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Home , Hemiballismus

The Treatment of the and Athetotic

R. B. GODWIN-AUSTEN, md,frcp Neurologist, Nottingham and Derby Hospitals and Nottingham University Medical School

Although has perhaps been regarded as a receptors and that the blockade of these same receptors somewhat academic specialty, an increasingly thera- (or the reduction in activity in the brain) peutic orientation in recent times is nowhere better might relieve the abnormal movements. This simple exemplified than in the diseases that affect the basal model is only partly satisfactory for some of the choreas ganglia. The 'extrapyramidal' diseases were the con- and is inadequate as an explanation in the athetotic ditions least satisfactorily explained on the basis of dystonias where our understanding of neurochemistry correlation between morbid anatomical change and remains minimal. But a significant proportion of patients physical signs. From the time of Parkinson himself until with abnormal movement disorders can now be helped by the early years of this century the anatomical site of the medical means and in these cases a knowledge of relevant lesion in Parkinson's disease remained obscure, largely neuropharmacology is necessary. because the pathological changes are subtle, whereas the changes in neurochemistry of the Parkinsonian brain were shown to be impressive directly the relevant techniques became available to demonstrate them (Ehringer and Horniekiewicz, 1960). Definition the choreas and torsion seldom Similarly, dystonias When or about disorders of movement show prominent morbid anatomical changes and these discussing writing there is a in and definition. It is not conditions cannot be and studied in the difficulty description reproduced unknown for two to use dif- experimental animal. But the emphasis for the genesis of experienced neurologists ferent terms to describe a patient with a abnormal these conditions has been shifted to a study of chemical single . There are also terms that sometimes changes, especially since a number of drugs have caused seem to confuse, such as choreo-, or disorders that are similar to or identical with those oc- merely terms derived from neuropathology which, in a clinical curring naturally. As a direct result of these studies a setting, may be purely speculative (e.g. 'progressive number of drugs capable of reducing or suppressing pallidal atrophy'). The simplest and most satisfactory many of the symptoms have become available. The classification is that suggested by Marsden and Parkes diagnosis of extrapyramidal diseases is therefore no (1973), who divided abnormal movements into , longer an academic exercise but an essential prerequisite to , , tics and athetotic . There is the effective management of the patient. seldom difficulty in distinguishing tremor from other Patients suffering from diseases causing chorea or since it is a regular rhythmical movement. athetotic dystonia present a bizarre appearance and are Chorea and myoclonus may be difficult or impossible to sufficiently unusual to make confident diagnosis the distinguish by clinical observation. Chorea is exception, although levodopa dyskinesias have made generally defined as irregular random and jerky movements that what was a very much more common- formerly rarity are continuous. In the movements are Place. Parkinson's disease provided the classical model of myoclonus usually a intermittent and consist of separate jerks or twitches that disease whose pathology is characterised by a depletion ?f may be Similarly, tics may be in- cerebral dopamine (and where the features of the stereotyped. distinguishable from myoclonus by observation but are disease can be produced by blockade of dopaminergic characterised by the subject being able to suppress the brain synapses) while relief can be obtained by treatment WJth movement partially by an effort of will that is ac- drugs active at the dopaminergic receptor (dopa- companied by a build-up of nervous tension. The feeling ^uie, apomorphine, bromocriptine). With the appear- ance of nervous tension is immediately relieved by the ab- of dopa dyskinesias the possibility arose that an normal movement. Athetotic dystonia is characterised analogous situation might exist ?that dyskinesias were by abnormal movements that are random, slow and caused by the reaction to dopamine of abnormal brain writhing in nature. They are usually associated with article is based on a paper read at the College disturbance of posture. C?nference held at Nottingham in September Any abnormal movement may be generalised, or may jgyWna^ involve predominantly proximal and trunk musculature

J?urnal of the Royal College of Physicians of London Vol. 13 No. 1 January 1979 35 or, alternatively, the distal muscles. Thus, a proximal significant intracranial calcification. tremor may be called titubation when it involves the head and neck, and proximal unilateral chorea is often called The Choreas hemiballismus. abnormal movements be Similarly, may severe When chorea is the diagnosis may be obvious. The focal or torticollis is an generalised: spasmodic example random jerking movements causing grimacing and of a focal dystonia, while tardive phenothiazine dyskin- purposeless twitching and twisting movements of the esia is an example of a focal chorea. limbs are characteristic. In the mild case, doubt may arise as to whether the movements are nervous restless- ness, particularly in a condition such as thyrotoxicosis Diagnosis where chorea may develop as part of the disease, or in cases where for There are a number of features in the history and on psychiatric phenothiazines, example, may be used and the is therefore at risk from general examination that must be sought in any patient being patient tardive if presenting with a disorder associated with abnormal . Repeated observation, necessary after medication with a small dose of involuntary movements. In the young patient, birth benzodiazepine, settle the matter. In chorea is history and childhood development is important in may children, fortunately rare since the incidence of chorea distinguishing the congenital from the acquired; birth Sydenham's has declined, but the distinction between and chorea anoxia or injury and a history of neonatal jaundice may 'fidgets' be difficult, and necessitate more than one be relevant. In the past medical history an encephalitic may again of observation. illness is still important, as is any history of rheumatic period The commonest cause of chorea is the treatment fever. The family history and possibility of consanguinity today of with the remain- should always be noted. Drugs, especially phenothiazines, levodopa and, among levodopa, the contraceptive pill and anticonvulsants, ing causes, drugs occupy an important place (Table 1). If these conditions are considered as a a number may all provoke dyskinesias. group, Classification depends on observation of the clinical of common chemical and pharmacological charac- features of the abnormal movement, but associated signs teristics emerge. rare when is ad- that must be looked for include , dysarthria, Chorea is excessively levodopa ministered to the normal whereas between 30 posture and gait abnormalities, and reflex changes. subject, and 50 cent of with Parkinson's disease Kayser-Fleischer rings are obviously essential in the per patients diagnosis of neurological Wilson's disease but liver failure develop abnormal movements within two years of the onset of treatment. This observation from other causes may present with abnormal in- levodopa might voluntary movements. suggest that other changes in the Parkinsonian brain are to In However, in the majority of patients it is the abnormal necessary for levodopa produce chorea. Hun- disease exacerbates the chorea and movement that constitutes the only significant finding, so tington's levodopa there are in the brain. that diagnosis and appropriate investigation depends on widespread 'degenerative' changes Patients the facial and buccal chorea of classifying the abnormal movement or dyskinesia. It is developing tardive et often helpful to consider at this stage whether the phenothiazine dyskinesia (Sigwald al., 1959) with dyskinesia is characteristic or recognisable. If not, the almost invariably have brain damage dementia and question should always be asked: 'Could the patient be frequently have undergone leucotomy. Similarly, in making the movement voluntarily and if so why?' Where the movement disorder is voluntarily produced the cause of the disease still remains to be determined; that is, the psychiatric abnormality must be diagnosed and treated Table 1. Causes of chorea. effectively. The problems of treatment in such cases are Drugs but, disturbance is very great fortunately, psychiatric Levodopa (with or without decarboxylase inhibitor) only exceptionally the cause of dyskinesias and the Phenothiazines majority of these conditions are entirely organic in their Butyrophenones pathogenesis. It is therefore unwise to conclude too Oral contraceptives readily that the disorder is due to psychological causes. Phenytoin Finally, it is useful in the diagnosis of an unusual Chorea dyskinesia to decide whether there is any associated Huntington's disturbance of muscle tone. In the and general, dystonias Associated with other diseases Parkinsonian states are associated with hypertonia Sydenham's chorea whereas in and chorea muscle tone is normal myoclonus or reduced. of muscle tone is an Asymmetry objective Thyrotoxicosis abnormality that provides important evidence for the Polycythaemia rubra vera organic basis of an abnormal movement disorder. Systemic lupus erythematosus Laboratory or radiological investigation is seldom of Idiopathic hypoparathyroidism and osteomalacia value in the diagnosis of these conditions. Serum Cirrhosis phenytoin or serum calcium levels may be relevant. lethargica Serum copper and measurements are caeruloplasmin Structural where Wilson's disease is a elec- Damage necessary possibility: infarction in cases of and troencephalography may help myoclonus, Stereotactic occasionally a straight X-ray of the skull may show

36 Journal of the Royal College of Physicians of London Vol. 13 No. 1 January 1979 patients with cirrhosis and there is The first two factors in the causation of chorea widespread brain damage. Thus, a 'chronic brain syn- (chronic brain syndrome and dopaminergic hypersensi- drome' is the first prerequisite for the development of tivity) are relatively unamenable to treatment. Where chorea in some cases. brain damage is focal, as in cases of hemiballismus, In patients developing chorea in association with stereotactic thalamotomy can prevent the chorea by a With the in thyrotoxicosis or phenytoin medication no such brain further destructive lesion. improvements treatment is now seldom necess- damage can be demonstrated. It would seem that in these medical this procedure examples an abnormal sensitivity of some brain ary. mechanism has developed. Many patients with Very little is known of the pharmacology of receptor Parkinsonism on levodopa develop chorea only after sensitivity, although we must hope for future advances since this would seem a fruitful area for months of treatment and the movements may vary in highly therapy. severity independently of absolute blood levels and Kartzinel and his colleagues (1976) showed no change in which decrease after a short period off levodopa. These ob- dopa dyskinesia following treatment with caffeine, is a inhibitor and servations also suggest an abnormal sensitivity of the powerful phospho-diesterase might brain resulting in chorea. Chorea gravidarum and the therefore affect receptor sensitivity. Similarly, no alteration in occurs with simultaneous chorea associated with oral contraceptives may represent dopa-dyskinesia a similar state of altered sensitivity of the striatal treatment with oxpentifylline, which is a more specific neurones resulting from a previous rheumatic illness. phospho-diesterase inhibitor (Godwin-Austen, 1978). The fact that chorea is on the The reduced levels of brain gamma-aminobutyric acid apparently dependent formation and release of has to be of (GABA) found in Huntington's chorea (Perry et al., dopamine proved the because that 1973) and in Parkinson's disease can probably be in- greatest therapeutic significance drugs cerebral such as or tetra- creased by treatment with phenelzine or sodium deplete dopamine reserpine benazine, or that at the valproate respectively but such treatment does not affect antagonise dopamine receptor et al., and the chorea (Marsden, 1975; Price et al., 1978), although (oxiperomide (Bedard 1978), phenothiazines m will chorea in the of tardive in some cases was butyrophenones) suppress majority dyskinesia improvement if administered in obtained by Linnoila and his colleagues (1976) by patients adequate dosage. in Parkinsonian chorea as a treatment with valproate. Reduction of dose of anti- Thus, patients showing adverse effect of be achieved con- levodopa, improvement may cholinergics may reduce dopa dyskinesia and, (but usually at the expense of some increase in the versely, treatment with physostigmine may exacerbate it one or more of the in (Klawans and Rubovits, 1974) but these effects are Parkinsonism) by following changes treatment generally mild and it would seem that of the known 1. Reduce total dose of neurotransmitters occupies the primary role in levodopa. dopamine 2. More smaller doses of the genesis of chorea. However, Curzon (1973) drew frequent levodopa. 3. Reduce the dose of attention to the fact that hyperkinetic states were not anticholinergics. 4. In addition to or (1) give associated with any evidence of increased dopamine drugs: that have but different serotonin turnover in the brain, which suggests that a (a) dopaminergic activity state or of altered receptor sensitivity exists at the dopa- pharmacokinetics (bromocriptine), (b) that alter the of minergic synapse rather than any excessive dopamine pharmacokinetics dopamine turnover. formation () or breakdown (dep- renyl), or Levodopa and dopaminergic drugs such as bromo- (c) that antagonise dopamine at the receptor (oxi- criptine provoke chorea in Parkinsonism when given ^one and exacerbate chorea in patients who already peromide). show dyskinesias from levodopa. Lee and his colleagues In chorea due to phenothiazines, Huntington's chorea, Uy/8) have demonstrated chemical changes indicative of and senile chorea, symptomatic treatment with tetra- benazine if with such as ypersensitivity at the dopaminergic receptor in Parkin- associated, necessary, drugs sonian striatum from patients who had been treated with , thiopropazate or , is the treatment of choice. The smallest dose sufficient to chorea ?pa during life. Thus, the second necessary basis for the suppress without sedation is but adverse effects of evelopment of chorea would seem to be a hypersensi- appropriate Parkinsonism and additional of the dopamine receptor. It is now known that depression may require tivityere treatment with or anti- are at least two types of dopamine receptor (Costall anticholinergics tricyclic and Naylor, 1975) and whether the one or the other is depressants respectively. ^sponsible for chorea or an imbalance between the two is still uncertain. Athetotic Dystonia

Dopa-induced chorea is dose-dependent so that The group of conditions characterised by focal or ^?thdrawal of the drug or reduction in dose leads to rapid generalised athetosis and dystonia are heterogeneous in sappearance of the chorea. The same is true of their and and no common chemical ^ pathology aetiology k?paminergic drugs such as apomorphine, piribedil and or neuropharmacological characteristics have yet been ?mocriptine. Similarly, drugs that reduce the synthesis demonstrated. As with the choreas, no satisfactory action of dopamine at the receptor tend to reduce or animal model is available. These conditions are rare olish chorea. This fact would that chorea is to make the of series of human cases ^ suggest enough study very Pendent on the formation and release of dopamine, difficult, so it is not surprising that our understanding of a^d is the third necessary prerequisite for the genesis of these conditions is limited and treatment unsatisfactory chorea. (Table 2).

J?urnal of the Royal College of Physicians of London Vol. 13 No. 1 January 1979 37 may claim benefit from full dosage Table 2. Causes of athetotic dystonia. of benzhexol or benapryzin but this is the exception. Generalised, As with chorea, Parkinsonian patients on chronic 1. IDIOPATHIC treatment with levodopa may develop focal dystonias Dystonia musculorum deformans with of the limbs, spasmodic tor- (a) hereditary ticollis or, commonly, painful flexion of the toes and (b) sporadic inversion of the ankle. These abnormal movements athetoid induced movement Paroxysmal by disappear when the dose of levodopa is reduced. administered to from focal 2. SECONDARY Levodopa patients suffering or athetotic does not increase the Athetoid generalised dystonia indeed it lead to benefit Wilson's disease movements; may occasionally Hallervorden-Spatz disease (Rosenthal et al., 1972). Post-traumatic or anoxic No abnormality of neurotransmitter concentration or Post-encephalitic turnover in the brain has been demonstrated in these Drugs (a) Acute disorders. However, athetotic dystonia may, in a phenothiazines significant proportion of cases, be improved by treatment butyrophenones with drugs that reduce dopamine synthesis or block its metoclopramide action at the receptor. This response is more variable Chronic (b) than in the choreas and, in general, dosage has to be levodopa adjusted at a level where Parkinsonian features are manifest. But the use of com- Focal tetrabenazine, possibly bined with render mobile and in- Spasmodic torticollis pimozide, may a who was to Benign hemifacial spasm dependent patient previously subject gross and continuous athetosis. It is noteworthy that medical treatment is particularly disappointing in the focal dystonias, although the oc- casional case of blepharospasm will respond dramatically to tetrabenazine. Finally, the hemiathetotic may be helped by stereo- In the athetotic the or of the dystonias body part body tactic thalamotomy, but the outcome of the procedure is is to slow and movements subjected writhing twisting variable and difficult to foresee and it should be carried to the bizarre but characteristic disturbances of leading out in a centre with particular experience of these cases. The abnormal movement and are posture. postures Cervical rhizotomy has been used for the treatment of exacerbated movement or mental effort and by voluntary spasmodic torticollis, but the work of Meares (1971) relieved relaxation or In the by sleep. generalised showed that the prognosis in this condition was worse hemiathetosis) the trunk dystonias (including proximal following surgery than in patients treated by conservative muscles are most affected, whereas in the focal dystonias symptomatic means. a single muscle group may be affected (e.g. blepharo- spasm). References Wilson's disease is the condition in which only specific Bedard, P., Parkes, J. D. and Marsden, C. D. (1978) British Medical treatment is available and, fortunately, in the majority of Journal, 1,954. cases where the diagnosis is made early, substantial Costall, B. and Naylor, R. J. (1975) European Journal of Phar- of the can be achieved and macology, 33,301. improvement dystonia usually Curzon, G. the Medicine, 66, be In all the (1973) Proceedings of Royal Society of symptomatic therapy may unnecessary. 873. other conditions causing athetotic dystonia symptomatic Ehringer, H. and Horniekiewicz, O. (1960) Klinische Wochenschrift, treatment is all that is available. 38,1236. Godwin-Austen, R. B. observations. Paroxysmal athetoid spasm is a rare paroxysmal (1978) Unpublished Kartzinel, R. and Calne, D. B. 26, disorder to anticonvulsant treatment (1976) Neurology (Minneapolis), usually responding 741. with phenytoin or carbamazepine. Klawans, H. L. and Rubovits, R. (1974) Journal of Neurology, The acute drug-induced dystonias might be expected Neurosurgery and Psychiatry, 37, 941. to provide an important clue to the pathogenesis and Lee, T., Seeman, P., Rajput, A., Farley, I. J. and Horniekiewicz, O. treatment of these conditions. The patient (1978) Nature, 273,59. symptomatic Linnoila, M., Viukari, M. and Hietala, O. (1976) British Journal of with acute from dystonia phenothiazine overdosage may, Psychiatry, 129, 114. for example, show posturing of the head typical of Marsden, C. D. (1975) In Modern Trends in Neurology (ed D. spasmodic torticollis or opisthotonos and scoliosis of the Williams). London: Butterworths. D. British trunk reminiscent of dystonia musculorum deformans or Marsden, C. D. and Parkes, J. (1973) Journal of Hospital Medicine, 428. states. The acute of p. post-encephalitic dystonia pheno- Meares, R. (1971) Lancet, 2, 149. thiazine can be and overdosage immediately dramatically Perry, T. L., Hansen, S. and Kloster, M. (1973) New England Journal relieved by anticholinergic drugs. Patients with post- of Medicine, 288, 337. encephalitic states frequently gain great benefit from Price, P. A., Parkes, J. D. and Marsden, C. D. (1978) Journal of and 702. continuous medication with high dose anticholinergic Neurology, Neurosurgery Psychiatry, 41, Rosenthal, R. K., McDowell, S. H. and Cooper, W. (1972) Neurology medication but, the have unfortunately, anticholinergics (Minneapolis), 22, 11. very little effect in other forms of athetotic dystonia. An Sigwald, J., Bouttier, D., Raymondeaud, A. and Piot, A. (1959).Revue early or mild case of dystonia musculorum deformans or Neurologique, 100,751.

38 Journal of the Royal College of Physicians of London Vol. 13 No. 1 January 1979