Page 2 P H Y S I O T H E R A P Y MARCH, 1971 P A R K I N S O N S D I S E A S In 1817, Jam es P arkinson, a general practitioner in Shore­ ditch, wrote “A n Essay on the Shaking Palsy” . H e prefaced it with these rem arks: “T he disease is o f long duration: to connect, therefore, the symptoms which occur in its later stages with those which m ark its commencement, requires a continuance o f observation o f the same case, o r at least a correct history o f its symptoms, even fo r several years. O f both these advantages the writer has had the opportunities of availing him self.” By his repeated observations he had come to certain conclusions regarding the “ nature o f the m alady” and its probable relief or cure. H e mentions that previously “ the disease has escaped particular notice” and he considered it his “ duty to subm it his opinions to the exam ination o f others, even in their present state o f im m a­ turity and im perfection” . We are still in a state o f im m aturity an d imperfection regarding this fairly com m on disease. M uch has been written from 1817 onw ard, m any things are know n ab o u t the Shaking Palsy, bu t its essential nature still escapes us. D E F I N I T I O N T he words P arkinson’s Disease, Parkinsonism , P arkinson’s Syndrom e are often used synonom ously. Like many, Jam es P arkinson had greatness thrust u pon him : Jean- M artin C harcot applied the eponym Parkinson’s disease to patients with this disease, thereby giving credit to James Parkinson’s masterful description o f the malady. N o t that he was the first to describe it: in his essay Parkinson speci­ fically refers to the writings of G alen (A .D . 129-199) and Sylvius de la Boe (1614-1672). Besides being a medical practitioner Jam es P arkinson was also actively engaged in the politics o f his day. It therefore seems inappropriate to apply the suffix “ -ism” to his nam e when we consider his medical ideas and not his political ideology. T he term Parkinsonism is inapt and, even when used, to o vague: it covers a m ultitude o f sins o f comm ission! Parkinson’s syndrome m ight be applied to th at group :of symptoms and signs which are collectively present under know n etiological conditions e.g. post-encephalitic Parkinson’s syndrome, arteriosclerotic Parkinson’s syndrome, P arkinson’s syndrome due to carbon-m onoxide, or manganese poisoning, etc. In other words to apply the nam e “ syndrom e” to the sym pto­ m atic group of this disorder, and to call idiopathic that variety o f the disease described by Parkinson. However, it is as well to point out now, as will be described again later, th at the distinctions idiopathic, post-encephalitic and arteriosclerotic are probably no t relevant an d cannot truly be made. All the other varieties o f the syndrome are examples o f isolated sym ptom s o f basal ganglion disease occurring simply o r in com bination with other unrelated symptoms and with a very different pathology e.g. necrosis of the globus pallidus following CO poisoning, the Parkinson- D em entia complex o f G uam , and posttraum atic forms o f the disease etc. Parkinson ’s Disease can be defined clinically no better th an Jam es Parkinson’s original description which stresses the point th at “ the submission o f the limbs to the direction o f the will can hardly ever be obtained in the perform ance o f the most ordinary offices of life” . It is this hypokinesia or akinesia th at m akes life so difficult for a patient with this disease. Parkinson correctly starts his description o f the disease by stating th at “ so slight and nearly im perceptible are the first inroads o f this m alady, and so extremely slow is its progress, th at it rarely happens th at the patient can form any re­ collection of the precise period of its commencement. The first symptoms perceived are a slight sense of weakness, E A . V A N W IE R IN G E N , M.B., C h.B., M .M ed. (Int.) (Pret.) Lecturer in M edicine, K arl Brem er H ospital, Bellville. w ith a proneness to trem bling in some particular p a rt . m ost com m only in one o f the hands and arm s.” H e then describes the progress of the disease: the inability “ in preserving an upright posture” ; “ employments accomplised with considerable difficulty, the hand failing to answer with exactness to the dictates o f the will” ; walking becoming more difficult as the legs are not raised high enough o r “ with th at prom ptitude which the will directs” ; and finally “as the disease proceeds tow ards its last stage, the trunk is alm ost perm anently bowed, the m uscular pow er is more decidedly diminished, and the trem ulous agitation becomes violent” . All the difficulties the patient encounters in his daily activities are described fully till the final complete dependency on the services o f his nearest relatives. It is very strange th at none of the six cases he describes showed th a t increase in tone throughout the somatic! m usculature, clinically m ost obvious in the limbs, which is know n as rigidity. W hether Parkinson failed to appreciate this or did not distinguish it from the akinesia is not at all clear. It is, however on this triad o f sym ptom s, hypokinesia, rigidity and trem or, that the clinical diagnosis o f Parkinson’s disease depends. O ther abnorm alities were appreciated later and are present to a greater or lesser extent in m any patients: spontaneous spasms o f conjugate gaze (oculogyric crises), loss o f involuntary blinking movem ents o f the eyes, but a prolonged blinking response to tapping the bridge of the nose (glabellar reflex), loss o f postural reflex mechanisms, seborrhoea, and hyperhydrosis. Loss o f weight is a constant feature, reflecting both the heightened energy requirements to propel a rigid body mass and decreased food intake from lengthy meals, difficulty in chewing and swallowing. A not inconsiderable pro p o rtio n o f patients are constipated and a few have difficulty with m icturition tending to residua after voiding. P A T H O L O G Y D enny-Brown described the anatom ical changes in Parkinson’s disease as enigmatic. A gain it might be said th at the difficulty is in connecting the anatom ical changes “ which occur in its late stages with th a t which m ark its com m encem ent” , such “ continuance o f observation” obviously not being possible. W hat today is regarded as perhaps the m ost im portant feature, the loss of cells in the substantia nigra, with loss of the pigm ent melanin in these cells, was first described in 1925. P rior to this (1908) demyelinization o f the ansa lenticularis and related efferent pathw ays o f the pallidum was noted, as well as progressive loss o f cells in the globus pallidus (1913). T he other pigm ented nuclei o f-th e brain­ stem, the locus coeruleus and the dorsal (efferent) nucleus o f the vagus also show loss of pigment. Furtherm ore, acidophilic cell inclusions have been n oted: first by Lewy (1923) and subsequently by many others. The problem with these inclusion bodies is th at some workers have described them as a constant feature, others have failed to find them, and to m ake m atters worse they have been seen in s p e c im e n s where the only clinical diagnosis was that o f senility and no features o f P arkinson’s disease were present in life. However, their presence requires explanation. T he image association o f a n inclusion body is always th at o f a virus disease, and P arkinson’s disease has been closely associated to a pre­ sumed virus disease, encephalitis lethargica. Bethlem and D en H arto g Jager (1960) found Lewy bodies regularly in idiopathic paralysis agitans an d not in know n post-encephali­ tic cases. D enny-Brown on the other hand found n u m e r o u s inclusion bodies in one post-encephalitic case. A n electron- R ep ro du ce d by S ab in et G at ew ay u nd er li ce nc e gr an te d by th e P ub lis he r (d at ed 2 01 3. ) MARCH, 1971 P H Y S I O T H E R A P Y Page -3 microspic analysis has revealed the similarity o f the fine filamentous structure of these inclusion bodies with the ultra-structural appearance o f m elanin granules. Is the Lewy body then perhaps a n altered form o f m elanin? These are the m ost im portant features o f th e pathology. Widespread changes have however been noted in the cerebral c o r te x , striatum , reticular form ation o f the brainstem , the inferior olives and the sym pathetic chain ganglia: consistently h o w e v e r , the cortico-spinal tract appears to be spared. From the m aterial, the pathologist has difficulty in deciding w hether the disease process is post-encephalitic, arteriosclerotic o r idiopathic. T he arteriosclerotic group are clinically those comm encing at a n age of approxim ately 60 years with the attitude and trem or of Parkinson’s disease usually with a shuffling m anner o f w alking (“ m arche a petits pas”) and occasionally m ild m anifestations o f pseudo­ bulbar palsy. O ther than the above-nam ed pathological findings there is a n association with small lacunar infarcts in the putam en. T he arteries and arterioles show degrees of atherosclerosis com patible with the age of the patient and in all respects this group can be considered as “ P arkinson’s Disease with arteriosclerosis” . Where there is a n evident antecedent history o f the e n c e p h e l i t is lethargica which was epidemic throughout the world from approxim ately 1918 through 1926, and spora­ dically perhaps until 1930, the resulting Parkinson’s disease may be labelled post-encephalitic. W hen all other etiological considerations are elim inated a group rem ains, which, for want of better, is labelled idiopathic. Poskanzer and Schwab have however even throw n som e doubt o n this approach by form ulating their cohort group theory by which they imply a group o f the popu lation ageing together which were ages 5-59 in 1920. T heir distribution curves show th at with an increase in age the incidence of P arkinson’s disease increases as well. They therefore regard m ost, if not all, cases of P arkinson’s disease to be a late sequel o f encephalitic lethargica. Im portant corollaries from this hypothesis are that forty years or m ore m ay elapse between an initial, presumably infectious insult an d the development of a secondary neurological m anifestation (such as Parkinson’s syndrome), as well as that when this cohort ages and its members die off the disease should disappear. H ere lies the difficulty: few patients under the age o f 5 years were reported with encephalitis lethargica when it occurred: presum ing a person was age 5 in 1926 he will only be 60 years o f age in 1981, after which date the expected decrease in incidence could only become apparent. There is no doubt that the incidence o f Parkinson’s disease is greater a t the present time than in the previous century o r even at the tu rn o f this century. This might also be explained by the fact th a t the over-all life expectancy has greatly increased an d since P arkinson’s disease is usually a disease commencing in the late middle-years, m o re'cases could be expected today than previously. The other causes which are frequently listed as causing Parkinson’s disease are however different. A cute anoxia, such as with CO-poisoning, results in necrosis o f the globus pallidus and clinically these patients resemble an akinetic mutism with rigidity of all four limbs o r a decerebrate rigidity. Clinically it is not truly Parkinson’s disease. M anga­ nese mine workers are reported to show P arkinson’s disease indistinguishable from the idiopathic variety. T he pathologi­ cal changes in cases with manganese poisoning an d idiopathic Parkinson’s disease also do not differ. Poisoning is the result of inhalation, followed by coughing up of the dust which is then swallowed. In 1924 M ella experimentally produced basal ganglia changes in the R hesus monkey by poisoning it with manganese. I think that the role o f m anganese has not been elucidated. M erritt states th a t the occurrence o f symptoms of Parkinson’s disease in a middle-aged or elderly male who 1S exposed to m anganese raises a difficult medico-legal Problem. T he dystonias produced by certain drugs, particularly of the phenothiazine group, may superficially resemble that of P arkinson’s disease, but the course is benign, resolving on cessation o f drug intake, except in the elderly where the clinical manifestations m ay be irreversible. Akinesia and dystonia are the hallm arks o f the toxic effects o f these drugs and it only confuses the issue to consider these as examples of P arkinson’s disease. BIOCHEMICAL CHANGES Latterly, it has become obvious th at biochemical ab erra­ tions fo rm p art of P arkinson’s disease and th e persuance of these findings has led to the newest advance in the treatm ent o f this disease an d to better understanding o f past treatm ent. In 1957 W eil-M alherbe and B one detected dopam ine in the b rain ; its restricted distribution in the striatum , globus pallidus and substantia nigra, was appreciated in 1959. At this time it was proposed that dopam ine was a transm itter substance o f the central nervous system, specifically o f the basal ganglia an d associated structures. In 1960 Ehringer and H om ykiew icz dem onstrated th a t the level o f dopam ine in these areas was greatly depressed or absent in patients dying o f Parkinson’s disease. B arbeau et al (1961) found that the urinary excretion o f dopam ine, strangely enough, was also decreased and th at this finding correlated p a rti­ cularly well with the akinetic-rigid patient o r with a very far advanced stage o f the disease. It is not found when trem or or other dyskinesias are the m ain sym ptom s. The drop in dopam ine excretion in the urine from the norm al is som e 3.0-40 per cent which cannot be due only to a decrease in dopam ine production in the brain: basal ganglia dopam ine accounts for only 1 per cent of th e total body dopamine. It is acceptable therefore to believe that there m ay be a m ore generalized defect in P arkinson’s disease. O ther evidence to support this concept have been the frequent abnorm al glucose tolerance curves, diffuse fibrotic changes in the liver, abnorm al brom sulphtalein tests an d a slightly elevated serum ceruloplasmin. Transferrin has been found to be significantly increased where trem or was the dom inant sym ptom : the serum iron and serum iron binding capacity rem ain within norm al limits. T o fit all these findings together we shall have to regard Parkinson’s disease n o t as a disorder uniquely confined to the brain, but as a generalized defect and th at the disease may be a. systemic disorder. W hether these effects are secondary to the pathological change found in the dorsal nucleus o f the vagus which is the control-tow er o f the a u to ­ nom ic parasym pathetic system to the thoracic an d abdom inal viscera, or w hether Parkinson’s disease represents a prim ary enzyme defect cannot be said. Indirect evidence favouring the first is that there appears to be a diurnal variation in the rhythm of activity of tyrosine transam inase in the liver due to variation in the activity of adrenergic control pathways. One apparent link ties some o f these findings together. T he m etabolic pathw ays for the form ation o f the catechola­ mines and the form ation of m elanin have a com m on source in phenylalanine, an essential amino-acid. Phenylalanine I* . V p-tyrosine -> 3.4 dihydroxy -» melanin phenylalanine (DOPA) / D opam ine \ ( and other 1 V catecholamines / T he decrease in melanin in the pigm ented neurones o f the brain and the decreased content o f dopam ine in basal ganglia might therefore be considered as derangem ents of one single biological system. R ep ro du ce d by S ab in et G at ew ay u nd er li ce nc e gr an te d by th e P ub lis he r (d at ed 2 01 3. ) Page 4 P H Y S I O T H E R A P Y MARCH, 1971 Some aspects o f m elanin should therefore be considered. A great deal is know n ab o u t cutaneous melanin, very little ab o u t neurom elanin and on histochemical ground they could be considered separate substances. Melanogenesis in th e melanocytes o f th e epidermis is under control o f M.S.H. (melanocyte stim ulating horm one o f the anterior hypophysis). A n attem pt to treat patients with P arkinson’s disease with M .S.H ., however, led to an aggravation of the symptoms. Parkinson’s disease is extremely rare am ong the B antu whilst schizophrenia is com m on. Patients with schizophrenia excrete 3.4 dim ethoxyphenylethyl-am ine (D M PE A ), a dim ethylated derivative o f dopam ine which gives a characteristic “ pink spot” on paper chrom atogram s; this sam e substance has been found in the urine o f patients with Parkinson’s disease. T he hypokinesia o f Parkinson’s disease and the catatonia o f schizophrenia m ay therefore be related clinical m anifestations due to the same underlying defect in dopam ine m etabolism . F urtherm ore, the phenothiazine drugs are effective in the treatm ent o f schizophrenia, but, as already mentioned, produce a dystonic syndrom e, occasional­ ly w ith a m arked akinesia resembling P arkinson’s disease. T o complete this circle, chronic schizophrenics on long-term phenothiazine therapy develop a peculiar pigm entation of the skin. Finally, the ultrastructural resemblance between the Lewy inclusion-body and norm al m elanin is an interesting recent finding. M elanin is a strong electron acceptor an d the question arises w hether it may be concerned in dopam ine synthesis. Following th e discovery of th e lowered dopam ine content o f the basal ganglia in Parkinson’s disease a n attem pt at a therapeutic approach was m ade by trying to substitute this substance. D opam ine does not cross the blood-brain barrier, but its precursor, dopa, does. Through trial an d e rro r it was finally found th a t th e L-isomer was the physiologically active principle an d th at large doses were required to be therapeutically effective. G e o rg e . Cotzias’ results in 1967 were repeated in m any centres in E urope and America with the sam e prom ising results. A lthough the premise was rational and the results in keeping with it, the explanation o f the iaction o f this drug is not quite so facile. W hat does L -dopa d o ? What does L-dopa d o t I t w ould appear 'a s if less th an half of the oral dose (capsule o r tablet) is absorbed from the gut. T he lion’s share o f the absorbed quantity has first o f all to saturate the decarboxylating enzyme (which converts it to dopam ine) an d which is present in the blood and other extra-cerebral tissues. Only then can the rem ainder pass over the blood- brain barrier into th e brain where it selectively accumulates in the basal ganglia as show n by isotope-tagged L -dopa autoradiographic studies. In the brain it is presumably immediately decarboxylated to dopam ine. A prom ising new development is the use of a decarboxylase inhibitor which selectively inhibits extra-cerebral decarboxylase, thus in­ creasing the L -dopa available for transfer across the blood- b rain barrier and leading to a reduction o f the dose to be taken by the patient. A m inute am ount o f the L -dopa taken by m outh is there­ fore finally used for its specific therapeutic response and this represents a gross w astage o f a very expensive drug. W hat does the newly-formed dopam ine then d o ? As already stated dopam ine is considered a central nervous system transm itter substance and (one o f ?) its norm al anatom ical site is an ascending nigra-striatal pathw ay. I t is n o t conceivable th a t the newly-formed dopam ine can influence the degenerated neurones in the substantia nigra: these cells are dead and as neurones are considered to be noh-m itotic cells, cannot regenerate. However, a sick but n ot dead neurone’s function could conceivably be restored .and this could explain the com m on observation in patients with Parkinson’s disease th a t increasing im provem ent occurs with steady doses o f the drug. T his makes a strong point to give L -dopa to early mild cases o f the disease as a prophy­ lactic measure in order to prevent progression o f the disease. O n the other han d it m ay be th at non-dopam inergic neurones are converted to dopam inergic ones during prolonged treatm ent which could explain the late developm ent o f involuntary movem ent of a choreiform nature. A practical, although extremely simplified, view is that there appears to be a delicate balance between the con­ centrations o f the various central transm ittor substances, the m ost im portant being acetylcholine and the catecholamines, particularly dopam ine. T he scale is tipped in favour of the form er in Parkinson’s disease owing to the decrease in dopa­ mine. C orrection o f this im balance in the p ast has been by lowering the effectiveness o f acetylcholine through the adm inistration o f anticholinergic drugs such as benztropine, orphenadrine, trihexyphenidyl, procyclidine, etc., as well as the naturally occurring belladonna alkaloids. T he scale is then balanced again, albeit at a lower level. D opam ine now lifts the scale in its own favour and should therefore restore the balance at a m ore physiological level. SUMMARY A n attem pt has been m ade to define Parkinson’s disease in terms o f its clinical, anatom ical an d biochem ical aberrations. The ap p aren t link between the anatom ical (melanin) and biochemical (dopam ine) aspects is the com m on m etabolic pathw ay from phenylalam ine through 3.4 dehydroxy- phenylalam ine (D OPA ). A tenuous link between the clinical (catatonia; akinesia), anatom ical (m elanin: race, and pigm entation effects o f phenothiazine) and biochemical (D M PE A ) is provided by the com parison of schizophrenia w ith Parkinson’s disease. Finally, although the rationale fo r treating patients with Parkinson’s disease w ith L -dopa w ould appear to be th a t of simple substitution of a deficiency state (o f dopam ine) the interpretation o f the therapeutic effects is, as Jam es P arkinson said, still in a state o f im m aturity an d imperfection. DID YOU K N O W ?.. that you can order foam rubber or foam plastic made up to any size, shape or thickness fo r: Medical cushioning Anti Static cushioning Examination couches Exercise floor mats Paraplegic packs Wheelchair cushions ' Wedges for heart patients SONDOR (PTY.) LTD. CAPE TOWN JOHANNESBURG DURBAN PORT ELIZABETH R ep ro du ce d by S ab in et G at ew ay u nd er li ce nc e gr an te d by th e P ub lis he r (d at ed 2 01 3. )