Movement Disorders: Neurology

By C. David Marsden and Stanley Fahn

Neurology, Volume 2: Movement Disorders is a part of an international series of critical reviews of topics in neurology. This volume focuses on Parkinsonism and dyskinesia, a condition characterized by abnormal involuntary movements. Organized into 18 chapters, this book first elucidates the problems, causes, pathology, brain neurotransmitter changes and receptors, depression, dementia, fluctuations of disability, and treatment of Parkinson's disease. Subsequent chapters then explore the problems, controversies, and surgical approaches involved in certain dyskinesias. The role of dopamine receptors in movement disorders is also explored. This book will be valuable to neurologists-in-training, as well as to those in research field or in practice in this field of interest. The book's clinical content will help in the management of patients with movement disorders.

• Language: English
• Publisher: Elsevier Science
• Release date: Oct 22, 2013
• ISBN: 9781483163147

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1

Problems in Parkinson’s disease

C.D. Marsden and Stanley Fahn

Publisher Summary

This chapter discusses problems in Parkinson’s disease. The management of Parkinson’s disease today is a complex and demanding affair. Although peripherally acting dopa decarboxylase inhibitors have markedly reduced the incidence of anorexia, nausea, and vomiting provoked by levodopa, this still remains a major problem in a minority of patients. The sudden cessation of levodopa in a patient who has taken the drug for many years may cause a confusing akinetic coma-vigil state, which can easily be reversed by reintroducing levodopa, if necessary, by a nasogastric tube. Commonly, those developing mental changes already have early or obvious dementia. Most patients with Parkinson’s disease or postencephalitic Parkinsonism show some response to levodopa.

INTRODUCTION

The management of Parkinson’s disease today is a complex and demanding affair. The individual patient often poses a changing sequence of different problems, each demanding separate attention. There has been a considerable increase in knowledge about all aspects of Parkinson’s disease in the last decade. The editors have chosen certain topics for presentation in separate chapters because of their interest and importance to understanding of the disease, and because there is now a substantial body of information to discuss on each of these topics.

Although the cause of Parkinson’s disease still is not known, useful, if negative, information has been obtained in the fields of epidemiology, virology and genetics, as is discussed in Chapter 2 by Roger Duvoisin. Any understanding of the etiology of Parkinson’s disease must depend upon a thorough knowledge of the pathology of the condition. In Chapters 3, 4 and 5 respectively, Lysia Forno reviews the histopathology; Oleh Hornykiewicz, the changes in neurotransmitter chemistry; and Urpo Rinne, the alterations of receptors in the brain.

The clinical features of Parkinson’s disease generally are well-known, but the extent to which intellectual and affective disorders are inherent to the condition is controversial. Richard Mayeux in Chapter 6 reviews the evidence available on these topics, which are increasingly being discussed in the literature.

The routine drug treatment of Parkinson’s disease does not require repetition. However, all practitioners are faced with the difficult problem of emergence of fluctuations of response during chronic therapy. In Chapters 7 and 8 the editors discuss and categorize, along with David Parkes and Niall Quinn (Chapter 7), the clinical features and pathophysiology of such fluctuations.

Many new drugs, other than anticholinergics, amantadine, and levodopa preparations, are being tested in Parkinson’s disease. New directly-acting dopamine agonists are proving their value when levodopa fails. Bromocriptine is now in routine use in Europe, and newer ergoline derivatives are under extensive clinical trial. The practitioner must find it difficult to assess the relative worth of these different directly-acting agonists; Abe Lieberman and Menek Goldstein survey this field in Chapter 9. Deprenyl is another new drug, on which sufficient experience has been gained in Europe to assess its role, as is discussed in Chapter 10 by Merton Sandler and Gerald Stern.

The many variants of the ‘akinetic-rigid syndrome’ often cause diagnostic confusion. Roger Bannister and David Oppenheimer discuss the interrelationship of idiopathic orthostatic hypotension, the Shy-Drager syndrome, striatonigral degeneration, and olivopontocerebellar degeneration, and their concept of ‘multiple system atrophy’, which links these entities, in Chapter 11.

Many other practical problems that face the practitioner in the management of a patient with Parkinson’s disease are not discussed, because it is difficult to provide a definitive statement on these matters. To cover these gaps, and to give some guidance on present views, the editors state their own approach to coping with some of these problems.

WHEN SHOULD LEVODOPA TREATMENT BE STARTED?

On theoretical grounds, one could take opposite views on whether to start levodopa treatment at the time of diagnosis. On the one hand, it could be argued that early treatment, by replenishing the missing neurotransmitter, may reverse changes in the postsynaptic dopamine receptors which are responsible for some of the problems in the management of the disease. On the other hand, it has been argued that levodopa itself is toxic. This may come about in one of two ways: saturating the brain with levodopa might lead to the formation of unnatural neurotoxic metabolites such as 6-hydroxydopamine, or could lead to excess formation of naturally-occurring, but neurotoxic intermediaries in the dopaquinone-melanin pathway. There is no convincing human or experimental evidence for any of these suggestions, so we have to turn to the clinical evidence to decide one way or the other.

Unfortunately, this too is controversial. On the one hand, Lesser et al.³ claim by retrospective analysis of their population of patients that chronic treatment with levodopa is detrimental. They base this conclusion on finding that the level of disability after chronic therapy is related more to the duration of treatment than to the duration of the disease. On the other hand, Markham and Diamond⁴ claim exactly the opposite.

Until this dilemma is solved by further studies, the editors advise their patients to delay levodopa therapy until disability warrants it. The judgment as to when that point is reached depends upon the individual patient, his tolerance of the disease, and his individual circumstances and requirements. Until that point is reached, many patients gain benefit from an anticholinergic and/or amantadine.

Another issue may assume importance in the future, namely whether dopamine replacement therapy should be started with levodopa or with a directly-acting dopamine agonist. Whether the latter approach will provide longer and smoother benefit can only be resolved by comparative clinical trials which currently are being undertaken.

MANAGEMENT OF DRUG PROBLEMS

Gastrointestinal upset

Although peripherally-acting dopa decarboxylase inhibitors have markedly reduced the incidence of anorexia, nausea and vomiting provoked by levodopa, this still remains a major problem in a minority of patients. The new formulation of Sinemet (levodopa/carbidopa = 5/1 instead of 10/1) has helped to some extent, but neither this, nor the use of Madopar (levodopa/benserazide) has abolished the problem. Of course, such peripheral decarboxylase inhibitors have no effect on these symptoms when provoked by directly-acting dopamine agonists, such as bromocriptine or pergolide. A new approach to this problem has been the use, in Europe, of peripherally-acting dopamine antagonists, the best of which is domperidone.

Myocardial infarction

A common problem is what to do when a patient with Parkinson’s disease has a heart attack. Protection from the peripheral effects of levodopa and dopamine agonists is required after recent myocardial infarction, which predisposes to drug-induced cardiac dysrhythmias. The editors feel that it is safe to continue levodopa, provided that sufficient carbidopa (at least 100mg/day) is given at the same time. Likewise, domperidone can protect the heart against unwanted effects of dopamine agonists. In countries in which domperidone is not available, it may be more prudent to switch such patients to levodopa/carbidopa. Certainly, the editors believe it is more important to continue some form of dopamine replacement therapy in this situation than to stop it, which causes dramatic and distressing relapse of the parkinsonism.

Accidental sudden withdrawal of levodopa

In the editors’ experience, the sudden cessation of levodopa in a patient who has taken the drug for many years may cause a confusing akinetic ‘coma-vigil’ state, which can easily be reversed by reintroducing levodopa, if necessary, by nasogastric tube. Alternatively, where it is available, an intravenous injection of the water-soluble, fast-acting dopamine agonist, lisuride can be used.

Drug holidays

One of the ploys suggested in recent years to cope with some of the complications of chronic levodopa treatment has been the deliberate withdrawal of levodopa, a so-called ‘drug holiday’. The editors will not go into the rationale behind this approach, or into its theoretical implications for the controversy about the cause of loss of efficacy of levodopa therapy. However, they will comment on its practical value. The impression has grown that this is a useful approach for coping with violent fluctuations that may emerge during chronic levodopa treatment. In fact, the published descriptions of this technique referred mainly to its use in patients with loss of response and/or toxic side-effects of chronic levodopa therapy¹,⁴. Stopping levodopa in such patients leads to disappearance of mental and dyskinetic complications, with return of the symptoms and signs of Parkinson’s disease. When levodopa is reintroduced, a therapeutic response can be achieved, usually at a much lower dosage, often without such toxic complications. However, in the editors’ experience, drug holidays do not produce useful lasting benefit in those with severe fluctuations in response to treatment. Although there may be some initial improvement, this soon is lost, and the patient returns to his former state in a matter of weeks or months. Furthermore, the drug holiday itself will have left a profound impact on both the patient and on his physician. During the period of drug withdrawal, the patient will have relapsed back to a state of physical disability due to untreated Parkinson’s disease that may come as a complete and devastating surprise. The emotional impact often is profound, the patient and his relatives are severely disturbed and occasionally, disasters occur due mainly to aspiration and deep vein thrombosis. In view of these difficulties and unsatisfactory long-term response, full drug holidays are not recommended.

Recently, Goetz et al.² have been evaluating a modified drug holiday, one lasting only for 2 days per week. This approach is usually not accompanied by the disastrous physical and emotional complications seen with the prolonged drug withdrawal. These authors claim that such ‘weekend holidays’ often, but not always, reduce the toxic complications of levodopa treatment in the subsequent week. How useful this is going to be remains to be established, but it is a maneuver that appears safe and can be undertaken at home.

Psychiatric disturbances

Another common problem for the patient on long-term levodopa therapy is the emergence of a range of mental side-effects. These include a typical toxic confusional state, isolated hallucinosis, delusions, obsessional behavior, global dementia, and psychotic disorders including severe depression and a schizophreniform syndrome. Although many of these conditions can occur in the untreated patient, the first possibility to be considered is that they are a side-effect of drug therapy. Any of the antiparkinsonian drugs may cause a toxic confusional state or hallucinosis. If mild, the first step might be to withdraw amantadine and/or anticholinergics. Recovery may be delayed for days or even weeks. If the disturbance is severe, disrupting family life, or threatening work, it may be necessary to admit the patient to the hospital in order to withdraw all drugs, including levodopa, temporarily.

Commonly, those developing such mental changes already have early or obvious dementia. Reintroduction of levodopa in such patients often causes recurrence of their psychiatric symptoms with little or no improvement in their mobility.

Repeated attempts to introduce a variety of levodopa preparations or dopamine agonists are prevented by such mental complications. A common situation is a patient who is immobile, but rational, or who is mobile, but mad. It may seem illogical, but sometimes the addition of a small dose of a neuroleptic such as thioridazine may allow a compromise between the two extremes.

Not all confusional states, hallucinatory and delusional experiences, or frank dementia are due to drugs in Parkinson’s disease. A familiar clinical experience is the patient who has lost benefit of levodopa after chronic therapy, who increasingly becomes confused or demented, and who does not improve mentally or get any worse physically when all drug treatment is stopped. In this situation, thioridazine or a more sedative drug, such as diphenhydramine, may provide some calming benefit.

There is also the problem of a patient in whom chronic levodopa therapy is associated with excessive daytime sleepiness, often accompanied by nocturnal restlessness and noisiness. Of course, this reversal of sleep rhythm is characteristic of many dementing illnesses, and many of these parkinsonian patients show other evidence of dementia. Such daytime sleepiness, however, commonly is a toxic side-effect of levodopa, and can be improved by a reduction of dosage or by ‘weekend drug holidays’.

DRUG FAILURES

In some patients, dopamine replacement therapy either never works (primary drug failure), or eventually completely ceases to work (secondary failure).

Primary drug failure

Most patients with Parkinson’s disease or postencephalitic parkinsonism show some response to levodopa. The commonest cause for primary drug failure is that the patient has some other disease. Benign essential tremor does not respond to levodopa. Other conditions that may be confused with Parkinson’s disease include progressive supranuclear palsy and the various manifestations of multiple system atrophy (see Chapter 11). Perhaps the greatest difficulty occurs in separating Parkinson’s disease with dementia from primary dementing illnesses with features of an akinetic-rigid syndrome. The latter include Alzheimer’s disease, multi-infarct dementia, normal pressure hydrocephalus and, in a younger age group, the aftermath of severe head injury or anoxic encephalopathy. The best clue for separating Parkinson’s disease from these other conditions is the relative timing of onset of the motor disorder and the dementia, but it must be admitted that the diagnosis on occasions can be exceedingly difficulty.

Another problem relates to drug-induced parkinsonism. It is not widely recognized that parkinsonism produced by antipsychotic drugs may persist for as long as 1 to 2 years after stopping the offending agent. Such patients, by virtue of their psychiatric illness, often cannot give an accurate drug history, so may be mistakenly thought to have Parkinson’s disease. Contrary to general belief, drug-induced parkinsonism does respond to adequate doses of levodopa, which do not necessarily provoke psychotic disturbances. If there is any question that a patient may be suffering from drug-induced parkinsonism, it is the editors’ practice to withdraw levodopa treatment at 6-monthly intervals for 2 years to see if remission has occurred.

There remains a small proportion of patients, who as far as can be ascertained during life have Parkinson’s disease, but who do not respond at all to levodopa. Why this should be so is not known, but it is suspected that they will be discovered to have some other pathology.

Secondary drug failure

A large number of patients with Parkinson’s disease on chronic levodopa therapy develop fluctations, as discussed later in this volume, but we are not concerned with this sort of failure of treatment here. The problem at issue is that of the patient who gradually and progressively loses response to treatment which, eventually, seems to be conferring no benefit at all.

A common early symptom heralding this sequence of events is the appearance of unexpected falling. Falls in Parkinson’s disease may be due to a number of causes. The patient with sudden transient freezing may trip over his own glued feet. Another cause is the emergence of loss of postural reflexes, such that when the patient turns, arises, or is pushed suddenly, he falls to the ground. Unfortunately, loss of protective reflexes also occurs in Parkinson’s disease so that such patients crash to the ground, damaging themselves. The combination of sudden transient freezing with loss of postural and protective reflexes can be disastrous. Many such patients become terrified of falling, and develop secondary psychological disturbances such as agoraphobia and space phobia. Sadly, levodopa has little or no effect on the problem of falling when it is severe.

Another, much less common cause of collapse in Parkinson’s disease is postural hypotension, which is discussed in detail in Chapter 11.

The other feature characteristic of the emergence of secondary drug failure is the appearance of intellectual deficit. This problem is discussed at length in Chapter 6 and the contribution of drug toxicity to mental disturbances has been described earlier.

However, it is necessary to mention the practical difficulties imposed by the incontinence that often accompanies these developments at this stage of the illness. Male incontinence is a common problem in Parkinson’s disease. Many causes contribute, including prostatic hypertrophy, anticholinergic-induced bladder atony, recurrent bladder infections and perhaps even Parkinson’s disease itself by changing external sphincter tone. Levodopa therapy sometimes improves incontinence, but frequently the question of whether or not to undertake prostatectomy arises. In the editors’ experience, providing the patient is fit for anesthesia and has clear evidence of prostatic hypertrophy, prostatic resection by the transurethral route may help. A bladder neck resection in the absence of prostatic hypertrophy, unfortunately, often leads to continual dribbling and incontinence. Luckily, incontinence in parkinsonian females is a less frequent occurrence.

Finally, it is worth considering why complete drug failure may occur after a patient has been previously responsive to levodopa. Direct-acting dopamine agonists also appear ineffective in this situation. Such patients fall into two groups. First, there are those who have parkinsonism as a feature of multiple system atrophy. In the early stages of the illness, predominantly presynaptic dopamine neurons have degenerated to produce symptoms of parkinsonism, while the postsynaptic cells containing dopamine receptors are still intact and could respond to levodopa or dopamine agonist therapy. The pathology of these conditions, however, relentlessly progresses so that eventually the postsynaptic cells in the striatum are lost and with them the dopamine receptors. These patients can now no longer respond to dopamine replacement therapy, although there may still be some response to anticholinergic drugs.

The second group consists of patients who do, in fact, have Parkinson’s disease, but who eventually fail to respond to therapy. The explanation for this phenomenon is not clear, but it is possible that this group of patients ultimately develop degeneration of dopamine receptors and, hence, cannot respond to levodopa replacement treatment. Biochemical studies reveal that some parkinsonians have decreased numbers of dopamine (and acetylcholine) receptors in the striatum, and this group responds poorly to therapy (see Chapter 5). The question as to why some patients with Parkinson’s disease, in which the principal pathology is loss of monoamine neurons, would also lose dopamine receptors is not perfectly clear. Perhaps there can be transsynaptic degeneration of the dopamine receptors, or of the striatal neurons on which they lie. This phenomenon might occur in Parkinson’s disease secondary to loss of nigrostriatal neurons, by a mechanism that may be analogous to transsynaptic degeneration in the visual pathways. Alternatively, chronic levodopa therapy itself may cause irreversible damage to dopamine receptors, although there is no evidence for this hypothesis.

References

1. DIRENFELD, L. K., FELDMAN, R. G., ALEXANDER, M. P., KELLY-HAYES, M. Is L-dopa drug holiday useful? Neurology. 1980; 30:785–788.

2. GOETZ, C. G., TANNER, C., NAUSIEDA, P., WEINER, W., KLAWANS, H. Modified outpatient drug holiday in the management of parkinsonism. Neurology. 1981; 31:135.

3. LESSER, R. P., FAHN, S., SNIDER, S. R., COTE, L. J., ISGREEN, W. P., BARRETT, R. E. Analysis of the clinical problems in parkinsonism and the complications of long-term levodopa therapy. Neurology. 1979; 29:1253–1260.

4. MARKHAM, C. H., DIAMOND, S. G. Evidence to support early levodopa therapy in Parkinson disease. Neurology. 1981; 31:125–131.

5. WEINER, W. J., KOLLER, W. C., PERLIK, S., NAUSIEDA, P. A., KLAWANS, H. L. Drug holiday and management of Parkinson disease. Neurology. 1980; 30:1257–1261.

2

The cause of Parkinson’s disease

Roger C. Duvoisin

Publisher Summary

This chapter focuses on cause of Parkinson’s disease. The etiology of Parkinson’s disease is unknown at this time, and there is a dearth of sound clues upon which to base reasonable speculations. It appears, then, from the best available data that there is very little, if any, familial concentration of Parkinson’s disease. A negative correlation between smoking and Parkinson’s disease has been noted by several investigators. The postencephalitic Parkinson syndrome that followed encephalitis lethargic was very distinctive in the 1920s. It is clear from reviewing medical charts of the 1930s and 1940s that to many physicians, the terms chronic encephalitis and parkinsonism become synonymous and that the nosological distinctions between Parkinson’s disease and postencephalitic Parkinsonism had become confused.

‘Parkinson’s disease remains so utterly inexplicable.… that we are constantly drawn to it by the lure of the mysterious’.… Brissaud, 1895⁶.

INTRODUCTION

In considering the possible cause of Parkinson’s disease, one is faced at the outset with doubts regarding its nosologic unity. Is it in fact a disease, a group of similar diseases, or nothing more than a syndrome of diverse etiology? This uncertainty reflects the fact that the definition of Parkinson’s disease rests primarily on a combination of clinical and pathological features, none of which is pathognomonic. The clinical features of the disorder are distinctive enough in most cases to permit easy recognition and the postmortem morphologic alterations of the nervous system appear rather characteristic but no clinical or pathological feature is unique to this disorder alone. There is no chemical or serological marker for Parkinson’s disease.

Moreover, a small proportion of patients confidently labelled ‘Parkinson’s disease’ in life turn out at postmortem examination, or even on long-term follow-up, to have a distinctive identifiable disorder such as olivopontocerebellar atrophy, striatonigral degeneration, even progressive supranuclear palsy. Clearly these are different diseases. Thus, in fact, the patient population clinically diagnosed as Parkinson’s disease includes representatives of several distinct morbid entities.

However, there is a general consensus among many students of parkinsonism that there is a condition which may be termed Parkinson’s disease, which may reasonably be held to be a particular morbid entity on combined clinical and pathological grounds and which accounts for the great majority of Parkinson patients currently encountered in neurological practice. It is with this disorder that the chapter is concerned.

GENERAL SPECULATIONS

The etiology of Parkinson’s disease is unknown at this time and there is a dearth of sound clues upon which to base reasonable speculations. Its pathology provides few insights into possible etiologic factors. The distribution of the neuronal degeneration is too selective and too widely scattered throughout the neuraxis to permit attribution to a vascular process. The highly selective involvement of certain neuronal populations, notably the pigmented neurons of the brain stem, suggests a metabolic basis for the degeneration. The clinical fact of ‘chemical parkinsonism’ induced by neuroleptic drugs encourages this view. Many of the neuronal systems affected are catecholamine synthesizing cells, which further points to the possibility that some feature of catecholamine metabolism, perhaps a cytotoxic metabolite, might play a role in the pathogenesis of the observed neuronal degeneration. However, other neuronal systems which are not monaminergic, such as the cranial motor nerve nuclei¹⁷,³³, are also affected. Recently attention has been directed to the Alzheimer-type changes seen in the cerebral cortex in some Parkinson’s disease patients²⁶,³⁵. It is difficult to suggest some unique metabolic feature which might be common to all these neurons and not to others.

The notion of ageing associated with a selective vulnerability of certain neuronal systems, first suggested by Gowers³¹ as an explanation of the pathogenesis if not the cause of Parkinson’s disease has been repeatedly discussed. At the clinical level, the similarity of the flexed posture, bradykinesia and marche a petit pas of senility suggests a common element. The number of substantia nigra neurons is appreciably diminished in Parkinson’s disease patients in comparison to age-matched controls⁶⁴. Cell counts have shown evidence of a progressive decrease in the number of neurons in this nucleus with age⁴⁰. Thus it appears reasonable to suggest that some individuals may be born with a lesser number of nigral neurons or suffer some selective insult to the nigra later in life and that, with the normal decline of nigral nerve cells with age, the number may in time fall below a critical value resulting in decompensation of the neuronal system involved and the appearance of parkinsonism. The notion of selective ageing or selective vulnerability clearly implies an inherent and hence genetically determined predisposition. The corollary notion of some injury to the involved neuronal system, implies an environmental factor or factors which might be infectious or toxic, specific or nonspecific. Thus, ultimately, these speculations lead to the two etiologic hypotheses which have long seemed most attractive, first, that Parkinson’s disease is a genetic disorder and second, that it is due to viral infection of the nervous system. Both hypotheses could operate together in a multifactorial process. The genetic hypothesis is more easily tested and will be discussed first.

THE ROLE OF HEREDITY

It is a matter of common clinical experience that occasional patients with Parkinson’s disease report having one or more similarly affected relatives. Gowers had noted a century ago that 15 percent of his cases of paralysis agitans gave a history of secondary cases in their families³². Comparable figures have been noted in more recent clinical surveys⁴¹,⁴⁹. The suggestion naturally follows that genetic factors may play a role in the etiology of Parkinson’s disease although it is by no means certain that these secondary cases in fact reflect familial concentration. Several reports of affected siblings and pedigrees have been described, such as those of Bell and Clark³, Allen¹, and Spellman⁷⁴ which appear to support that suggestion.

Allen, an early clinical worker in the field of medical genetics, collected 24 kindreds in North Carolina over 40 years ago in which parkinsonism appeared to occur as a dominant disorder. It is difficult to assess the significance of his observations, however, in view of the sparse clinical data provided, the lack of specified diagnostic criteria and atypical features in some cases such as an unusually young age of onset and death from ‘the palsy’ at an early age. Thus, this report can only be considered of historical interest.

The most recent multiple case family is that reported by Spellman⁷⁴ in 1962. The proband had some atypical features including onset before the age of 35 years, emotional lability ‘with a tendency to cry easily’ and ‘inconstant dorsiflexion of the toes bilaterally’ on plantar stimulation. One member of the family died at the age of 39 after having been ill for 10 years, another at the age of 42 after having had parkinsonism for 8 years. Clumsiness and ’slight ataxia’ were noted in other cases. In view of such atypical features and the evidence of cerebellar involvement, one may reasonably doubt that these patients had Parkinson’s disease. Rather, such kindreds probably represent families of olivopontocerebellar atrophy, a condition which sometimes mimics Parkinson’s disease and which may occur in either autosomal dominant or recessive hereditary patterns. Possibly some kindreds may represent essential tremor which is clearly a hereditary trait.

The presumed role of heredity in Parkinson’s disease received strong support from the large family study carried out by Mjönes⁵⁹ in Sweden in the years 1933–44. This was the most extensive and systematic genetic study of parkinsonism done up to that time and it understandably exerted a profound influence on the subject. Mjönes found secondary cases in 38 percent of the families of 250 probands collected from several Swedish clinics and concluded that Parkinson’s disease was an autosomal dominant disorder with incomplete penetrance. However, his study may be criticised for several methodological flaws which seriously undermine the conclusions. The probands represented a heterogenous group representing several disorders in addition to Parkinson’s disease. Different criteria were employed in diagnosing probands and secondary cases; mere relationship to a proband was itself considered a diagnostic indication for ‘without this factor a number of abortive or incipient secondary cases would undoubtedly have been interpreted as, for example, essential tremor’. A large proportion of Mjönes’ secondary cases had tremor alone. Whereas 7 percent of the siblings of the 194 probands classified as ‘paralysis agitans’ by stated criteria were counted as secondary cases, if those who had tremor alone are excluded, the prevalence of secondary cases falls to approximately 3.4 percent of the siblings. Thus it seems very probable that Mjönes appreciably overstated the familial concentration of Parkinson’s disease. It is difficult to judge whether the observed prevalence of secondary cases among the proband siblings does in fact represent familial concentration without a control population evaluated in a comparable manner.

In a family study carried out by Duvoisin et al.¹³ the prevalence of secondary cases among the adult siblings of 85 index cases was compared to that among the spouses and spouse siblings who served as a control population. All siblings, index cases and spouses were examined by the same team of neurologists following a standardized protocol. The number of secondary cases found among the patients’ siblings (4/146) was not significantly greater than that encountered among the spouse siblings (3/145). If we lower the denominator by eliminating siblings under the age of 55, the number becomes 4/62 versus 3/62, respectively. The control population made it possible to make sure that cases of Parkinson’s disease were not missed by excluding from the analysis cases with tremor alone. An equal number, 5, of cases of essential tremor were found among the proband siblings and spouse siblings. A significant pitfall was illustrated by one family with several secondary cases. The proband had initially been given the diagnosis of Parkinson’s disease by several experienced clinical neurologists, but over the 4-year course of the study, gradually developed signs of cerebellar involvement, optic atrophy and bilateral extensor plantar responses. The diagnosis was then changed to olivopontocerebellar atrophy.

Martin et al.⁵⁶ subsequently performed a similar study of 130 patients comparing the prevalence of secondary cases among the proband siblings with that among the spouse siblings. Secondary cases were confirmed by personal examination or by ‘communication with a physician’. The prevalence of secondary cases among the proband siblings (16/488) was only slightly greater than that among the spouse siblings (7/450). If one considers only the siblings in the ages at risk, those over the age of 55, these figures are 11/285 (3.9 percent) versus 5/194 (2.6 percent). A weakness of this study is that all siblings were not examined, only those who were reported to be affected. It is possible, therefore, that some secondary cases may have been missed. It is also possible that the secondary cases confirmed ‘by communication with a physician’ might have had another diagnosis had they been personally examined by the investigators. Even accepting the data as presented, however, the evidence for a role of heredity is negligibly small. Interestingly, the prevalence of secondary cases among proband siblings in these three studies is nearly identical, if one excludes Mjönes’ cases with tremor alone. (Table 2.1).

Table 2.1

Prevalence of Parkinson’s disease among younger siblings compared with that among adult sibs: siblings over 25 and 55 years of age

Martin et al. noted that 15 of their probands gave a history of having an affected parent. These 15 probands had 77 siblings, 10 of whom were affected. The authors culled 11 similar families from Mjönes’ report and from this pooled data, using Falconer’s method²² arrived at an estimate of 40 ± 11 percent heritability. So modest a degree of heritability points to an inherited predisposition to the disease which must be multifactorial in etiology; it is too low for a monogenic mendelian transmission.

Kondo et al.⁴⁸ more recently conducted a family survey similar in methodology to Mjönes’ study, relying on information supplied by the proband and on medical records but avoiding cases who were reported to have tremor alone. They found that 19 percent of the siblings of probands who had an affected parent were also affected and calculated a heritability of 91 percent. One cannot evaluate the accuracy of diagnosis in the probands from the data provided by these authors, but in view of the serious pitfalls encountered in chart studies and the unreliability of anamnestic data for genetic analysis, their conclusions must be regarded with considerable skepticism.

It appears, then, from the best available data that there is very little, if any, familial concentration of Parkinson’s disease. The most solid data, that relating to the prevalence of secondary cases among the siblings of probands, provides no evidence for a significant genetic contribution to the etiology of Parkinson’s disease. It is only in those families reporting an affected parent that some indication of familial concentration can be found. However, this evidence is weakened by the fact that the allegedly affected parents were not available for examination. This is a serious defect because of the common difficulty in distinguishing essential tremor and because multiple case families may represent olivopontocerebellar atrophy. This entity may be very difficult to distinguish from Parkinson’s disease early in its course over a period of several years in the evolution of the disease. Duvoisin et al.¹³ noted that in every family in which the proband reported multiple cases ‘close examination …. made it apparent that Parkinson’s disease was not the correct diagnosis’. Careful examination of the clinical features recorded in some of the multiple case families, such as the family described by Spellman discussed above and including some of Mjönes’ families, reveals neurological manifestations that clearly exclude the diagnosis of Parkinson’s disease. In the light of these considerations the high estimate of heritability proposed by Kondo et al. seems open to serious doubt and even the lower estimate of Martin et al. may be regarded with some