hepatic dysfunction. Cognitive impairment, being mild in this sample, showed less marked correlation with neurological disorder than might have been expected; it was evident, moreover, that some patients who seemed superficially to be impaired performed well on psychometric tests.
Finally an attempt was made to assess the response of neurological and psychiatric symptoms to treatment by retrospective review of 129 patients over a mean period of10 years . Most gains had occurred during the early years of treatment, with significant improvement in cognition and ’incongruous behaviour’. By contrast depression and irritability seemed not to improve. Aspects of neurological disability also decreased significantly, both early and later during treatment, including tremor, rigidity and overall neurological scores. Dysphagia, however, appeared often to persist and dysarthria to have a poor prognosis.
These largely encouraging results from treatment were mirrored in earlier reports. Scheinberg et al. followed 30 patients with both neurological and psychiatric disorder; 25 showed marked resolution of neurological deficits and 14 showed lessened psychiatric disturbance. Goldstein etal. demonstrated gains on serial psychometric testing, often continuing for several years. All improved to some extent, in a manner that generally paralleled their improvement in neurological status but was less dramatic in degree.
Progressive supranuclear palsy
Steele etal. described a group of patients with an unusual progressive neurological disorder showing as an akinetic-rigid syndrome with ocular and mental features. Outstanding signs include supranuclear paralysis of external ocular movements, particularly in the vertical plane and involving downward gaze, dysarthria, pseudobulbar palsy, dystonic rigidity of the trunk and neck, and cognitive impairment. Signs of pyramidal tract and cerebellar dysfunction may also be seen. A tendency to fall over backwards is characteristic. In the later stages the eyes are fixed centrally, and widespread rigidity reduces the patient to a helpless bedridden state. The onset is usually in the sixth decade, with death some 5-10 years later.
Subsequent reports have confirmed the main features of the syndrome. Treatment with levodopa may sometimes ameliorate the rigidity and ophthalmoplegia for a time, but treatment response is often disappointing.
The pathology shows cell loss, neurofibrillary tangles, gliosis and demyelination, particularly affecting the basal ganglia, brain stem and cerebellar nuclei. The tangles consist of bundles of straight filaments and do not show the paired helical structure seen in Alzheimer’s disease. The distribution of changes is remarkably constant and usually there is a surprising lack of cortical involvement. Steele et al commented on the resemblance of the histological features to those of postencephalitic parkinsonism or the parkinsonism-dementia complex of Guam, though the distribution of changes is different. The aetiology is unknown. Degenerative or viral processes are suspected, but attempts at transmission to primates have been unsuccessful.
Among the psychiatric manifestations cognitive impairment is very common, affecting over 80% of de Bruin and Lees’ patients in some degree. Five of the 67 patients had presented with symptoms leading to an initial diagnosis of Alzheimer’s disease, though early aphasia, apraxia and agnosia were never observed. Personality change, abnormal behaviour, emotional lability, depression and social withdrawal were all common.
The most striking cognitive change is bradyphrenia, with slowing of response and lack of initiative. Judgement is often found to be impaired and abstracting ability may be poor. The question of memory impairment in the disease has been controversial, with differing reports in different series. Here the clearest evidence has come from Litvan et al.’s comparison of 12 patients with matched healthy controls. This revealed significant deficits in learning, consolidation and retrieval, also abnormally rapid rates of forgetting. By contrast ’information scanning’, which requires the use of short-term memory processes, remained intact. Verbal fluency tests also showed definite impairment.
The memory disorder may owe much to deafferentation of the subcortical-frontal projections, since the cortical neurones themselves are generally spared. D’Antona et al. have shown marked prefrontal hypometabolism on PET scans in comparison with controls of equivalent age. These observations are relevant to the question of ’subcortical dementia’ discussed just below.
Ovsiew and Schneider have reported a patient with autopsy confirmation of the disease in whom a schizophrenic psychosis was a central feature and present from the earliest stages.
While the disease itself is rare, certain observations made on the mental state of such patients by Albert et at. have provoked considerable interest. The pattern of cognitive impairment seen in progressive supranuclear palsy appears to have distinctive features which may reflect the relative confinement of pathology to subcortical structures. Albert et al. termed this picture ’subcortical dementia’. In this they made a valuable contribution, by underlining the fact that cognitive failure does not always imply cortical disease. The cortex depends for its functioning on inputs from the reticular activating systems and other subcortical structures, and when these fail the cortex, though intact, may cease to display its potential.
Albert et al. contrasted the behaviour pattern in patients with progressive supranuclear palsy with that seen in patients with cortical disease processes. Among five cases seen personally and 42 adequately described in the literature, several key features were evident in the mental state. Though described as ’forgetful’ it could frequently be shown that the patient could produce the correct answer if given encouragement and an abnormal amount of time in which to respond. Memory as such appeared not to be truly impaired, but rather the timing mechanism which enables the memory system to function at normal speed. Slowness of thought was similarly prominent; tasks requiring verbal manipulation or perceptual-motor skills were performed incorrectly under normal pressures, but adequately when time was extended. Thus, when the patient was allowed to proceed at his own pace, or when provided with structured situations to elicit responses that did not occur spontaneously, his intellect could prove to be surprisingly intact. Defects of higher cortical function such as dysphasia, agnosia or apraxia were strikingly absent, though calculation or ability to deal with abstract material were sometimes defective. Personality and mood changes fell into two categories – the larger group was indifferent, apathetic and depressed, while the smaller showed progressive irritability and/or euphoria. Brief outbursts of rage were common, and inappropriate forced laughing and crying were often in evidence.
A woman of 65 with the disease showed extrapyramidal rigidity, slowed speech and marked limitation of upward and downward gaze. Her cognitive state was described as follows:
’She was alert, attentive and socially appropriate. Immediate recall of digits was seven forward and five backwards. Recent memory was deficient in an unusual way: her first answer to almost every question was ”I don’t know”. However, if the examiner encouraged her by saying ”Sure you know; just take your time”, she would correctly respond to 95% of the questions. The latency between question and response was often inordinately long-in some cases as long as 4.5 minutes (often taxing the patience of the examiner). Remote memory was intact
Language functions were as follows … No paraphasias were heard. Naming was excellent on confrontation for high and very low frequency words. Although she complained of having difficulty with words, she had no naming defect. She did, however, have a time-related word-finding defect: in 1 minute she was able to find only three words beginning with the letter B. At 5 minutes she had listed 12; at 10 minutes 23; at 15 minutes 33. Tests of repetition, comprehension of spoken and written language, and reading aloud were normal, except for the slow reading rate.
For simple mental calculations her responses were quick and accurate. With more complex arithmetic problems, she was slow but correct. Her proverb interpretations were concrete and she had difficulty finding similarities in two similar objects.’
A 58-year-old woman had dysarthria, a broad-based ataxic gait and striking impairment of upward and downward gaze. ’Evaluation of mental status revealed an awake, generally placid or apathetic woman who reacted in a seemingly angry manner to the examiner’s attempts to question her. Despite her apparent anger, she could nonetheless be coaxed to cooperate. Digit span was six forward. Questions designed to test recent and remote memory led to the following situation: either she refused to answer or she answered incorrectly. However, when the examiner waited, either silently or with attempts to encourage her, for longer than normal waiting periods (even as long as 4-5 minutes for a single question) she then gave the correct answer to
70-80% of the questions. This indicated that her stock of knowledge was not impaired as one might otherwise have concluded. Rather, she was delayed in reaching into the stock for the correct answer. Tests of language and gestures revealed no aphasia or apraxia. No inattention or primary perceptual problems were seen. Proverb interpretations tended to be concrete. Her ability to find the categorical similarities between similar items was impaired. Her calculating ability was poor.’
Attention was drawn to rather similar pictures in other diseases with subcortical pathology, and the authors tentatively proposed that the common mechanisms underlying them were those of impaired timing and activation. Impaired functioning of the reticular formation, or a disconnection of the reticular-activating systems from thalamic and subthalamic nuclei, might be the cause of slowing of intellectual processes, even though the cortical systems for perceiving, storing and manipulating knowledge remained intact.
The situation in progressive supranuclear palsy, ify which the cortex is known to be largely spared, is likely to exist in some other dementing processes also. Parkinson’s disease with intellectual impairment (p. 653) is an obvious example; Huntington’s chorea is another (pp.469-70). Normal-pressure hydrocephalus, Wilson’s disease and the dementia associated with deep lacunar infarcts (p. 384) have also been viewed in this way . It could conceivably be the case that some variants of the dementias of old age may have a subcortical rather than a cortical origin to the cognitive difficulties, or at least a prominent subcortical component in the aetiology of the clinical picture. An interesting possibility is that the ’normal’ effects of old age upon cognitive functioning may reflect subcortical rather than cortical ageing processes.
These suggestions have attracted a good deal of interest, since it is possible that pharmacological means might be found to help patients with subcortical dementia perform at an improved level. To the extent that subcortical dementias are due to disturbances of activating, alerting or timing mechanisms, then drugs which have an effect on the anatomical or biochemical systems dealing with these mechanisms could prove to have therapeutic value.
Corticobasal degeneration (cortical-basal ganglionic degeneration)
This rare disorder was first described by Rebeiz et al. in 1968. Further series of patients have been reported by Gibb et al. and Riley et al. (. The condition is reviewed by Watts et al. . It consists of degeneration in defined regions of the cerebral cortex coupled with marked pathology in the striatonigral system and other subcortical nuclei. The clinical presentation can resemble progressive supranuclear palsy (p. 666), while the pathological changes share features in common with Pick’s disease (p. 462). A clinical hallmark is the asymmetry of the motor manifestations, such that one limb may become completely incapacitated before symptoms develop on the other side.
It presents usually in late middle or early old age, with akinesia, rigidity, limb apraxia and a combination of 1 supranuclear gaze palsy, myoclonus, limb dystonia or cortical sensory loss. Postural instability may be marked. The myoclonus is induced by action, and is often markedly stimulus sensitive. Ataxia, chorea, blepharospasm and pyramidal tract signs may also be seen. Not infrequently the patient develops an ’alien limb’, whereby the hand and arm feel ’foreign’ to the patient and tend to wander involuntarily and uncontrollably. This feature is discussed by Sawle et al. who ascribe it to damage to the medial frontal cortex and supplementary motor area.
Cognitive disabilities may be notably mild or absent even when severe apraxia hampers the majority of voluntary activity. Other patients, however, develop marked parietal lobe deficits by way of dyscalculia, constructional apraxia or visuospatial impairment. Severe generalised dementia supervenes in perhaps a third of cases. Progressive incapacity leads to death after 4-10 years. Treatment with levodopa is often ineffective, though baclofen may help the rigidity and clonazepam may dampen the myoclonus .
Pathological findings consist of cortical atrophy with cell loss and gliosis, mainly affecting the peri-Rolandic frontal and parietal regions in contrast to the frontotemporal atrophy of Pick’s disease. Subcortical regions are also markedly affected, especially the globus pallidus, putamen, substantia nigra and lateral thalamus. The subthalamic nucleus, red nucleus and locus caeruleus are also involved. Abnormal neurones show marked resistance to staining methods (achromasia) and a swollen appearance similar to the ballooning of Pick cells. Classic Pick bodies are not, however, present. Basophilic inclusions are seen, especially in the substantia nigra, also globose neurofibrillary tangles similar to those of progressive supranuclear palsy.
CT and MRI show ventricular enlargement and cortical atrophy which may be asymmetrical in distribution. Brain imaging with PET has revealed distinctive features which mirror the pattern of pathological involvement . Cortical hypometabolism is evident in the superior temporal, inferior parietal, posterior frontal and occipital association cortices, with a markedly asymmetrical pattern which may be of value in differential diagnosis. 18F flurodopa uptake is reduced in the caudate and putamen, again in an asymmetrical manner.
(multiple system atrophy
Adams et al. drew attention to this rare disorder, closely similar to Parkinson’s disease in clinical manifestations but with a distinctive pathological basis. Affected patients show rigidity, akinesia, slowed movements and a flexed posture. At autopsy the striking features are extensive neuronal loss in the zona compacta of the substantia nigra, but without Lewy bodies, and marked degenerative changes in the putamen and caudate nuclei.
One of Adams et al.’s four cases also showed olivopontocerebellar degeneration. Many cases have since been reported with this striking combination, pr6minent cerebellar ataxia then preceding the parkinsonian symptoms. Approximately half, moreover, are handicapped by fainting due to postural hypotension, and other signs of autonomic failure may include impotence and sphincter and deglutition disturbances. Such patients show neuronal loss in the intermediolateral tract of the spinal cord andthe dorsal vagal nuclei of the brain stem (Shy-Drager syndrome). Dementia may develop but is uncommon. Cosset et al. reviewed 35 cases with both striatonigral degeneration and olivopontocerebellar degeneration, ranging in age from 30 to 75, half of whom also showed progressive autonomic failure. They termed this combination ’progressive multisystem degeneration’. Several patients also showed pyramidal signs, slight muscle atrophy, intention myoclonus and upward gaze palsy.
Nowadays it is usual to group these various conditions together under the title of multiple system atrophy, using the term striatonigral degeneration when parkinsonism predominates, Shy-Drager syndrome when autonomic failure is prominent, and olivopontocerebellar atrophy when cerebellar features are outstanding . A cytological hallmark by way of oligodendroglial cytoplasmic inclusions has recently been described, and these are present whatever the clinical predominance .
The condition should be suspected when a parkinsonian syndrome coexists with ataxia, vertical gaze palsy, pyramidal signs and autonomic failure. Quinn considers that it is less rare than commonly supposed, perhaps accounting for up to 10% of patients with parkinsonism. Treatment with levodopa is usually without benefit, presumably because striatal dopamine receptors are lost, and may sometimes worsen the condition.
The dystonias comprise a group of disorders in which sustained muscle spasms invade muscle groups, causing writhing or twisting movements or distorting the body and limbs into characteristic postures. The abnormal movements differ from tics or choreiform movements in being much slower and sustained, and in their tendency to involve the proximal and axial musculature. Reviews of the classification of these disorders and changing conceptions about them are provided by Owens and Marsden and Quinn .
Almost any body part may be involved. Typically at the onset the dystonia occurs only during some specific motor act, affecting a restricted group of muscles (focal dystonia). It may remain localised, or spread to involve contiguous body parts (segmental dystonia) or virtually all of the body (generalised dystonia). ’Axial dystonia’ is a focal dystonia affecting the trunk. ’Hemidystonia’ affects one half of the body alone, and ’multifocal dystonia’ affects several discrete regions. The different syndromes that result are often specially labelled-torticollis in the neck, blepharospasm in the muscles around the eyes, and dystonia musculorum deformans when the disorder is generalised. Focal and segmental dystonias greatly outnumber other forms; in the large series of almost 1000 cases reported from the Dystonia Clinical Research Center in New York these accounted for some three-quarters of cases, generalised dystonia occurring in less than a fifth .
All dystonic movements and postures are worsened by attempts to move. When the spasms are continuous they result in characteristic postures which are maintained except during sleep. When intermittent they cause repetitive, often rhythmic, jerks and spasms, for example in torticollis. The shorter the spasms the more ’myoclonic’ is the dystonia. Some patients may show an additional cornponent of tremor.
Some dystonias are symptomatic of structural or metabolic brain disease, following in the wake of perinatal hypoxia or kernicterus (athetoid cerebral palsy) or accompanying Huntington’s or Wilson’s diseases. The symptomatic dystonias tend to be asymmetrical or unilateral, and to show other evidence of brain damage by way of fits, intellectual impairment or pyramidal tract damage. Other dystonias may be induced by drugs such as neuroleptics or levodopa. The range of possible causes is legion as listed by Marsden and Quinn . In the majority of cases, however, no cause is found and the condition is labelled as a primary or idiopathic dystonia. A pathological cause is identified in some 45% of patients with generalised or multifocal dystonia, but only in 10% of those with focal dystonia. Hemidystonia by contrast is due to a structural cause in over 80% of cases, for example a stroke, head injury or brain tumour. It is essential that Wilson’s disease, though rare, is excluded in all patients with onset of dystonia below the age of 50.
Age affects the chances of identifying a cause; in Fahn et al.’s series 40% of cases were symptomatic when onset was in childhood, 30% when onset was in adolescence and 13% when onset was over the age of 20. Age also has a marked though ill-understood effect on the likelihood of progression to generalised dystonia – this occurred in 60% of Fahn et al.’s patients with onset in childhood, in 25% with adolescent onset, but in only 3% of adult-onset cases. The legs are usually affected first in children, less commonly in adolescents, and very rarely in adults.
An interesting small group of patients has been reported by Burke et al in whom persistent dystonia developed after a considerable delay of 1-14 years following static cerebral insults such as anoxia, trauma or infarction. In the trauma and infarction cases the body part affected corresponded to the site of the cerebral damage. Schott has drawn attention to patients who developed segmental dystonias in the wake of quite mild peripheral injuries such as falls, twisting the back or straining the arm or thumb, the movement disorder developing as the symptoms from the injury subsided. The site of the dystonia corresponded closely to that of the initial injury. Such rare examples contribute to the mystery surrounding the genesis of this group of conditions.
The dystonias are of importance to psychiatrists on many counts. Both acute and chronic forms can emerge as side effects of neuroleptic treatment, the latter providing considerable problems of management (p. 645). They are also of interest in that they are markedly ’psychosensitive’, being readily aggravated by intercurrent stresses and tensions. This can be so marked that at least in the earlier stages a psychogenic disorder is suspected, this being reinforced when psychological treatment leads to amelioration. Diagnostic mistakes can also arise from the bizarre nature of the movement disorder and the strange postures induced, leading to an impression of simulation, hysteria or catatonic posturing. Strange paradoxes can add to the confusion, as when the patient can run, dance or mount stairs normally while walking provokes considerable difficulty. Some patients can even walk backwards when walking forwards is a problem. Strange tricks or manoeuvres such as the geste antagoniste (p. 673) may be discovered by the patient to control the movement disorder. Difficulties with diagnosis are increased by the absence of abnormalities on formal neurological examination and investigation in the idiopathic dystonias, where diagnosis depends essentially on familiarity with the clinical pictures produced.
Not surprisingly, in view of the above, differing opinions have been held about the causation of dystonia from time to time. Many examples, and particularly the focal forms, were long considered to be psychogenic in origin, for example torticollis and blepharospasm. A measure of doubt still exists in relation to some examples of writer’s cramp and other occupational cramps as discussed below. But the accumulation of evidence now increasingly favours the view that both focal and generalised dystonias form part of a spectrum, founded equivalently in some subtle disturbance of brain biochemistry which awaits elucidation.
The resurgence of such a view has depended on a number of factors – the demonstration of relationships between the different forms, observation of transitions from one form to another, the similarities in clinical picture between symptomatic and idiopathic cases, and not least the provocation of classic examples by a range of pharmacological agents. Moreover careful control cornparisons have increasingly failed to confirm an excess of personality abnormalities or other psychopathology among the persons affected.
Genetic studies have pointed to an inherited vulnerability to idiopathic dystonia and a common origin for the different subvarieties. Fletcher et al. surveyed 100 British families containing 107 members with generalised, segmental or multifocal dystonia (53 generalised dystonia, 46 segmental, 7 multifocal and 1 hemidystonia). Of the index cases 58 had affected relatives. Altogether 79 secondary cases were discovered, almost half being unaware of their problem (generalised dystonia in 15 cases, segmental in 25, focal in 27, multifocal in 6 and tremor in 6). It was concluded that 85% of the cases were caused by an autosomal dominant gene or genes, with approximately 40% penetrance and highly variable expression. About 14% of singleton cases possibly represented fresh mutations. The estimated risk for siblings or children in familial cases was 21%, and the risk in sporadic cases 8-14%. There was no evidence of increased parental consanguinity.
A genetic contribution to adult-onset focal dystonia is less clearly established but also seems probable. Waddy et al examined the relatives of 40 patients with torticollis, orofacial dystonias and writer’s cramp. Ten of them had relatives with some form of dystonia, segregation analysis again suggesting the presence of an autosomal dominant gene or genes with reduced penetrance.
In a small proportion of cases it is nonetheless still accepted, even by experienced observers, that the dystonia is primarily psychogenic in origin (p. 679). And of course in many patients there will be a strong interaction between organic predisposition and the modulating influence of emotional and environmental factors.
Dystonia musculorum deformans
(generalised torsion dystonia)
Dystonia musculorum deformans is the term commonly used for a generalised torsion dystonia of unknown aetiology which leads to severe and progressive crippling. A genetic basis is apparent in many cases. It must be distinguished from the symptomatic torsion dystonia which may follow severe perinatal anoxia or kernicterus; a similar picture may also be the presenting feature in Wilson’s disease and was occasionally encountered after encephalitis lethargica.
The idiopathic generalised disease is rare. It occurs both sporadically and familially and particularly among persons with Jewish ancestry. Eldridge suggested that both autosomal dominant and recessive forms might exist, the latter being common among Asjikenazi Jews. This is now considered erroneous, and dominant inheritance with varying penetrance is proposed for both Jewish and non-Jewish cases. Recent linkage studies have localised the defective gene to the long arm of chromosome 9 in both Jewish and non-Jewish kindreds, close to the genes for gelsolin, arginosuccinate synthetase and dopamine-p-hydroxylase . The greater penetrance in Jews than non-Jews may be due to different mutations operating at this locus. Moreover it is already clear from studies of certain kindreds that other genetic loci must sometimes be involved.
Within families who inherit the major disease other members may show formes frustes of the disorder abnormalities of gait, abnormal arm postures, minor speech defects, or static postural abnormalities such as pes equinovarus or kyphoscoliosis.
Apart from these genetic allegiances little is known about aetiology. Pathological studies have occasionally reported abnormal findings in the basal ganglia, substantia nigra and elsewhere, but these are regarded as nonspecific or even artefactual. However, the evidence points to involvement of the basal ganglia, both by analogy with examples which are symptomatic of known brain lesions and the response which may be observed to stereotactic surgery. The essential abnormality in idiopathic cases is likely to be a biochemical disturbance, though to date few definite leads have been obtained. The most notable abnormality in two cases examined at autopsy by Hornykiewicz et al. was reduced noradrenaline in the lateral and posterior hypothalamus, mamillary bodies, subthalamic nucleus and locus caeruleus.
The symptoms usually commence in childhood or early adolescence. The first symptom is commonly a disturbance of gait, with plantar flexion, inversion and adduction of the foot when walking. At first the picture is sometimes bizarre with respect to the precise functions affected, as already mentioned above. More rarely the initial disturbance may appear in the upper limbs with abnormal postures or actions. A characteristic dystonic posture consists of extension and hyperpronation of the arms, with flexion of the wrist and extension of the fingers. Occasionally the onset is with involvement of the trunk or with torticollis.
In the early stages the motor abnormalities may become apparent only when activity is attempted and nothing unusual can be found on examination at rest. Remissions lasting for several months at a time may occur, all adding to the erroneous impression that the disorder is psychogenic in origin. Indeed an hysterical disturbance is not infrequently diagnosed initially, particularly when there are coexistent emotional problems or adverse environmental factors. Thus patients are occasionally encountered who have undergone years of psychotherapy for ’hysterical spasms’ before progression of the disorder reveals the true state of affairs. The mistake is easily made in view of the rarity of the disorder and the bizarre nature of the symptoms. Other objective signs of a cerebral lesion are absent, with normal tendon reflexes and unimpaired intelligence. Moreover the dystonic postures which can occur in conversion hysteria are sometimes indistinguishable from the transient early disturbances of dystonia musculorum deformans.
Later the muscle spasms occur even when the body is relaxed, producing irregular spontaneous movements or fixed dystonic postures. The movements cease during sleep but plague the patient continually while awake. Other parts of the body come to be affected, usually with symmetrical involvement of all four limbs, the trunk and the neck The proximal muscles tend to be affected more than the distal, and a rotatory element in the axial musculature is typical. The trunk is forced into marked lordosis or scoliosis, and fixed contractures of the limbs lead eventually to severe crippling and permanent deformity. Speech, swallowing and breathing may ultimately be affected. The tendon reflexes become difficult to obtain or may be exaggerated, but the plantar responses remain down-going. There are no abnormalities of sensation.
Rapid progress and widespread involvement is usual when the onset is in childhood or adolescence. Maximum disability is usually reached within 5-10 years, after which the disease tends to arrest or sometimes may even improve very slightly. In about 5% of patients spontaneous remission occurs, usually lasting for only weeks or months but very occasionally being permanent .
An important subgroup which must not be overlooked comprises patients with dopa-responsive dystonia or Segawa’sdisease. This accounts for an estimated 5-10% of patients with onset in childhood or adolescence. The onset is typically with a curious abnormality of gait, for example walking on the toes with a wide base, progressing thereafter to the axial muscles producing lordosis and scoliosis. Parkinsonian features are prone to develop with bradykinesia, rigidity and tremor, and spasticity with pyramidal signs may be present. Diurnal fluctuations and improvement after sleep have been emphasised, but probably do not discriminate the group from other dystonias. Worsening after exertion is characteristic. In Nygaard et al.’s review of 86 cases, 36 were sporadic and the rest had more than onq family member affected.
The dramatic response to levodopa sets the group apart. Small doses give immediate benefit, with a return to normal or near normal after several days or months. Minor gait abnormalities may persist, but full functional capacity is usually regain.
Doses as small as 100 mg have proved effective, though the average is in the range of 500-1000 mg. Dyskinesias have not emerged as a problem with long-continued therapy. Patients have responded after remaining untreated for 25-45 years, and the benefit has been sustained in follow-ups of 10-20 years.
In the symptomatic torsion dystonias the responsible cerebral pathology may lead to intellectual impairment or progressive dementia. In the idiopathic disease, however, this is not so. Eldridge reported that it was common to find exceptionally good intelligence in the Jewish cases. Precocious mental development may have been noted before the appearance of the symptoms and academic performance could be unusually good thereafter despite the gravity of the physical handicap. Unaffected siblings of patients have also been found to have significantly higher intelligence than carefully matched controls .
Treatment of dystonia musculorum deformans is often disappointing in the present state of knowledge, but in favourable cases drugs can bring substantial benefit. It is essential that all children and adolescents should have a 3-month trial of levodopa to see if they have the doparesponsive form, particularly if the dystonia has started in the legs. If this fails the next drug to try is benzhexol, which helps about half of cases, sometimes very considerably . A start must be made very gradually, building up to high dosage over several months to avoid side effects. In children doses of up to 120mg per day may prove to be well tolerated. Other drugs which may help if benzhexol fails include diazepam, clonazepam, baclofen, carbamazepine, tetrabenazine, or neuroleptics such as phenothiazines, haloperidol or pimozide. A combination which can be helpful in very severe dystonia is low dosage tetrabenazine with pimozide and benzhexol . Unilateral thalamotomy can be helpful when the disease is asymmetrical and extremely disabling, but bilateral operations carry risk of impairing speech and swallowing.
Treatment should also be directed towards helping the patient and his family adjust to the profound emotional problems generated by the distressing and long drawnout illness. Psychotherapy can sometimes be of considerable assistance, especially in view of the good intelligence of many of the patients. Some bring astonishing powers of adaptation to bear in learning to cope with their severe disablement. The Dystonia Society gives valuable support and information.
Spasmodic torticollis (cervical dystonia)
Spasmodic torticollis is characterised by involuntary spasms of the musculature which lead to repeated d\ stonic movements of the head and neck, or sustained abnormal postures, or both. The element of sustained spasm in the picture serves in the differentiation from a tic. It may at times represent either a focal or a segmental dystonia, the latter when it spreads to involve the upper limbs.
Males and females are equally affected with an onset mainly between the ages of 30 and 50. A family history of the disorder is rare but emerges in occasional cases . The onset is usually insidious though in some cases it can be related to an acute shock or an episode of emotional disturbance. Local trauma precedes the onset in up to 10% of cases. Sometimes a pulling or drawing sensation is felt in the neck for several weeks before the aaual movements appear, or pain may be experienced locally.
The movements are typically irregular, forcible and writhing in character, involving several of the neck muscles along with the upper parts of the trapezii. The sternomastoid is usually prominently involved, drawing the head laterally and rotating the chin in a charaaeristic manner. Less commonly there may be simple lateral flexion, or the head may be pulled directly forwards (antecollis) or backwards (retrocollis). In time the spasms come to be almost continuous and the affeaed muscle groups may show considerable hypertrophy. Aching may be prominent, and cervical spondylosis may develop from the continual abnormal postures of the neck. Other abnormal movements are occasionally deteaed – facial twitches and grimaces, blinking, shrugging of the shoulders, or twisting athetoid movements of the upper limbs.
Once the condition is well developed the patient finds himself powerless to relax the offending muscle groups or to resist the abnormal movements except for short periods of time. The movements are noticeably affeaed by emotional influences, becoming more powerful and frequent under tension, excitement or distress. Any sudden startle or shock is likely to be followed immediately by a spasm. Self consciousness usually aggravates the condition, likewise walking or engaging in strenuous activity.
The movements subside during sleep, and may temporarily come under a greater measure of control when the patient is engaged in activities such as eating or drinking. An unexplained but striking feature is the ability of some patients to control the spasms by resting a hand or finger lightly against the chin, and not infrequently on the side away from which the turning movements are made (geste antagoniste) .
The course is usually slow progression over many years but the outcome is extremely variable. Some patients are only mildly affected and can continue with their usual occupations, while others become permanently and severely incapacitated. A few show arrest or resolution of the disorder, others show spontaneous remissions varying from a few days to several years. This uncertain natural history adds greatly to the difficulties of gauging the effects of treatment. The picture may also modify as to detail over time, quick movements changing to slower spasms, or spasms giving way to sustained postures. Different muscle groups may come to be implicated, subsequent relapses even involving turning to the opposite side.
Among 1 03 cases Patterson and Little found that 13% pursued a static course, 42% were progressive, 40% were recurrent or intermittent, and two patients had complete remissions without treatment. On follow-up 25% were worse, 12% unchanged, 12% slightly improved, 42% much improved and 7% ’cured’. Ten per cent were unable to work, 49% were partially incapacitated for work and 29% were able to work as well as ever.
Meares found that patients tended in general to deteriorate in the first 5 years and then become static. After the first 10 years slight improvement might be seen, those who had had the disability for this length of time often showing considerable adaptation to its effects. Remissions had occurred in a quarter of cases but almost exclusively in the first 5 years. Certain factors could be identified which appeared to be associated with an improved prognosis . Patients who remitted tended to be younger at onset, with a mean age of 30 compared to 40 for the remainder. They had significantly higher scores on questionnaires measuring neuroticism and anxiety, and rather more evidence of conflict by way of premorbid marital or sexual disturbance. The type of onset also showed some predictive value: the insidious development of a slow turning movement generally signalled a poor outcome, whereas a tic-like jerking onset or a prodromal period of aching in the neck muscles was characteristic of those who remitted.
Theories about aetiology have been widely divergent, ranging from psychodynamic to organic, with many suggestions that both sets of factors may be at work. The condition is now firmly classified among the dystomas, but that does not entirely end the argument. In some cases the torticollis is clearly intimately related to other dystonic manifestations, whereas in others it develops as an isolated manifestation in a setting of emotional trauma. In these latter it can sometimes be hard to escape the conclusion that psychological factors are primarily responsible, albeit operating in an individual who is constitutionally predisposed. In working towards a better understanding, attempts have been made to subdivide the syndrome into different varieties and to define the characteristics of each:
Brissaud differentiated a ’mental torticollis’ which developed from a coordinated purposive act, which, by frequent repetition in predisposed persons led ultimately to its involuntary reproduction. Signs of mental instability were common in such cases. By contrast ’torticollis spasm’ was uncoordinated, painful and sometimes persisted during sleep. Wilson proposed a purely psychogenic type, sometimes occupational in origin and similar to writer’s cramp; a ’torticollis tic’ in the nature of a mannerism; an hysterical variety corresponding to Brissaud’s ’mental torticollis’; and organic varieties which could follow encephalitis lethargica or local infections irritating nerves.
Hyslop suggested a division into torticollis of peripheral and of central origin. Peripheral varieties arose from inflammatory conditions affecting muscles or peripheral nerves, from vestibular disorders, or by way of compensation for paresis of external ocular movement. In such examples there was usually fixed involuntary spasm. Central torticollis could be either organic or psychological in origin, extending on a spectrum between these two extremes.
Tibbetts divided 72 cases into ’typical’ and ’atypical’ varieties according to the character of the movements involved. The former showed tonic and clonic movements, or sustained severe spasm if tonic alone; the latter showed much preoccupation over little spasm or else movements which were chaotic and inconsistent. There was strong inferential evidence for regarding the typical cases as organic and the atypical cases as psychogenic in origin. Thus the typical cases more often showed neurological abnormalities, facial dyskinesias or other abnormal movements, and more often had pain as the initial complaint. The atypical cases contained a higher proportion with abnormal mental states at onset and a heaviei loading for neurosis. They also showed a much higher incidence of remissions and improvements.
It is possible therefore that different varieties of torticollis may owe their origins to dissimilar mechanisms, unified though they may be in their dystonic manifestations. It may be useful to examine the evidence usually quoted in favour of psychogenesis, and then that supporting an organic causation.
Evidence regarding psychogenesis
Earlier studies which purported to show a high prevalence of neurosis or abnormalities of personality lacked adequate control comparisons . More recent studies using surgical or healthy controls have signally failed to uphold such findings . Jahanshahi and Marsden found no difference from controls who had cervical spondylosis on a large battery of personality inventories, but this postal survey contained a large number of non-responders.
Precipitation by emotional trauma was striking in certain patients reported by Paterson . One, for example, heard a shout, looked up turning his head sideways and saw a load about to fall on him. The torticollis commenced from that moment. In such examples the condition has appeared to represent conversion hysteria or a manifestation of an anxiety state. , however, could identify no psychological precipitants in their cases. Cockburn found that 13 of 46 torticollis patients had had a major psychological trauma during the year before the symptoms began, but so did 10 of the controls.
Alternatively, torticollis has been regarded as conditioned by movements at work (occupational torticollis) in the manner of an overleamed and conditioned response. In five of Paterson’s patients the onset could be traced to some voluntary purposive act which had become involuntarily repeated – for example in a telephonist who had to turn her head to the side during work, and in two men whose disorder set in during army training.
Finally, psychotherapy has met with success in certain patients , extending even to complete resolution of the disorder. This, however, is slender evidence in favour of psychological causation, in view of the known sensitivity of dystonic movement disorders to on-going stresses and conflicts.
Evidence regarding organic causation
In the great majority of cases there is no clear evidence of pathology either peripherally or centrally in the nervous system, but small numbers show associations with other neurological disease. Torticollis has sometimes emerged along with parkinsonian features after encephalitis lethargica, or proved to be the initial feature of a progressive torsion dystonia. Indeed its association with other disorders of movement has attracted increasing attention. Poppen and Martinez-Niochet reported that half of their cases showed additional abnormalities by way of grimaces, blepharospasm, tremors of the limbs or choreoathetoid movements. Tibbetts found that 10 of his 49 ’typical’ cases developed new patterns of movement disorder on follow-up, including facial dyskinesia and dysarthria. Couch was able to discern dystonic muscular activity extending to other body parts in 80% of patients with spasmodic torticollis of long duration. This was commonest in the shoulders but could involve the arms, trunk and legs as well.
The nature of the torticollis movements strongly supports the inclusion of the disorder among the focal dystonias. The force, duration and timing of the spasms are very similar to those seen in the generalised disease. The induction of short-lived torticollis as a dystonic side effect of treatment with neuroleptic drugs or levodopa is further evidence favouring this view. Detailed analysis of the movements with physiological recording has shown that sustained dystonic activity usually predominates, along with irregular jerking movements and sometimes rhythmic activity . In some cases the muscles of the back, shoulder girdles and pectorals were also involved. Altogether the complexity of the movements suggested more than a learned pattern of behaviour, and appeared quite unlike the patterns of an hysterical disorder.
Additional information has come from investigations of vestibular function in the disorder. Bronstein and Rudge found that more than 70% of patients showed a directional preponderance of vestibular-induced nystagmus, in a direction opposite to that of the head deviation. Smooth pursuit and optokinetic nystagmus were occasionally affected. Thus in addition to extrapyramidal disturbance there may be involvement of the vestibular system too, perhaps reflecting breakdown of central connections which signal and control posture. Bronstein et al. further describe three patients in whom torticollis followed unilateral eighth nerve lesions caused by an acoustic neuroma, surgery or basilar artery ectasia.
Autopsy studies have been relatively few and have shown little clear-cut pathology. A variety of changes have been reported in the basal ganglia and substantia innominata, but the significance of the pictures described is uncertain . A structural basis for the syndrome therefore remains elusive, as with the dystonias generally, but some cerebral biochemical basis might yet be brought to light.
In conclusion it would seem that evidence has steadily accumulated in favour of an organic causation and away from a psychological explanation for the fundamentals of the disorder. The abnormal movements appear to be mediated by some disturbance of brain function, possibly biochemically based, and to which the individual is predisposed. The surveys outlined on p. 670 suggest the likelihood of genetic influences. In these respects, views about spasmodic torticollis are following in the same direction as those concerning the other partial and segmental dystonias. In some cases the hypothetical disturbance will be sufficiently severe to become clinically overt without superadded pathology, either physical or psychological in nature; in others emotional influences, well known to aggravate dystonic disorders, may have served to precipitate the opening manifestations, and these may then resolve with psychological treatment.
Physical methods such as massage, traction or immobilisation in collars and braces usually meet with disappointing results. Attempts at immobilisation commonly lead to bruising and chafing, and any benefit is promptly lost on removal of the restraint.
Drug therapy has also proved disappointing. Anticholinergics such as benzhexol are sometimes helpful but less so than in the dystonias which set in during childhood. Adults are more prone to side effects, and often cannot tolerate the high dosage required for therapeutic response. Benztropine, diazepam, and neuroleptics such as phenothiazines or haloperidol, may help a proportion of patients in the early stages, but benefits are often transient.
The treatment that has emerged as most useful is injection of botulinum A toxin (BOTOX, Dysport into the affected muscle groups. This should be undertaken only in clinics which have special experience of using the technique. It leads to relief from the neck deviations and associated pain in a high proportion of patients.
Careful choice of injection sites is important, the aim being to weaken the most active muscles from among the sternomastoid, splenius capitis and trapezius. Improvement usually follows within a week. Mild neck weakness may be experienced for some days after the injections, also dysphagia which may persist for a week or two. The beneficial effect typically lasts for 2-4 months, after which repeat injections become necessary. Experience has shown the feasibility of continuing treatments over many years, although antibodies to the toxin may ultimately develop and lead to unresponsiveness. The toxin appears to act by preventing the calcium-mediated release of acetylcholine from nerve terminals, probably by interfering with reuptake into presynaptic vesicles. The affected neuromuscular junctions are permanently inactivated, the waning of effect resulting from the establishment of new junctions by a process of sprouting from presynaptic axons. ,
Alternative approaches include intensive behaviour therapy employing massed practice, aversion techniques or systematic desensitisation to the anxiety induced by the head movements . Biofeedback may meet with substantial success in certain patients, either as an aid to simple relaxation or more directly by electromyograph feedback from the offending muscle groups . Psychotherapy directed at the exploration of conflicts, or analysis of the settings in which the movements first appeared, has been reported to produce improvement and even cornplete relief in occasional patients . Surgical approaches have included selective division of cervical nerve roots, peripheral denervation, thalamotomy and even sternomastoid myotomy in very disabled patients, but the advent of treatment with botulinum toxin should reduce the need for such invasive procedures.
Writer’s cramp is one of the numerous ’occupational cramps’ in which there develops a specific impairment of some educated motor skill, usually due to spasm in the muscles employed. All affect a particular manual skill which has achieved dexterity through frequent practice, and tend at least initially to spare other movements whether skilled or unskilled. The type of error occasioned by the spasm is reminiscent in many respects of the distinction between an unpractised movement and one which has been brought to deftness through constant repetitions .
The condition affects both sexes, with onset usually in the third or fourth decades. In a small proportion the patient reports some accident or injury to the hand or arm immediately before symptoms begi. Some 5% describe a similar condition in other family members. The fingers and hand develop spasm when attempting to write, causing the writing to sprawl in a jerky manner or pushing the point of the pen into the paper. At first the disorder appears only when fatigued or after writing for some time, but later it is evident immediately attempts at writing begin. Both agonists and antagonists can often be seen to be involved, sometimes with the spasm extending well along the upper limb. The finger movements are jerky and incoordinated and tremor may be prominent.
The precise picture varies considerably from one patient to another but the outcome in terms of disability is broadly similar. Certain tricks or strategies are often tried to circumvent the problem, with unusual postures and ways of holding the pen. These may bring new faulty habits and divorce the patient still further from the original skill.
To a remarkable extent other manual functions are typically unaffected, with normal preservation of skills such as sewing or manipulating small objects. Here, however, it has become evident that a distinction must be made between ’simple’ and ’dystonic’ writer’s cramp. In the latter, which may form a substantial proportion of cases, spasms come to interfere with other actions such as sewing, knitting, shaving or using a knife. The forearm tends to pronate and the fingers extend as attempts at writing continue. Among 91 patients seen in a neurological clinic, Sheehy et al found that 14 had been impaired in both writing and other manual acts from the start while the remainder began with difficulty in writing alone; 30 of these 77 later progressed to the dystonic variety after a period of months or years. The spectrum of disorders encountered has been further broadened by the description of patients with tremor and myoclonus induced by writing, this also commonly extending to other manual functions .
There is no muscular wasting or weakness, and the reflexes are normal. Sensory functions remain intact, but pain, aching and feelings of stiffness often develop in the muscles on account of the spasm. A minority of patients may show subtle neurological signs, such as reduced arm swing or some increase in tone on the affected side. Tremor may be evident in the outstretched arm, or a dystonic posture in the dystonic variety.
It is necessary to distinguish these pictures from those seen with other diseases which affect fine coordinated movements, such as arthritis, carpal tunnel syndrome, Parkinson’s disease or early torsion dystonia. Writer’s cramp, suigeneris, should only be diagnosed when there is no other physical or neurological abnormality to explain it, and when, at least at the outset, actions other than writing are performed with normal facility.
The course may fluctuate but is chronically progressive in the majority of patients. Spontaneous remissions occur in perhaps one in 20 patients, usually during the first 5 years. In general the prognosis is poor with lifelong disability though arrest of progression can occur at any stage. Sometimes the left hand becomes similarly involved after the patient has laboriously trained himself to write with this.
The aetiology has always been a puzzle, especially with the simple variety. Attempts have been made to explain it in terms of psychodynamic and learning theory models. Thus the disability has been viewed as akin to hysteria, arising out of unresolved conflict, particularly ambivalence towards the occupation. The spasms involve both prime movers and their antagonists in a manner resembling hysterical motor abnormality; and the disability may be influenced by external factors in a very remarkable manner-for example in patients who cannot write when sitting but can do so when standing . It is only very rarely, however, that patients have seemed to gain or take advantage of the symptoms in any degree. Some re-train themselves successfully to write with the left hand and immediately return to work, while those who are cured by re-training or desensitisation rarely appear to develop other substitute symptoms.
Others have pointed to certain personality configurations in the patients which are thought to be aetiologically relevant. Obsessional features are said to be prominent, with striving conscientious attitudes at work and habitual overcontrol of emotions. Crisp and Moldofsky found that all seven patients whom they studied were of this type. In addition they had special difficulties in expressing aggression. The emotional conflict associated with the onset of the disability frequently centred around the need to write under frustrating but unavoidable circumstances. Bindman and Tibbetts supported such findings. It was suggested that an excessive predisposition to react with muscle tension in the arm when experiencing anger and frustration may have contributed in an important fashion to the genesis of the disorder.
Most observers, however, have found their patients to be generally stable and well adjusted , and control comparisons using a variety of personality inventories have failed to detect an excess of psychopathology . Where anxiety levels have been high, these have usually resolved immediately after treatment has been successful.
The learning theory model proposes that writer’s cramp is the outcome of faulty learning processes; or that whatever its origin its persistence may be explained on the basis of the establishment of maladaptive conditioned responses. Close observation often shows that the cramps tend to arise as soon as the pen or hand touch the paper, and become intensified by further movements of the fingers and thumb as writing proceeds. The good outcome which can sometimes be achieved by conditioning and desensitising techniques lends support to such views.
Increasingly, however, writer’s cramp is now viewed as a variant of dystonia, representing along with other occupational cramps a subtle and task-specific manifestation of focal limb dystonia. How far this may apply to both simple and dystonic writer’s cramp remains uncertain. but the possibility is raised by examples of transition from the one to the other .Patients carrying the gene for torsion dystonia have sometimes experienced an episode of writer’s cramp for months or years in childhood or adolescence. The condition can also be seen in association with spasmodic torticollis. A few patients, particularly those with younger onset, may go on to develop dystonic spasms of the entire upper limb, a torticollis or a generalised dystonia . These scattered observations are as yet rather insubstantial, but combine to suggest that writer’s cramp should be added to the list of the focal dystonias. The predisposition so engendered may, nevertheless, sometimes need to combine with factors of a psychological nature before the disability becomes overt.
It is not inconceivable that dystonia should sometimes affect one highly practised and finely focused skill alone, while leaving others employing the same muscle groups intact, especially when this is perhaps the most complex skill motorically for the patient. Admittedly, tyowever, this has often been advanced as a principal argument in favour of a psychogenic rather than an organic causation. The possibility would seem especially plausible in relation to the other occupational cramps discussed below, where motor skills particularly valued by the person are concerned; the playing of a musical instrument, for example, is notoriously disrupted by anxiety, and increased tension is a powerful influence in making dystonic tendencies overt. In a most interesting manner the dystonias repeatedly illustrate the interaction of physiogenic and psychogenic influences.
Treatment has traditionally involved a prolonged period of rest away from writing, followed by the teaching of relaxation and graded re-educative exercises. Return to work must then be gradual with strict avoidance of fatigue. Unfortunately such measures are likely to meet with incomplete and temporary results. In particular the gains obtained during treatment sessions often fail to generalise adequately to other situations.
Psychotherapy has rarely led to striking benefit. Nevertheless sources of current conflict warrant careful evaluation, especially conflicts in relation to work, and counselling on such matters may bring a measure of relief. Diazepam is sometimes of considerable value in relieving spasm and abating secondary anxiety. Propanolol may help with tremor. Antiparkinsonian drugs have been tried with occasional partial benefit. Hypnotherapy has sometimes been claimed to produce marked improvement when combined with correction of a faulty writing posture .
A promising approach has come from behavioural treatment as described by . Deconditioning procedures were employed to treat both the spasm and tremor evoked by attempts at writing. Simple apparatus allowed shocks to be delivered to the left hand whenever the pen was gripped too tightly by the right, or when it deviated from a prescribed course of linedrawn patterns. Of 39 patients so treated satisfactory results were obtained in 29, with 50-100% improvement after 3-6 weeks of treatment . Follow-up showed satisfactory maintenance of response up to 4.5 years later in 24 patients, and the five who relapsed had shown greater psychological disturbance than those who did well. Beech found that reciprocal inhibition could be helpful, proceeding slowly along a carefully constructed hierarchy of situations which only gradually approached the act of writing, and accompanied by relaxation at every stage. A randomised trial comparing relaxation with ’habit reversal’, in which patients were taught to practice tightening the muscles that oppose the spasm, showed no benefit of the one procedure over the othe. The use of biofeedback techniques to bring the increased tension in the muscles to the patients’ attention at an early stage has achieved success in certain case.
Finally, botulinum injections have been tried with the intention of weakening the muscles principally involved in spasm, with modest benefit in a proportion of patients .
Other occupational cramps
Other examples of restricted disability which centre on educated skilled manual actions are often referred to as ’occupational cramps’ or ’craft palsies’. They show many features in common with writer’s cramp, and arguments about their aetiology closely parallel the discussion above.
Telegraphist’s cramp was formerly the subject of much attention , apparently affecting some 14% of telegraphists using Morse and keyboard techniques in Australia. Factors identified as contributing to it included previously existing neurosis, workload and perhaps adequacy of equipment, training and supervisory practices. Analogous conditions have been observed among typists, tailors, painters and cigar makers. Sheehy el al. have reported examples of typist’s cramp, several progressing to other manual dystonias. Golfers may develop jerks, tremors or spasms (’the yips’ especially during puttin.
A particularly interesting variety has been described among musicians, often intimately related to the manual
demands made by the instrument played. Newmark and Hochberg reported 57 examples. The chief cornplaint was of inadequate control of the upper limb which interfered with playing. Persons with primary complaints of pain or trauma, or who had arthritis, parkinsonism or other central nervous system pathology were excluded.
Among 22 pianists the problem concerned flexion of the fourth and fifth fingers during playing, often after light touch upon the keyboard. Four guitarists and one banjo player showed curling of the third finger into the palm, disrupting tremolo passages. Five clarinetists suffered from extension of the third finger, sometimes with coincident flexion of the fourth and fifth fingers. These patterns were stereotyped in relation to the instrument in question, and highly activity-specific.
The remaining patients exhibited a variety of dysfunctions, ranging from problems with individual finger movements to more gross hand movements or spasms of the pectoralis major. In no case did the movement disorder spread beyond the hand, though in a minority other activities were affected, most commonly writing and typing.
The difficulties were insidious in onset, in general were non-progressive and were unrelieved by cessation of playing for up to several years at a time. They had often been preceded by trauma, tendonitis or significant increases in practice time shortly before the onset of symptoms. The authors favoured trauma as the main aetiological factor, peripheral damage setting in train a dystonic disorder as in the patients reported by Schott (pp. 669-70). Sheehy et al. have described similar problems in pianists, and a form of cramp in violinists in which the fourth and fifth fingers of the left hand lose their skill and press into the finger board.
Blepharospasm and oromandibular dystonia
(cranial dystonia, orofacial dystonia)
Blepharospasm consists of an uncontrollable tendency to spontaneous and forcible eye closure. It may begin unilaterally but both eyes are usually soon affected. Repeated contractions of the orbicularis oculi can progress to almost constant involuntary spasm, sometimes rendering the patient virtually unable to see. Spasms are provoked by bright light, embarrassment, attempts at reading or looking upward. Facial grimacing may be extensive in the efforts to keep the eyes open. Some patients find tricks that help – yawning, humming, touching the eyelids or eyebrows, neck extension or forced jaw opening. All spasms disappear during sleep.
It is most common in middle-aged or elderly women, with onset particularly in the sixth decade. For some considerable time, even years, it may be intermittent, and the aggravation by emotional influences may give a strong impression that psychological factors are operative. A considerable proportion of patients show depression around the time of onset . The affected patients are typically stable, however, and without precipitants that could explain the disorder .
Oromandibular dystonia has a similar range of onset and also more frequently affects women than men. Prolonged spasms affect the muscles of the mouth, jaw and sometimes the tongue (lingual dystonia). They last for up to a minute and are repetitive but irregular in timing. The lower perioral muscles and the platysma may also be involved. The jaw may be forced open or abruptly closed, the lips purse or retract, and the tongue protrudes or curls within the mouth. Severe grimacing occurs and talking and eating may be rendered difficult. The condition can cause great social embarrassment. Spasmodic dysphonia and dysphagia may also be present.
The picture can at first sight resemble the orofacial dyskinesias seen as a late effect of neuroleptic medication (p. 641) but in essence the movements are different . Orofacial dystonia consists of repetitive prolonged spasms rather than the incessant flow of choreiform lip smacking, chewing and tongue rolling movements seen in tardive dyskinesia.
The spasms are typically provoked by embarrassment, fatigue or attempts at speaking, chewing or swallowing. Certain tricks may be learned to abort them, such as grasping the lower jaw firmly or shaking the head. In the early stages the capricious nature of the spasms may produce bizarre results, for example in one of Marsden’s patients who could not speak without provoking spasms but could sing normally, and in another where the reverse obtained.
While each of these two disorders can be seen in isolation, there is a strong tendency for them to be coupled together. Marsden’s composite material showed blepharospasm alone in 13 cases, oromandibular dystonia alone in nine, and both together in 17. In a more recent series of 264 patients with blepharospasm, 188 (71%) also showed oromandibular dystonia . When both are present they usually begin contemporaneously, though sometimes the blepharospasm antedates the oromandibular dystonia by several years. The composite picture has been labelled Meige’s syndrome, or ’Brueghel’s syndrome’ since both aspects are well depicted in the famous painting.
The course is usually chronic and protracted, but can be intermittent over many years. Blepharospasm remains mild in some 20% of cases, whereas other patients become profoundly disabled.
Grandas et al. found that some 10% patients with blepharospasm had experienced a partial or complete remission, lasting from months to several years, but with ultimate recurrence in the great majority. Half of Marsden’s patients with both blepharospasm and oromandibular dystonia progressed to dystonia elsewhere -to torticollis, dystonic posturing of the arms, respiratory spasms or flexion spasms of the trunk.
The aetiology of both conditions remains obscure, but they are now firmly included within the dystonia spectrum. Blepharospasm was formerly often considered to be psychological in origin, but its frequent association with oromandibular dystonia has served to dispel this view. An organic basis is supported by its emergence as a side effect of treatment with neuroleptics or levodopa, and its occasional development in Parkinson’s disease or as a sequel to encephalitis lethargica. Similar associations apply to oromandibular dystonia which may also accompany Wilson’s disease. In both conditions the nature of the spasms-prolonged, repetitive and irregular in timing-is typical in all respects of other dystonias.
Continuous chronic blepharospasm has also been reported after head injury or subarachnoid haemorrhage, or in association with cerebral tumours, degenerative conditions or cerebral arterial disease. Rostral midbrain lesions appear to be particularly closely related to its developmen. In all such settings blepharospasm can sometimes resemble a psychogenic disorder but for the history and abnormal findings on neurological examination. In the large group of patients reported by Grandas et al. dystonia was observed in other parts of the body in 78% of cases -oromandibular dystonia in 71%, torticollis 23%, laryngeal dystonia 17%, respiratory dystonia 15%, arm or hand 10%, pharyngeal 7%, trunk 2% and leg or foot 2%. A postural tremor was evident in the arms in 12%. A family history suggestive of blepharospasm or dystonia elsewhere was found in almost 10% of cases, suggesting a genetic predisposition.
Whether or not a purely psychogenic form of chronic blepharospasm should be recognised remains uncertain. As an acute disorder blepharospasm may accompany severe depression or anxiety, and forcible eye closure with resistance to eye opening is well recognised in conversion hysteria. Such cases, however, are usually transient, and accompanied by much overt emotional disturbance or other conversion phenomena. It would seem most unlikely that the chronic continuing syndrome could owe much to a psychogenic aetiology, sensitive though it is to psychological influences once it has become established. ,
Treatment can raise very considerable problems. Some two-thirds of patients with blepharospasm are rendered functionally blind, and responses to drug treatment are often ill-sustained. With both blepharospasm and oromandibular dystonia there may be a good response to anticholinergic medication provided this can be tolerated in adequate dosage. Levodopa and lisuride helped a proportion of Grandas et al.’s patients with blepharospasm. Tetrabenazine, lithium, or neuroleptics such as haloperidol and pimozide, are also often tried. Severe cases of blepharospasm may require section of branches of the facial nerve, or muscle-stripping operations to remove selected parts of the orbicularis oculi muscles.
Recently injections of botulinum A toxin have achieved a secure place in the treatment of both conditions. For blepharospasm, injections are made into the orbicularis oculi muscles or subcutaneously, producing benefit after 1-3 days which usually lasts for 2-3 months. Side effects are transient ptosis and diplopia. For oromandibular dystonia, injections are made into the appropriate jaw and tongue muscles with EMG guidance. Unwanted side effects are dysphagia and jaw weakness, again usually transient .
Other dystonias and spasms
Other forms of dystonia rarely present to psychiatrists, though laryngeal dystonia may sometimes suggest an hysterical aphonia. In the adductor type the voice is choked and strangled, whereas with the abductor type it is breathy and effortful with whispered segments. Drugs are of little help, but skilled botulinum injections can again give substantial relief. Pharyngeal dystonia presents with difficulty in swallowing, and respiratory dystonia with difficulty in breathing. For details neurological textbooks should be consulted. Hemifadal spasm consists of twitching, tonic spasm and often synkinesis of the muscles innervated by the facial nerve. Though not a dystonic manifestation this too can now be treated effectively with botulinum injections to the facial muscles . Other than this the spasms can be helped in some degree by phenytoin, carbamazepine or clonazepam.
Finally, despite all that has been done to exonerate the majority of cases of dystonia from a psychogenic aetiology, it seems probable that some cases are determined exclusively by psychological factors. In Fahn et al.’ series of 932 patients from New York, 24 (2.6%) were eventually labelled as psychogenic. The authors suggest that the rebound in orientation towards dystonia has led to underdiagnosis of such cases. The label should be applied only when there is clear-cut evidence of a conversion reaction or of malingering. The movements and postures will then often resolve with placebo therapy.
Findings indicative of such a situation include false weakness, false sensory complaints, marked psychiatric disturbance such as self-inflicted injuries, or incongruous and inconsistent movements and postures. These last are, of course, difficult judgements to make in view of the bizarre manifestations which so often accompany organically derived dystonia. A major factor suggesting factitous disorder or malingering is complete resolution of the symptoms when the patient is left alone and supposedly unobserve. Transient relief from hypnotherapy or a barbiturate interview does not suffice to make a diagnosis of psychogenic disorder. It is noteworthy that the severity of psychogenic disturbance can be severe enough in some cases to have led to fixed permanent contractures.
Fahn et al. reported five patients who they believed satisfied the criteria for ’hysterical’ dystonia. All showed additional findings which led to a suspicion of conversion disorder, e.g. pain induced by light touch, inappropriate weakness or the presence of factitious injuries. And rather than a history of action dystonia preceding the dystonic postures, these had been present from the outset. Further experience of psychogenic dystonia is reported by Fahn .
In an extraordinary example reported by Batshaw et al. the diagnosis eventually was of Munchausen’s syndrome:
A 35-year-old woman presented with severe dystonia, thought variously to be psychologically and organically based, and finally revealed by the patient herself to have been factitious. She had first presented at the age of 29 with dystonic posturing of the right foot and a left torticollis of 2 months duration. This was thought to be psychogenic in origin and she was given psychotherapy over a 3-year period. However, the dystonic symptoms spread and worsened so that by 32 she could not walk. She referred herself to the National Institutes of Health where a diagnosis of torsion dystonia was made. Fixed contractures were present by then. Suspicious features included the lack of a family history, the rather late age of onset, the unusual symmetry of involvement and the paucity of involuntary movements
Drugs were without benefit and she underwent left and right ventral thalamotomies. Because of aphonia she did not speak for the next 18 months during which she developed trismus leading to the need for gastrostomy. Episodes of acute opisthotomous and tonic-clonic seizures were unaccompanied by abnormalities on the EEG. Intravenous diazepam led to respiratory arrest necessitating tracheostomy. She reported constant pain from dystonic spasms and was given narcotic analgesics.
A nursing home placement was considered, but just before the decision was made she awoke one morning and began to speak normally. She appeared to be deluded and hallucinated but this was thought to be manipulative in intent. She was transferred to a psychiatric unit and a behaviour modification programme was started. She soon began using her arms, and walked for the first time in 2 years though with an equinus gait. She began eating normally, the gastrostomy tube was removed and the tracheotomy closed, and by the time of discharge all evidence of dystonia had disappeared.
She admitted that she had feigned the whole illness, and others earlier in her career. She had started to turn her right foot inwards while working at a school, in order to avoid the responsibility of taking children for a regular 2-mile walk without assistance. She remained well when followed up 12 months later.
Gilles de la Tourette’s syndrome
Gilles de la Tourette’s syndrome, though relatively rare, has attracted a good deal of attention, chiefly on account of the striking nature of the clinical picture. Multiple tics are accompanied by forced involuntary vocalisations which can sometimes take the form of obscene words or phrases (coprolalia). One of the chief interests of the condition has centred on this verbal component which has been interpreted as giving a clue to the underlying psychopathological mechanisms. However, it now seems unlikely that psychopathological factors are sufficient in themselves to cause the disorder, even though to some extent they may shape its manifestations. A good deal of evidence suggests that there may be an organic component, or perhaps some form of developmental defect, which is at least partly responsible for the genesis of the condition. Genetic influences seem to be important, and links have increasingly been drawn with obsessive-compulsive disorder.
Valuable reviews of the clinical picture are presented by Shapiro et al. , Lees and Robertso. The DSM-FV criteria for diagnosis of the syndrome are the presence of both multiple motor and one or more vocal tics at some time during the illness (although not necessarily concurrently); such tics occurring many times a day, nearly every day or intermittently for more than a year and without a tic-free period exceeding 3 consecutive months; an onset before the age of 18 years; marked distress or significant impairment in social or occupational functioning occasioned by the disorder; and the absence of general medical conditions or substances such as stimulants which could account for it. Patients referred for specialist help can certainly be markedly disabled, but it has become increasingly clear that the majority of sufferers are only mildly affected and unknown to health professionals . Many of the latter would therefore fail to meet the DSM-IV criteria completely.
The condition is a good deal commoner among boys than girls, in a ratio of approximately 3:1. Onset is rare after 11, the great majority beginning between the ages of 5 and 8. In these respects the syndrome resembles the generality of tics in childhood. Motor tics tend to begin around the age of 7, vocal tics some 4 years later, and coprolalia at the time of puberty. Very occasional examples have been reported with onset in adult life , though of course these do not conform to the full DSM-IV criteria above. A family history of simple tics is not uncommon, occurring in 30% of Shapiro et al patients, but it was formerly considered rare to find other family members with the fully developed syndrome. However, several families have now been reported with multiple members affected .
Simple tics are usually the first manifestation. Tics may be defined as ’sudden, quick, involuntary, and frequently repeated movements of circumscribed groups of muscles, serving no apparent purpose’ . They are distinct from chorea and other abnormal motor movements in their stereotyped pattern, the same event occurring time and again, and in the ability of the subject to hold the movements in check for a short while at the expense of mounting inner tension. They usually cornmence around the eyes or in the face, head and neck, spreading later to the limbs and trunk. Before long there are typically multiple tics, often of great force and severity – blinking, grimacing, jerking of the head, shrugging of the shoulders or jerks of the arms and legs. Whole body movements may be involved, leading to bending, jumping, skipping, hopping, stamping or twirling. cornpulsions to touch or smell objects, smelling the hands, or to hit and strike objects or the subject’s own body are often observed. Complex coordinated movements occasionally appear, such as brief slapping of the face or thighs, or wringing of the hands. The picture may at times be highly bizarre, and the detailed pattern may change over time.
Vocalisations can occur from the outset but are usually added later. Most begin within 5 years of onset. At first they are often inarticulate sounds – sniffs, grunts, barks, throat clearing, snorting or coughing noises which accompany the motor movements. These may then progress to the enunciation of words, sometimes muttered and barely discernible but sometimes loudly and clearly articulated. The vocal tics commonly occur at the end of sentences or clauses, without impairing the overall speech rhythm.
Common oaths and expletives are frequently involved, or brief obscene phrases of aggressive or sexual content (coprolalia). The obscenities are often uttered loudly, with an unusual cadence or pitch, and sometimes with imprecise pronunciation of phonemes. The coprolalia occurs without any appropriate stimulus, and in common with other vocal tics it usually breaks through in the pauses between sentences. Some patients repeatedly utter the same swear word over and over again, or use long strings of elaborate obscenities. About a third of patients also utter emotionally charged words of great personal significance, again often spoken oddly with unusual emphasis on particular syllables. One of Lees’ patients would occasionally shout the word ’cat’, and another ’Elvis’.
The utterance of obscenities commonly sets in at about the time of puberty, but may start as early as 10 or be delayed until well into adult life. It ultimately develops in perhaps a third of patients reported from clinic samples, though with great variation in different reports. Among sufferers generally it is probably quite rare. ’Mental coprolalia’ in the form of a compulsion to think obscenities is perhaps commoner than overt coprolalia, and transition from the former to the latter may be observed. Copropraxia consists of the involuntary and inappropriate making of obscene gestures, the commonest in the UK being the palm-backed V sign
It has been shown that when computer programs generate letters or phonemes in a random manner, second and third order texts appear increasingly more like English language . There is also an unexpected repeated occurrence of physical obscenities, which by the fourth order of processing have largely disappeared. Similar results are obtained with second order German. Thus coprolalia in Gilles de la Tourette’s syndrome may conceivably result from a ’short circuiting’ in brain function leading to the production of high probability strings of phonemes out of proponion to other words.
Both the tics and the utterances are affected by emotional stress, becoming more severe with anxiety, excitement, anger, boredom or self consciousness. The patient may struggle greatly to conceal the coprolalia, disguising^ or distorting obscene words so that their true nature is not at first detected. Intense efforts at control may succeed for a while, but at the expense of mounting inner tension and ultimately an explosive recrudescence. The coprolalia tends to cease when the patient is alone but the tics do not. Both are often markedly relieved by alcohol. The tics
cease or diminish markedly during sleep and are also said to disappear during sexual arousal . They usually diminish during periods of intense concentration or when the patient is firmly preoccupied with matters which do not arouse anxiety.
Echo-phenomena have often been stressed in the literature but occur in less than one-third of cases. There may be compulsive repetition of words spoken by others (echolalia), or compulsive imitation of actions (echopraxia).
The intelligence of affected persons varies widely but in some series a surprising number have shown superior ability. Most studies have shown the distribution of intelligence to be within normal limits. Robertson reviews studies which have looked for evidence of specific impairments, noting that language skills appear to be essentially unimpaired whereas visuopractic deficits have emerged with fair consistency. As a result significant discrepancies have often been observed between verbal and performance IQ scores. Attentional deficits have also been highlighted, and may account for Tourette children often falling behind their peers at school despite normal intellectual ability. Channon et al. made comparisons between adult patients with the disorder and matched controls on a variety of attentional tests, demonstrating significant impairments on serial addition, block span sequence. Trail Making and several vigilance tasks. Impairment was found both in sustaining attention and in focusing and shifting sets between salient stimuli. Such deficits were not explicable in terms of depression, anxiety or obsessionality, and showed no relationship to the dosage of drugs taken.
Other features which have often been claimed include a high prevalence of childhood neurotic symptoms and disturbed family backgrounds, but proper controlled cornparisons are not available. Similar difficulties surround the reports of antisocial behaviour and conduct disorder in a high proportion of patients, including lying, stealing and aggressive behaviour generally. Inappropriate sexual behaviour, including exhibitionism, has also sometimes been stressed. A high prevalence of self-injurious behaviour has occasionally been reported, including head banging, lip biting and pummelling of the head and chest . More serious but rare instances include eye damage and touching hot objects. Al] such disorders are relatively uncommon in patients seen in the community, so may in part be an artefact of the selective reporting of patients referred expressly because of such problems
More convincing associations have emerged with behavioural disturbances antedating the appearance of the syndrome, including attention deficit hyperactivity disorder (ADHD). These have been reported in up to twothirds of children, often being the symptoms for which they are referred to a physician. Sleep disturbances including nightmares, somnambulism and night terrors have occurred in up to a third. There is also some evidence that depression and anxiety may be more common in adults with the disorder than in the normal population . There is little to suggest any special relationship with psychotic illness, though not surprisingly there have been occasional reports of patients with bipolar affective disorder or schizophrenia.
Increasingly, however, there is evidence of a close association with obsessive-compulsive disorder, to the extent that this is sometimes regarded as an integral part of the condition, perhaps with shared genetic allegiances . In addition to ritualistic behaviours and compulsions to touch objects, a high proportion of patients report obsessional thoughts and activities. These sometimes amount to frank obsessive-compulsive illness. Frankel et al. found that half of their patients had significantly elevated scores on a questionnaire for obsessional-compulsive symptoms, many scoring as highly, as patients with obsessive-compulsive illness. Robertson et al similarly showed elevated scores on the Leyton Obsessional Inventory. Obsessional features were observed in two-thirds of the patients reported by Nee et al. and Montgomery et al. . The latter study also found a high prevalence of obsessive-compulsive illness among the first-degree relatives of patients.
Caine et al. found that almost half of the children in their epidemiological survey had obsessional ideas, often with associated ritualistic motor behaviour. The commonest included ’evening up’, whereby a series of rituals ensured that the body was symmetrical and balanced, also counting games and touching rituals to ward off bad omens. Cummings and Frankel drew attention to certain similarities between the syndrome and obsessive-compulsive disorder, including age of onset, life-long course with waxing and waning, involuntary intrusive experiences and worsening with depression and anxiety. They advanced the hypothesis that the tics and vocalisations of Gilles de la Tourette’s syndrome may be aberrant manifestations of simple motor programmes generated in the basal ganglia, and that obsessions and compulsions represent more complex motor plans initiated by similar anomalous neural activity.
Course and outcome
Over time the severity of the disorder tends to wax and wane, periods of partial remission alternating with exacerbations. The symptomatology may also change as to detail, new tics developing as old ones disappear. Occasionally there may be periods lasting for days or weeks during which the movements remit completely
Firm information about the longer-term outcome is hard to obtain since there have been few prolonged follow-up studies. Moreover patients will tend to be lost to follow-up as they improve. It seems that the disorder may ameliorate in early adult life, and coprolalia has been said to remit in about one-tenth of subjects without medication . The impression, however, is that most patients are destined for life-long disability in some degree.
Bruun and Budman report a rather more encouraging picture. Of 136 patients who were followed for 5-15 years, 59% had been rated as mild to moderate when first encountered, but at follow-up 91% were now in these categories. More than a quarter had discontinued medication and most others were on lower doses than originally required. Half stated that they had improved spontaneously, most commonly in their late teenage years. A review of several studies suggested that some 30-40% of cases may remit completely by late adolescence, though it cannot be judged whether such remissions are permanent. Anecdotal evidence indicates that elderly Tourette patients rarely exhibit severe symptoms, and it is noteworthy that there have been few reports of elderly patients with the disorder.
The social impact of the illness, at least in the early years, is often disastrous. Some patients withdraw to a considerable extent, while others appear to maintain surprisingly good work records and social relationships despite their disability. Some patients remain only mildly affected all through, clinical impressions of the gravity of the disorder being influenced by those who are referred for specialist help.
Nosology and aetiology
Different views have been put forward about the nosological status of the condition. Some regard it as a rare and distinct disease entity, while others view it as merely the most severe and persistent presentation of the tic syndrome in childhood.
Gilles de la Tourette himself allied the condition with certain other rare motor and speech disorders reported from various pans of the world-the ’latah’ reaction among Malays, the ’myriachit’ of Siberia, and the ’jumping Frenchmen of Maine’. It is now realised, however, that this was erroneous. Latah is manifest as echopraxia, echolalia and coprolalia but tic-like phenomena do not occur. Automatic obedience is a prominent feature. It is essentially a severe startle reaction and does not occur without a provoking stimulus. Yap regards it as a culturally determined fear response found only in primitive cultures where persons have limited powers of control over the environment. Myriachit is similar. The Jumpers of Maine displayed analogous features as part of a religious ritual.
Corbett and co-workers present data which suggest that the fundamentals of Gilles de la Tourette’s syndrome differ little from those of childhood tics generally:
Among patients with tics attending child guidance clinics or adolescent departments it was shown that the tics usually began with facial movements, which in severe examples might come to involve progressively more caudal and peripheral parts of the body. The degree of spread could be used in assessing the severity of the tic, those with peripheral involvement tending to be the more persistent. Thus Gilles de la Tourette’s syndrome is not unique in its progressive spread.
Almost a quarter of Corbett et al.’s patients showed vocal tics along with tics of other parts of the body, thereby satisfying the essential criteria for Gilles de la Tourette’s syndrome. These were compared with further patients selected on the basis of coprolalia in conjunction with multiple body tics. The tics associated with vocalisations tended to affect several parts of the body concurrently and were particularly widely distributed and severe when coprolalia was present. In terms of intelligence and frequency of clinical evidence of brain damage, there was little to distinguish Gilles de la Tourette patients from other tiquers, but they showed a higher prevalence of psychiatric symptoms by way of antisocial behaviour and neurotic disturbances. The level of sociopathic factors in the family was several times that in the general patient population attending the hospital, likewise a history of parental mental illness. Both factors were particularly pronounced in those with coprolalia.
On follow-up, patients with vocal tics did less well than those without, and patients with coprolalia did particularly badly in terms of symptom resolution.
Thus on Corbett’s data Gilles de la Tourette patients appear simply to represent the more disturbed, severely affected and recalcitrant of childhood tiquers, with coprolalia representing the extreme of the distribution.
The main theories advanced to account for tics are psychogenic formulations, those based on learning theory models, those which view the disorder in terms of developmental defect, and those which postulate some specific brain disorder. Each may accordingly be applied to Gilles de la Tourette’s syndrome.
Psychogenic theories regard emotional traumas and conflicts as fundamental to the genesis of tics. Emotional precipitants can sometimes be discerned at the tune of onset, and a high prevalence of psychiatric disturbance has been reported in the patients and their families. The tics are seen as the direct or symbolic expression of emotional disturbance, aggression, anxiety or the handling of sexual conflicts.
Psychoanalysts have conceived of tics as the involuntary motor equivalents of emotional activity, allowing repressed impulses, usually of a sexual or sadistic nature, to make their appearance in disguised form . Such impulses have become ’independent of the organised ego’, that is to say they lack the normal integration with the totality of the personality. In a similar vein Mahler and Rangell regarded the symptoms of Gilles de la Tourette’s syndrome as expressing the conflict between erotic and aggressive drives on the one hand and internalised censoring controls on the other.
These psychoanalytic conceptions may not seem particularly convincing when applied to tics generally, but it is interesting that in Gilles de la Tourette’s syndrome one may meet with vocal and verbal manifestations which lend some support to such views. The noises can often be construed as aggressive, or erotic in character, while coprolalia displays such themes in unmistakable form. Morphew and Sim argued strongly for a psychogenic aetiology for Gilles de la Tourette’s syndrome, noting precipitating factors that were largely psychological in nature, and the improvements that could be seen after psychotherapy, leaving home or admission to hospital. Susceptibility to psychological influences need not, however, imply that these are causative. It would seem wiser merely to conclude that Gilles de la Tourette’s syndrome may reveal psychodynamic factors at work in an unusually clear fashion, rather than to grant them a primary role in the genesis of the disorder. Some observers with wide experience of the condition have been unable to find evidence of inhibition of hostility or other special personality characteristics, and suggest that any observed psychopathology is most likely to be a product of the illness rather than playing a causative role .
The learning theory model views tics as conditioned avoidance responses which have originally been evoked in a traumatic situation, then reinforced by the reduction of anxiety that follows . Because of stimulus generalisation the anxiety that the tic reduces will eventually be provoked by many more situations so that the tic becomes an increasingly stronger habit. In essence the tic is a simple learned response which has attained maximal habit strength.
Corbett pointed out that there is a striking similarity between tic movements and the movements seen in the startle response. This applies both to the nature of the movements and their distribution. Thus tics most frequently involve blinking, the face, head and neck, and the limbs, in that order, hich parallels the distribution of motor activity during startle. Startle responses, moreover, are sometimes associated with vocalisation, and are easily conditioned to neutral stimuli.
Even if such a model is felt inadequate to explain the origin of the tic, it is easy to see how secondary reinforcing properties may come to attach to it and help to perpetuate the habit. To the extent that problems of aggression and hostility are prominent in patients with Gilles de la Tourette’s syndrome the effects of their behaviour on others may sometimes powerfully gratify the habit. Behavioural treatment based on the learning theory model has met with some success (p. 687), though apparently less so with Gilles de la Tourette’s syndrome than with simple motor tics.
A developmental defect has been proposed as the basis of tics and derives support from certain indirect evidence. Such a conception presupposes no necessary special nexus of psychological conflict in the patient, nor some covert form of acquired brain damage, but merely that the normal maturational processes of control over motor movements have not been fully achieved. The patient is accordingly vulnerable to faulty conditioning procedures as set out above, or if he is destined for emotional disturbance his neurosis will be liable to choose the form of a tic on account of his motor lability.
Much of the data presented by Corbett et al. in tiquers fits with a conception of developmental defect. The preponderance in boys accords with their proneness to other developmental disorders. The restricted age of onset between 6 and 8 years suggests a developmental defect, similarly the marked tendency for simple tics to remit at adolescence. Corbett et al.’s tiquers showed an excess of other developmental disorders, such as encopresis and speech defects, when compared to the clinic population generally.
It is less clear whether developmental failure could account for the genesis of the more florid manifestations of Gilles de la Tourette’s syndrome. The frequency of a family history of simple tics argues in favour of some form of constitutional motor lability, but the tendency for the syndrome to persist through adolescence and indeed well on into adult life would suggest that more than developmental immaturity is involved.
Organic theories presuppose that some specific brain disorder contributes directly to the development of tics. This gained support when tics emerged as a sequel of encephalitis lethargica, sometimes in relative isolation. The question therefore arises whether the generality of childhood tiquers might have suffered some form of subclinical brain damage, even while showing little or nothing abnormal on neurological examination.
Pasamanick and Kawi explored the possibility of brain damage resulting from prenatal or perinatal factors, by identifying 83 childhood tiquers and tracing the birth records of each. When compared to the next born child, matched for sex, race, maternal age and place of birth, the frequency of complications of pregnancy and parturition was found to have been significantly higher among the children with tics. These results were interpreted in terms of Pasamanick’s theory of a ’continuum of reproductive casualty’, namely that complications of pregnancy and delivery may lead to brain damage extending in degree from that which is gross and obvious to that which normally evades detection. Depending on the nature and severity of the damage the child may later develop a variety of neuropsychiatric disorders, ranging from epilepsy and mental defect to behaviour disorders or reading retardation. Tics appeared to take their place as part of this spectrum.
Others, however, have argued that the normal or even superior distribution of IQ scores among children with tics, and the absence of other motor abnormalities, make it unlikely that brain damage can play a substantial role.
With regard to Gilles de la Tourette’s syndrome the consensus of opinion is that an organic basis awaits to be discovered, though the evidence for this is mainly inferential. The success of treatment with dopamine-blocking agents , and the occasional emergence of a not dissimilar syndrome along with tardive dyskinesia after long-term neuroleptic medication, point to dopaminergic hypersensitivity as a possible mechanism. To date, however, there has been no direct confirmation of this. Caine reviews several neurochemical investigations into the disorder, some showing reduced cerebrospinal fluid levels of homovanillic acid, the major metabolite of dopamine, but such findings have been questioned on methodological grounds. More recently Singer has reported increased numbers of presynaptic dopamine carrier sites in the striatum in three Tourette patients studied at autopsy, also reductions of cyclic adenosine monophosphate (AMP in the cerebral cortex . A rather striking finding has been reduction in the neuropeptide dynorphin throughout the basal ganglia in a patient with the disorder, with total absence of dynorphin-positive fibres in the dorsal part of the external segment of the globus pallidus . This has since been largely confirmed in further cases . However, such findings have yet to be incorporated into a coherent neurochemical explanation for the disorder. One report has suggested a histological cerebral abnormality, by way of immature cell structure in the caudate and putamen in a single case . The significance to be attached to this is very doubtful.
Clinical studies by Shapiro, Sweet and co-workers have pointed towards cerebral dysfunction in a high proportion of patients, but their findings were uncontrolled and have not been universally replicated . Thus they noted histories of clumsiness, perceptual problems or hyperactivity in childhood in many cases, evidence of perseveration or confabulation, and a high prevalence of left-handedness or ambidexterity. Psychometric testing often showed large verbal-performance’ discrepancies or gave other indications of brain damage. Half of their patients had mild to moderate non-specific abnormalities on electroencephalography, and a similar proportion showed minor asymmetries of motor function on detailed neurological examination. By contrast Lees et al. found abnormalities of this nature in only a small proportion of patients.
Brain imaging has so far not been greatly illuminating, though findings to date support the presence of subtle cerebral defects. CT and MRI scans have proved to be normal in the majority of patients examined, with a few showing mild cortical atrophy, ventricular asymmetry or such unexpected findings as porencephalic or arachnoid cyst. Abnormalities in the size of the caudate nucleus and asymmetries in other basal ganglia structures have occasionally been reported . PET and SPECT scanning have indicated hypoperfusion in the basal ganglia, thalamus, frontal and temporal cortex, and possibly decreased availability of striatal D2 receptor. Neurophysiological studies have shown that Tourette patients fail to manifest cortical electrical potentials preceding their simple tics, whereas they have a normal premovement negative potential (’Bereitschafts potential’) when they voluntarily mimic the same movements . This suggests that the tics are not generated through the normal cortical motor pathways utilized in willed movement but have a subcortical origin.
In conclusion it seems that none of these approaches to understanding the aetiology of Gilles de la Tourette’s syndrome is entirely satisfactory in itself. The study of the disorder illustrates the difficulty inherent in clarifying causes when there is no striking collateral evidence pointing to psychogenic factors or confirming cerebral disorder. Faulty conditioning processes would be most unlikely to result in so bizarre a syndrome when acting on an otherwise normal person; and if developmental immaturity was alone responsible one would expect more impressive evidence in other spheres to confirm it.
Complete explanations are unlikely to be obtained in terms of neurochemical malfunctioning alone, and it seems more probable that both psychological and organic factors interact to produce the final picture. Genetic predisposition has emerged as important as discussed below, and here it could be especially significant that the spectrum of genetic influence appears to embrace both the motor manifestations and aspects of personality functioning, viz. the liability to obsessive-compulsive features.
The coexistence in Gilles de la Tourette’s patients of multiple motor tics and verbal utterances is at first sight puzzling, but perhaps can be accommodated in what we know of the use of words and body gestures. Both are vehicles of emotional expression and of communication, and must share at some level in their internal representation. Mahler and Rangell suggest that the cardinal features of Gilles de la Tourette’s syndrome can all be regarded as different expressions of dysfunction of the ’system of expressional motility’. Certainly where aggression is concerned the normal processes of development lead from coarse motor expressions of hostile impulses to the more highly differentiated use of language, and the employment of obscenities in connection with aggression is firmly rooted in the culture towards which development proceeds.
Though the disorder is often sporadic, recent studies have increasingly supported a genetic contribution, with links between narrowly defined Gilles de la Tourette’s syndrome, chronic multiple tics without vocalisations, and obsessive-compulsive disorder. The precise genetic mechanisms remain unclear, but the presence of a single autosomal gene with varying penetrance has been suggested by some investigators. Polygenic inheritance is another possibility, and X-linked modifying genes may account for the increased prevalence among males.
Price et al. investigated 30 monozygotic and 13 dizygotic pairs of same-sex twins where at least one cotwin had Gilles de la Tourette’s syndrome. The concordance rates were 53% in the former and 8% in the latter. When the criteria were broadened to include tics of any sort the concordances rose to 77% and 23%, respectively.
The lack of full concordance among monozygotic pairs emphasises the additional role of non-genetic factors, and Leckman et al. were able to show that in nonconcordant pairs the unaffected co-twin had always had the higher birth weight. This suggests that prenatal events or exposures may have played a part in actualising the disorder.
Large family studies have shown an increased prevalence of Gilles de la Tourette’s syndrome and of chronic multiple tics in the relatives of probands, segregation analysis sometimes suggesting the presence of a major autosomal gene with incomplete penetrance . Family studies have also indicated that the same gene may be expressed as obsessive-compulsive disorder. Thus many relatives of Tourette patients describe obsessional-compulsive thoughts and actions in the absence of tics or vocalisations ; and obsessivecompulsive disorder has been found to be especially common among family members where Gilles de la Tourette’s syndrome appears to be an inherited disorder . Family aggregations have been confirmed in two particularly large pedigrees, one of
122 members from six generations in a British family , and one of 161 members over four generations in the USA. Thus while the exact mode of inheritance remains to a large extent uncertain, both family and genetic studies combine to suggest that there is a spectrum of disorder, extending from classic examples of the syndrome to other forms of tic and including also obsessive-compulsive disorder. The search for candidate genes by linkage analysis has not so far yielded definite results.
Until the advent of pharmacotherapy the treatment of Gilles de la Tourette’s syndrome was mostly disappointing. It was, moreover, difficult to evaluate the effectiveness of interventions on small numbers of cases because of the tendency of the disorder to show spontaneous fluctuations.
Psychotherapy often met with failure but improvements were sometimes reported, very occasionally with seeming total recovery . Nevertheless supportive psychotherapy and group counselling procedures find an important place in helping patients to cope with their disability. Abreaction has been attempted with a wide range of drugs, and Michael (1957) reported a patient who underwent a striking remission after a series of carbon dioxide inhalations when intensive psychotherapy had met with no response
Behavioural therapy can be effective with simple tics, for example ’massed practice’ which is based on the theory that voluntary practice of the tics for long periods of time will build up reactive inhibition to their recurrence . Clark reported remarkably good results with the technique in two out of three cases of Gilles de la Tourette’s syndrome. Coprolalia was eliminated by asking the patient to repeat the most frequently used obscenity as often as possible in a large number of treatment sessions. Others, however, have had less success, finding that practice may aggravate the tics by generating increased anxiety . Techniques in which the patient is taught to practise movements incompatible with the tic, or to substitute a neutral word for an obscenity, have also occasionally helped . Cohen and Marks have reported the value of an operant conditioning programme, involving rewards for tic-free periods of increasing length, which can be implemented in the patient’s home. Behavioural techniques also find a special place in the management of severe obsessive-compulsive behaviour when this is part of the condition.
Drugs such as diazepam may help temporarily by reducing anxiety, but dopamine receptor antagonists emerged as the first truly valuable medications. Connell et al. convincingly showed the effectiveness of haloperidol in simple tics in a double-blind comparison with diazepam, and Chapel et al. were among the first to report excellent results in Gilles de la Tourette’s syndrome. Haloperidol has since received enthusiastic support and remains among the drugs of first choice. Shapiro and Shapiro conclude that over 80% of patients gain improvement, though some 13% discontinue it because of side effects. Dysphoria and sleepiness can be troublesome and may outweigh the benefits in terms of tic control. A start is usually made with very small dosage, for example 0.2 5-0.5 mg daily, thereafter building up very gradually to an end-point of maximal improvement with the minimum of side effects. In many patients 2-3 mg daily is adequate for symptom relief, but sometimes much larger doses are required. Dosage can often later be reduced over several months or years without loss of benefit, sometimes to very low levels.
Pimozide is effective in many patients and is often less sedating, likewise sulpiride which is less prone to provoke extrapyramidal disturbance. Tardive dyskinesia has proved to be more than a theoretical risk in Tourette’s syndrome when neuroleptics have been administered over prolonged periods of time .
Clonidine, a centrally active alpha adrenergic agonist, has also been shown to be effective , though less regularly so than dopamine antagonists. However, differences in response by individual patients may indicate a trial of several different agents. The anticonvulsant clonazepam and the antidepressant clomipramine have also occasionally shown success, likewise calcium channel blockers such as nifedipine and verapamil. Documented responses have been reported with naloxone, lithium carbonate, tetrabenazine and fluvoxamine .
Operative intervention by way of stereotactic surgery to the dentate nucleus of the cerebellum, or the rostral intralaminar and medial thalamic nuclei, has been found to help occasional patients but will very rarely be indicated. Even in severely affected patients much can often be achieved by careful adjustment of drug regimens and proper attention to psychosocial aspects of management. Valuable support and information can be provided to patients by the Tourette Syndrome Associations both in the UK and the USA.