Postgradluate Medical Journal (December 1977) 53, 726-728. Postgrad Med J: first published as 10.1136/pgmj.53.626.726 on 1 December 1977. Downloaded from

Symptomatic * JOHN PEARCE M.D., F.R.C.P. Department of , Hull Royal Infirmary

Summary Nevertheless, depletion of the pigmented nerve cells Parkinson's disease, 'paralysis agitans', is charac- in the is an essential ingredient of terized by a number of abnormalities. both the idiopathic and the much less common A similar clinical picture may be symptomatic of symptomatic varieties of Parkinsonism. In addition other disturbances: these are briefly described and the to the nerve cell loss and formation of Lewy bodies differential diagnosis is discussed. in Parkinson's disease, there is also frequently found a degree of reduction of weight, dilatation of Introduction the ventricular system and widening of the cortical The characteristic features of paralysis agitans sulci. Similar changes have been found in post- have long been familiar to doctors in many disci- encephalitic varieties of disease, and are also plines. For the most part the diagnosis poses no constantly observed in the parkinsonian serious strain on the doctor's intellect or powers of associated with Alzheimer's pre-senile to observation. The typical resting , cog-wheel which reference will be made later. and plastic rigidity in the neck, trunk and limbs Protected by copyright. accompanied by the important disorder of posture Physical agents and the poverty and slowness of volitional movement Before coming to the more commonly encountered immediately attract attention. Diagnosis is almost , some rare causes of the syndrome must entirely based on clinical observation. It is frequently be mentioned. Firstly, instances of manganese made within a few seconds of the patient's entry to poisoning and carbon monoxide poisoning figure in the consulting room, and if the diagnostic impression all the major neurological treatises. They are is not formed at this stage it may escape recognition extremely rare in clinical practice, but both agents for some considerable time. are known to damage nigrostriatal neurones by Present day practice yields a population of the cytotoxic mechanisms. idiopathic type of disease as originally described by James Parkinson in 1817, in over 90/4 of patients. Trauma Practice in a mental hospital of course discloses a Trauma is frequently invoked as a possible cause much higher proportion of patients afflicted by drug- or aggravating agent in Parkinsonism. A history of induced disease, which will be discussed later. By trauma is given by about 10% of patients with idiopathic, we imply that the primary aetiological Parkinson's disease, but from this we should not http://pmj.bmj.com/ agent is unknown. A depletion of assume that it is a causative factor. Examples of central neuro-transmission (Bernheimer et al., 1973) aggravation of previously mild Parkinsonism by a operating mainly at the level of the substantia nigra head injury are occasionally encountered in practice, and its efferent pathway the corpus is the and more rarely one sees a patient with no previous fundamental biochemical basis which is probably history or evidence of symptoms of the disease who common to all patterns of Parkinsonism. It is, develops them in a dramatic fashion shortly after a however, clear that deficiency is not the head injury. The contentious argument rests on sole basis of the disease, for were this so, it would be whether the patient had the disease in a latent form on October 2, 2021 by guest. arrested or cured in every case by replacement of before the injury which then acted as an aggravating dopamine by various pharmacological manoeuvres. factor, or whether the brain damage initiated the The failures and relatively short-term success of disease de novo. There is virtually no evidence to dopamine replacement are sufficiently obvious to confirm that trauma can cause the disease. But, in indicate that there is much more involved than a medico-legal practice one sees a variety of un- simple deficiency of this transmitter substance. doubtedly organic sequelae of mild to moderate head injuries in elderly subjects which one would * Paper presented at a Trent Regional Symposium on seldom encounter in the younger brain. Amongst Parkinson's disease held at Doncaster Royal Infirmary on April 24 1976. Edited by Dr A. A. G. Lewis, and received for these, Parkinsonism features rarely, but when it does publication June 13 1977. it is reasonable to assume that trauma played a minor Symptomatic Parkinsonism 727 Postgrad Med J: first published as 10.1136/pgmj.53.626.726 on 1 December 1977. Downloaded from

role as a precipitating or aggravating factor. It is encephalitic Parkinsonism in greater or lesser degree striking that in the numerous head injuries encoun- (Parsons, 1928). The syndrome would develop tered in war-time, Parkinsonism was virtually never during the convalescent stage of the illness, or more encountered. Finally, to prove that trauma was a frequently in the next 12 to 18 months. In rare causal factor, it would be necessary to show that the instances, a delay of up to 10 years was recorded. To chances of acquiring the disease are greater among the classic features of rigidity, tremor, dysarthria and the injured portion of the population than among the flexion , were added tics and twitches of the uninjured: no supporting figures have ever been face, throat and jaw, attacks of and, most adduced to support this concept. characteristic of all, oculogyric crises. Other than the oculogyric crises, an early age of onset and a definite Cerebral tumour history of , there were no diagnostic Brain tumours are amongst the rarest causes of features. Tremor tended to be less frequent, stiffness symptomatic Parkinsonism. They almost invariably more marked. Excessive salivation was commoner produce their own characteristic combination of and muscular weakness rarer. Loss of ocular con- focal signs, raised , or vergence, pupillary abnormalities and marked mental disturbance. One has occasionally met asymmetry were typical but not diagnostic features. patients with long-standing Parkinson's disease of In the more severe cases the prognosis was worse than ten or more years' duration who have then de- in paralysis agitans, but the fact that there is still a veloped a brain tumour, usually a glioma and one large number of survivors in whom the disease has has regarded this as coincidental. Occasionally, apparently become stationary after the passage of however, a parasagittal meningioma or glioma of the many years, indicates that at least one variant of this corpus callosum or can present with extraordinary condition is comparatively benign. In Parkinsonism (Marguilies, 1953). The course of the passing, it is of interest that these patients have been illness is relentlessly downhill and the speed of unusually sensitive to dopamine replacement, and Protected by copyright. progression far greater than in idiopathic paralysis that oculogyric crises are usually unaffected by this agitans. These anomalous clinical features will treatment. usually direct attention to the need for further investigation. 'Arteriosclerotic Parkinsonism' We are all familiar with the cases of bilateral Commoner varieties of symptomatic Parkinsonism hemiplegia or patients who have sustained multiple Juvenile paralysis agitans minor . The latter group are often hyper- Hunt in 1917 reported a case of Parkinsonism tensive without major extracranial vascular disease beginning at the age of 15 and going on for 25 years but with a multitude of tiny lacunae which represent and found lesions of the at post- microinfarcts in the basal ganglia internal capsule mortem. Many similar cases have subsequently been and pons. The sliced brain in such a case in the described and are referred to as juvenile paralysis affected region resembles Gruyere cheese. The clinical agitans. Lesions in the substantia nigra and pallidum features of these patients are characteristic, and have been observed. The author has personally include bilateral spastic weakness of face, arms and

encountered eight examples of the syndrome which legs, often asymmetrical with enhanced reflexes http://pmj.bmj.com/ started before the age of 40 including one case and extensor plantar responses. Explosive laughter starting at 16 and three before the age of 30. Perhaps and crying, dysphagiaand a highly characteristic nasal the most striking feature of this syndrome is that dysarthria, and a brisk jaw-jerk constituting 'pseudo- although the disease appears fully developed with bulbar palsy' complete the picture. The bilateral tremor, rigidity and bradykinesia, it seems to ad- spastic weakness of the facial muscles produces an vance for a number of years and then remains immobile expressionless appearance, and the in- relatively stationary. The author's impression is that volvement of pyramidal tracts in both legs produces the natural history is considerably longer than in the a slow shuffling, short-stepped gait. The superficial on October 2, 2021 by guest. later onset idiopathic disease. Wilson (1940) thought resemblance to Parkinson's disease is thus evident. it doubtful that these cases really belonged to the But the resemblance is only superficial and the true group of classical Parkinson's disease. extra-pyramidal signs of basal ganglia disease are seldom seen (Pearce and Pearce, 1971). It is ofcourse Post-encephalitic disease true that the patients with Parkinsonism in their 70's The well known epidemic of encephalitis which and 80's will frequently have co-existing cerebrovas- started in Austria and France in 1916 and travelled cular disease, but all thecurrent evidence suggests that round the world left in its wake the complication of they are purely coincidental. Eadie and Sutherland Parkinsonism in a substantial number of patients. (1964) suggested that the incidence of arterial disease Among 925 encephalitics, 334 (36%.) manifested post- in parkinsonian patients did not differ from control 728 J. Pearce Postgrad Med J: first published as 10.1136/pgmj.53.626.726 on 1 December 1977. Downloaded from

subjects of similar age and sex distribution. Finally, 1. Dementia. 2. Parkinsonian signs. 3. Primitive direct pathological correlation between Parkinson- reflexes, (a) glabellar tap, (b) snout and sucking, ism and discrete cerebrovascular lesions is rare. (c) grasp, (d) palmo-mental. 4. Cerebral cortical and central atrophy (Selby, 1967). Drug-induced Parkinsonism Parkinsonism induced by drug therapy is now the The incidence of Parkinsonism in the context of commonest form of symptomatic disease. In 1961, dementia is of some interest, and is accompanied by Ayd found that of 3775 patients treated with drugs histological changes in the basal ganglia in primary of the phenothiazine group, 1472 had extra-pyra- Alzheimer's disease (Pearce, 1974). The interactions midal syndromes. Of these, 21 2% showed , of and basal ganglia are complex. The 15-4%y Parkinsonism, and 2-3y. including cortical lesion may cause a supranuclear denervation oculogyric crises. One can therefore expect to find of basal nuclei. Conversely, basal ganglia disease can parkinsonian signs in about 33%/ of all patients with cause dysfunction of the cortex by interruption of long-term phenothiazine treatment. Whether the proprioceptive pathways. In this context it is of disorder can be wholly prevented by concomitant interest that depletion of monoamines in the cortex medication with anticholinergic drugs remains has recently been shown in senile dementia. doubtful, but it is certain that symptoms and dis- ability are considerably lessened by such therapy. Conclusions How long it takes to induce Parkinsonism with With the exception of drug-induced disease, psychotropic drugs is clinically relevant. It has been symptomatic Parkinsonism is relatively uncommon observed between 3 and 6 weeks after treatment of in clinical practice. Its theoretical implications range tetanus with chlorpromazine. Under these circum- widely as has been suggested in this somewhat stances of relatively brief courses of therapy the sketchy survey of the field. When with syndrome is confronted Protected by copyright. entirely reversible when treatment is (i) atypical clinical signs; (ii) a syndrome whose pro- stopped. There is, however, evidence that after gression is unusual; (iii) a response to treatment continued treatment for many months or years, which does not withdrawal of the follow the expected course, the drug may, on occasion, not be clinician would be wise to reassess the patient and followed by the remission which usually occurs investigate further within 2 or 3 to clarify the possibility of weeks of its discontinuation. Parkinsonism secondary to some other primary Reserpine exerts its effect by displacing dopamine disease process. from nerve endings, and in this instance levodopa will reverse the iatrogenic syndrome. Phenothiazines and butyrophenones including haloperidol act by References causing blockade of the dopamine receptors, and in AYD, J. (1961) A survey of drug induced extrapyramidal these patients the beneficial effect of levodopa is less reactions. Journal of the American Medical Association, a 175, 1054. striking, and better response may be obtained by BERNHEIMER, H., BIRKMAYER, W., HORNYKIEWICZ, O., anticholinergic drugs. JELLINGER, K. & SEITELBERGER, F. (1973) Brain dopamine In all instances of apparent drug-induced Parkin- and the syndromes of Parkinson and Huntington. Clinical, morphological and neurochemical correlations. Journal of sonism, the clinical problem is whether the syndrome http://pmj.bmj.com/ is entirely or Neurological Sciences, 20, 415. iatrogenic whether the patient har- EADIE, M.J. & SUTHERLAND, J.M. (1964) Arteriosclerosis in boured latent Parkinson's disease which has become Parkinsonism. Journal of Neurology, Neurosurgery and manifest only by further dopamine antagonism Psychiatry, 27, 237. caused by the drug therapy. It may be argued that HUNT, J.R. (1917) Progressive atrophy of the . drug-induced cases which do not Brain, 40, 59. revert to normality MARGUILIES, M.E. (1953) Parkinsonism and brain tumour. on withdrawal of the drug are in fact examples of Archives of Neurology and Psychiatry, 70, 112. latent Parkinson's disease which has become un- MAWDSLEY, C. (1975) Parkinson's disease. In: Recent masked by the psychotropic agent. Advances in Neurology (Ed. by W. B. Matthews), p. 118. on October 2, 2021 by guest. Churchill Livingstone, London, Edinburgh. PARKINSON, J. (1817) An Essay on the Shaking Palsy. Whitting- Alzheimer's disease ham and Rolland, London. Although dementia is the most striking ingredient PARSONS, A.C. (1928) Ministry of Health Reports 1949. of Alzheimer's disease, a variety of subtle neuro- PEARCE, J. (1974) The extrapyramidal disorder ofAlzheimer's logical signs are almost invariably found in disease. European Neurology, 12, 94. this PEARCE, J. & PEARCE, I. (1971) Current concepts of Parkin- syndrome. A tetrad of clinical features has been sonism. Postgraduate Medical Journal, 47, 794. described which becomes relevant in this discussion SELBY, G. (1967) for relief of Parkinson's because of the high incidence (60%.) of a Parkin- disease. 1. Critical review. Journal of the Neurological sonian syndrome (Pearce, 1974). The tetrad Sciences, 5, 315. consists WILSON, S.A.K. (1940) Neurology, Vol. 2, p. 787. Arnold, of: London.