By David Burn, FRCP, MD
As a new century dawns, there will be renewed effort by the scientific community to understand and, in turn, treat many diseases better. With an increasingly aged population, neurodegenerative diseases will assume greater pre eminence – not least the disease described so beautifully by James Parkinson in 1817.1
Over what is now approaching 200 years, how has our understanding of Parkinson’s disease (PD) improved? How effective are our current therapies for the illness, and what are the shortcomings of such treatments? In this, the first of two articles, the disease itself is considered and the epidemiology, aetiology, clinical features, differential diagnosis and social consequences of PD are addressed. The aim is to provide a concise overview of PD, while at the same time highlighting deficiencies in current knowledge. A second article will then cover the treatment of PD.
How common is Parkinson’s disease?
PD is the second most common neurodegenerative disease experienced by man, Alzheimer’s disease being the most common. It affects 1 per cent of the population over 65 years of age, rising to 2 per cent over 80 years. It is estimated that 5 per cent of patients are diagnosed before their 40th year and that there are approximately 110,000 people with PD in the UK.
The disease is found worldwide, with apparently large differences in prevalence between countries that are more likely to reflect methodological technique than real variation.2
Exceptions to this include China and West Africa, where the disease may be less common.
The risk of developing PD increases with age and, in addition, the majority of studies have shown a male to female excess for the disease, with standardised rates of the order of 1.35.3
Early reports suggesting that PD may be less common in blacks than in whites have not been replicated. Indeed, recent studies have indicated that any apparent difference is more likely to reflect the fact that blacks have worse access to health care than whites.4,5
What is the pathophysiological basis of Parkinson’s disease?
The pathological hallmark of PD is the Lewy body. These consist of filamentous material derived from cytoskeletal elements. Classical brainstem Lewy bodies are found in pigmented neurones. They are intraneuronal, intracytoplasmic inclusions with a dense hyaline eosinophilic core and pale surrounding halo. Lewy bodies may be found, in smaller numbers, in several conditions other than PD and so are not strictly pathognomonic for the disease.
Neuronal loss, particularly in the ventrolateral tier of the substantia nigra, together with gliosis (enlargement and proliferation of astrocytes), comprise the other characteristic pathological features of PD.17
The neurones in the ventrolateral tier of the substantia nigra provide a dense dopaminergic innervation to the striatum.
There is a remarkable degree of “reserve” within the nigrostriatal system, in that up to 80 per cent of dopaminergic neurones are lost before the cardinal clinical features of PD begin to appear. At present, it is uncertain how long the preclinical period is during which these neurones are being lost. Recent studies have suggested a short pre-symptomatic period of three to four years,18
while pathological work has indicated a five- to 10-year period.19
By contrast, the concept of a so-called “PD-personality” would suggest a far longer pre-clinical phase, extending back several decades.20
Symptoms and signs of Parkinson’s disease
There has been little in the way of improvement in the description of the clinical features of PD since James Parkinson’s original eloquent account in 1817.
Bradykinesia is a sine qua non for parkinsonism in general. Rest tremor, extrapyramidal rigidity (so-called “lead pipe” and “cog-wheel”) and postural instability comprise the remaining symptoms in the classical tetrad of clinical features for PD (see Panel 1). The disease is not clinically homogenous – some patients present with a tremor-dominant form, while others have little tremor but more pronounced and early gait and balance disturbances ( the postural instability-gait difficulty subgroup). It should be emphasised, however, that 15-20 per cent of patients do not develop tremor, and that postural instability is a late feature of PD. Asymmetry of signs at the onset of the disease is common.
Numerous other symptoms, including autonomic dysfunction, cognitive impairment and sleep disturbance may occur during the course of the illness. More detailed description of these features is beyond the scope of this review, but for the interested reader, I would recommend the recent account by Quinn.21
Panel 1: Classical features of Parkinson’s disease
Slowness of movement
A rhythmic movement with a frequency of 4-6Hz noticed in patients at rest (the characteristic “pill-rolling movement”)
An increase in muscle tone, which may be likened to bending a piece of lead piping, often with a superimposed “ratchety” feeling (cogwheel)
Usually a late feature of the disease, which comprises impairment of righting reflexes with a tendency to fall
Is Parkinson’s disease easy to diagnose?
From the brief description above of the clinical features of the disease, coupled with the pathological findings, one might be forgiven for thinking that PD is a highly distinctive clinicopathological entity that is easy to diagnose with confidence. In reality, this is certainly not the case – two main sources of error may be found.
The first is in the early stages of evolving PD when the signs may be subtle and the symptoms protean and misleading. Thus, an early presentation with a “frozen” shoulder is common, while an onset believed by the patient (or doctor) to be acute may suggest that a cerebrovascular event has occurred. Aching pain in a limb may also be an early, and easily misinterpreted, feature of PD.
The second source of error comes from other conditions that superficially resemble PD, through the presence of bradykinesia, tremor, or both. This difficulty is highlighted by pathological studies in which patients diagnosed in life as having PD came to post-mortem. In several, a mis-diagnosis rate of 20 to 30 per cent has been found.22,23
Many of the conditions masquerading as PD also have a neurodegenerative basis but have distinctive pathology and, in general, have a less favourable prognosis. They include multiple system atrophy, progressive supranuclear palsy (also known as Steele-Richardson-Olszewski syndrome) and corticobasal ganglionic degeneration.24,25
In addition, essential tremor may be difficult to differentiate from tremor-dominant PD. However, a positive family history and response of the tremor to alcohol can help to differentiate essential tremor from PD.
Perhaps the most important differential diagnosis to consider when a patient presents with parkinsonism is whether their symptoms and signs may be drug-induced. This is because drug-induced parkinsonism (DIP) is potentially reversible upon cessation of the offending agent.
Reports linking DIP with the neuroleptic chlorpromazine were first published in the 1950s.26
Since then, numerous other agents have been associated with DIP. Many of these are widely recognised, although others are not. Panel 2 lists several drugs, other than neuroleptics, which have been associated with DIP.
Compound antidepressants may contain neuroleptic drugs (trifluoperazine in Motival, for example) and are not always recognised as potential culprits. The repeat prescription of vestibular sedatives and anti-emetics (particularly prochlorperazine and cinnarizine) are other commonly encountered causes of DIP. Offending agents are often classed as dopamine receptor blocking agents, although the pathogenesis of DIP is unlikely to be caused simply by dopamine receptor blockade. If this were the case, the incidence and severity of DIP should correlate with the drug dosage and length of exposure, and this is not clearly observed. DIP may be more common in the elderly and in women.27
The clinical features of DIP are often indistinguishable from PD, although the signs in DIP are more likely to be bilateral at the onset. Withdrawal of the suspected drug will lead to improvement and resolution of symptoms and signs in approximately 80 per cent of patients within eight weeks of discontinuation. However, DIP may take up to 18 months fully to resolve in some cases. In other patients the parkinsonism may seem to improve after stopping the drug, only for it to deteriorate later. In this situation, it is possible that the dopamine receptor blocking agent may have unmasked previously latent PD. This contention is supported by the findings of one recent study, which noted an increased risk of PD in subjects who had experienced a previous reversible episode of DIP.28
Panel 2: Non-neuroleptic drugs that have been associated with drug-induced parkinsonism
- Amphotericin B
- Calcium channel blockers
- Vincristine-adriamycin in combination
Short-term implications of PD
In the short-term, the prospect for good symptom control, with minimal impact upon lifestyle, is good in the majority of patients. However, the tremor-dominant PD patient may be an exception, as this symptom can be difficult to treat medically in 20 to 30 per cent of cases.29
A vicious cycle may then ensue – the patient finds the tremor embarrassing, which, in turn, exacerbates the tremor. Paradoxically, tremor-dominant PD is often considered to have a more favourable prognosis than other phenotypes of the illness.30
Although, medically, PD may be well controlled in the short-term, the psychological impact of facing a lifelong, chronic, progressive illness cannot be underestimated. Many patients hide their illness from families, friends and employers in these early stages, believing it carries some form of stigma.
Depression is a common yet under-diagnosed facet of PD but it is eminently treatable. A prevalence of 40 to 50 per cent has been suggested for depression in PD, although estimates vary widely between 3 and 90 per cent.31
There is good evidence that depression in PD represents an endogenous component of the illness, presumably through involvement of monoaminergic systems (serotoninergic, dopaminergic and noradrenergic have all been implicated). Depression may precede the onset of motor features in up to 40 per cent of patients. In a recent Global Parkinson’s Disease Survey, a multicentre international study that assessed quality of life in a cohort of 1,000 patients with PD, depression was the first factor, after motor disability and medication, to have an impact upon the daily life of the patients.32
Long-term implications of PD
PD patients and their carers may face a number of problems in the longer term, although not all of these are inevitable. They include motor deterioration, neuropsychiatric symptoms and autonomic dysfunction. Motor problems evolve at a rate of approximately 10 per cent of patients per year, so that 10 years into the illness, virtually all PD patients will have developed motor fluctuations and “wearing off”.
The typical scenario is a PD patient who has enjoyed a four- or five-year “honeymoon” period of good symptom control, who begins to notice a wearing off of the medication effect before the next dose is due. Increasing the medication leads to peak-dose dyskinesias at this stage, which comprise fidgety movements (chorea) or more sustained abnormal muscle contractions and postures (dystonia). As the disease progresses over the next few years, the swings in motor performance become more profound and the patient fluctuates between marked dyskinesias and periods of complete immobility. When the latter occur suddenly and unpredictably, they are referred to as freezing episodes. Falls become more common as the disease advances and, like the freezing episodes, these are difficult to treat. Patients who are younger at the onset of the disease develop dyskinesias earlier than older patients.33
The development of dementia in a patient with PD is a major factor in determining nursing home placement. Variability in study methodology and definitions applied mean that the quoted prevalence of dementia in PD varies considerably. However, a figure of 40 per cent would be accepted by most as a reasonable estimate and is higher than in an age-matched control population.34
Increasing age and duration of disease are the most clearly identified risk factors for the development of dementia. A patient with the postural instability-gait difficulty phenotype of PD (as opposed to the tremor-dominant type) may also be predisposed towards cognitive impairment.
The nature of dementia in PD, and also the underlying pathology, may be quite variable. Subcortical factors (damage to ascending neurotransmitter systems, co-existing vascular changes) as well as cortical involvement (Lewy bodies and Alzheimer-like pathology) are all potential contributors. In dementia caused by cortical Lewy bodies, visual hallucinations and fluctuations in attention are characteristic.35
Unfortunately, the drugs usually used to treat confusion and hallucinations (ie, conventional neuroleptics) are clearly contraindicated in PD patients, as they may lead to a catastrophic deterioration in motor function.
The use of “atypical” neuroleptics (olanzapine, for example) has been advocated by some for the treatment of neuropsychiatric symptoms in PD but even with these agents there is a risk of exacerbating motor dysfunction. Early trials in the US have suggested that clozapine may be useful in the treatment of neuropsychiatric disturbances in PD, without worsening extrapyramidal symptoms, but it is not yet licensed in the UK for this indication.36
The most common manifestation of autonomic dysfunction in PD is constipation. This may be worsened by the immobility associated with advancing disease and by anticholinergic drugs. Urinary urgency is common but frank incontinence is rare. Neuronal loss in the substantia nigra, which normally exerts an inhibitory influence upon the micturition centre, is the probable pathophysiological mechanism for this problem.
Orthostatic hypotension can occur in PD but usually presents at a late stage and is not a major management problem. Early and significant urogenital dysfunction or orthostatic hypotension would be more suggestive of multiple system atrophy than of PD.37
There is debate as to whether, following the introduction of levodopa, there has been an increase in life expectancy in PD.2
In the pre-levodopa era, a nearly threefold increased risk of death was described in patients with the disease (2.9; 95 per cent confidence intervals [CI] 2.4-3.6). Recent reports, where patients have benefited from treatment with levodopa, continue to demonstrate an increased mortality in PD compared with the general population, which is nearly twofold (Aberdeen 2.4, 95 per cent CI 1.6-3.4;38
East Boston 2.0, 95 per cent CI 1.6-2.6).39
The confidence intervals from these more recent estimates overlap with those from earlier studies. This overlap in confidence intervals implies that, while the introduction of levodopa may have initially delayed death, there remains an increased mortalitiy in PD despite this and other therapies.
Factors affecting prognosis have not been clearly established, although, as mentioned above, tremor-dominant PD may carry a better outlook.30,40
Socioeconomic consequences of Parkinson’s disease
It is estimated that caring for those with PD costs health and social services in the UK £380m per year. Almost half of this sum is spent on nursing home and other institutional placements. The annual cost of the disease per individual has been estimated (conservatively) by the Parkinson’s Disease Society (UK) to be £42,000.41
This does not take into account indirect socioeconomic costs, such as lost productivity from carers.
The cost per patient is not distributed linearly throughout the course of the illness. In other words, early in the disease process, when the patient is independent and needing relatively simple drug treatment, they are less costly than later in their illness, when institutionalisation and more complex (and expensive) drug regimens are required.42
Since James Parkinson’s description of the illness that now bears his name, our understanding of PD has undoubtedly increased markedly. The clinicopathological spectrum of PD, in particular, has been better defined. However, a number of unanswered questions remain, relating in particular to the aetiology and pathogenesis of PD. It is to be hoped that further advances can be made in these important areas as we move nearer to the 200th anniversary of James Parkinson’s treatise on the “shaking palsy”.
The genetics of Parkinson’s disease
We do not know the causes of Parkinson’s disease. However, there have been a number of exciting advances made in the past decade, implicating a significant genetic contribution to the aetiology of PD, at least in some cases.
In 1996, Polymeropoulos and co-workers reported linkage to chromosome 4q21-23 for a large family (the Contursi kindred), where pathologically proven Parkinson’s disease was inherited in an autosomal dominant manner.6
It was subsequently shown that the gene in question codes for a protein called a-synuclein and that this protein is a major constituent of a pathological hallmark of PD, the Lewy body (see below). However, a single base-pair mutation in the a-synuclein gene has been found in only a handful of families and has been excluded in many others where PD is inherited in an autosomal dominant way.7
Nevertheless, since a-synuclein is a component of all Lewy bodies, it is possible that a greater understanding of 4q21-23-mutation familial PD will shed light on so-called sporadic PD.
Table 1 lists several other gene loci recently linked to familial PD. The Park 2 gene, which codes for a protein called parkin, is of particular interest currently. Having initially been described in Japanese families as a cause of autosomal recessive PD, with early onset of tremor (before the age of 40 years), prominent lower limb dystonia and marked levodopa responsiveness, point mutations in the gene have now been discovered in several European families.8
There appears to be no correlation between genotype and phenotype, but parkin gene mutations in European families may be responsible for later-onset disease (up to 58 years).
Table 1: Summary of genes and Parkinson’s disease
|Gene||Mode of inheritance||Chromosome||Gene product||Comment|
|Park 1||AD||4q21-23||a-synuclein||Rare mutation|
|Park 2||AR||6q25.2-27||Parkin||Varied genotype|
|Park 3||AD||2p13||Unknown||Role in sporadic PD?|
|Park 4||AD||4p14-16.3||Unknown||Association with ET?|
|Note: AD = autosomal dominant, AR = autosomal recessive, ET = essential tremor|
The gene product for Park 3 is not yet known but there are a number of interesting candidate genes of relevance, including transforming growth factor-a (TGF-a). This factor exerts trophic actions on mesencephalic dopaminergic neurones in culture, so a deficiency of TGF-a could potentially render the neurones susceptible to oxidative stress.9
The penetrance of this mutation is approximately 40 per cent, suggesting a possible role for other factors, including environmental factors, in determining disease expression. This gene may also be of relevance in sporadic PD, when autosomal dominant inheritance may not be immediately apparent. Postural tremor was an early manifestation of parkinsonism in a large family with a 4p14-16.3haplotype. This suggests that there is a possible association between essential tremor and a subgrou[ of PD.
Investigation of the genetics of PD has focused heavily on the study of genes suspected of potential involvement with the pathophysiological process. These genes have, therfore, mainly related to the dopaminergic system. Mutations in the cytochrome P450 gene CYP2D6 (debrisoquine 4-hydroxylase) and related enzymes have been extensively studied in PD in view of the suggestion that the disease may be the result of an environmental toxin interacting with a specific genetic defect. Elevated frequencies of the common CYP2D6 mutant allele CYP2D6B were found to be twice as common among PD patients as in controls. The risk approximately doubles for subjects homozygous or heterozygous for this allele.10
While some studies have substantiated these early findings, others have not.11,12
Several genetic markers related to the dopaminergic system have been variably associated with PD, such as monoamine oxidase A,13
monoamine oxidase B,14
dopamine receptors and transporters.13
The recent report of an association of the N-acetyl transferase 2 gene locus with familial PD15
is also of interest, given its role in xenobiotic metabolism and the suggested role of these enzymes in detoxifying dopamine metabolites. However, a recent multicentre European study examined polymorphisms in five candidate genes (DAT 1, N-acetyl transferase 2, glutathione s-transferase, CYP2D6 and CYP1A1) and did not find any evidence to support a role for these polymorphisms in the aetiology of PD.16
Dr Burn is consultant and senior lecturer in neurology at the Regional Neurosciences Centre, Newcastle General hospital
Credit for Learning: 1
This article forms the basis of questions under the PJ/College of Pharmacy Practice Credit for Learning scheme
The Pharmaceutical Journal Vol 264 No 7085p333-337 February 26, 2000 Continuing education
|1.Parkinson J. An essay on the shaking palsy. London: Sherwood, Neely & Jones, 1817.|
|2.Ben-Shlomo Y. The epidemiology of Parkinson’s disease. In: Quinn NP, editor. Parkinsonism. London: BalliÃ¨re Tindall, 1997:55.|
|3.Zhang Z-X, Roman GC. Worldwide occurrence of Parkinson’s disease: an updated review. Neuroepidemiology 1993;12:195.|
|4.Schoenberg BS, Anderson DW, Haerer AF. Prevalence of Parkinson’s disease in the biracial population of Copiah County, Mississippi. Neurology 1985;35:841.|
|5.Mayeux R, Marder K, Cote LJ, Denaro J, Hemenegildo N, Mejia H, et al. The frequency of idiopathic Parkinson’s disease by age, ethnic group, and sex in Northern Manhattan, 1988-1993. Am J Epidemiol 1995;142:820.|
|6.Polymeropoulos MH, Higgins JJ, Golbe LI, Nussbaum RL. Mapping of a gene for Parkinson’s disease to chromosome 4q21-q23. Science 1996;274:1197.|
|7.Vaughan JR, Farrer MJ, Wszolek ZK, Gasser T, Durr A, Agid Y, et al. Sequencing of the a synuclein gene in a large series of cases of familial Parkinson’s disease fails to reveal any further mutations. Hum Mol Genet 1998;7:751.|
|8.Abbas N, Lucking CB, Richard S, et al. A wide variety of mutations in the parkin gene is responsible for autosomal recessive parkinsonism in Europe. Hum Mol Genet 1999;8:567.|
|9.Gasser T, Muller-Myhsok B, Wzolek K, Oehlman R, Calne DD, Bonifati V, et al. A susceptibility locus for Parkinson’s disease maps to chromosome 2p13. Nature Genet 1998;18:1.|
|10.Armstrong M, Daly AK, Cholerton S, Bateman DN, Idle JR. Mutant debrisoquine hydroxylation genes in Parkinson’s disease. Lancet 1992;339:1017.|
|11.Bordet R, Broly F, Destee A, Libersa C. Genetic polymorphism of cytochrome P450 2D6 in idiopathic Parkinson’s disease and diffuse Lewy body disease. Clin Neuropharmacol 1994;17:484.|
|12.Gasser T, Muller-Myhsok B, Supala A, Zimmer E, Wieditz G, Wszolek ZK, et al. The CYP2D6B allele is not over represented in a population of German patients with idiopathic Parkinson’s disease. J Neurol Neurosurg Psychiatry 1996;61:518.|
|13.Plante-Bordeneuve V, Taussig D, Trassard O, Said G, Wood NW, Marsden CD, et al. Evaluation of four candidate genes encoding proteins of the dopamine pathway in familial and sporadic Parkinson’s disease. Neurology 1997;48:1589.|
|14.Kurth J, Kurth M, Podulso S, Schwankhaus J. Association of a monoamine oxidase B allele with Parkinson’s disease. Ann Neurol 1993;33:368.|
|15.Bandmann O, Vaughan J, Holmans P, Marsden CD, Wood NW. Association of slow acetylator genotype for N-acetyl transferase 2 with familial Parkinson’s disease. Lancet 1997;350:1136.|
|16.Nicholl DJ, Bennett P, Hiller L, Bonifati V, Vanacore N, Fabbrini G, et al. A study of five candidate genes in Parkinson’s disease and related neurodegenerative disorders. Neurology 1999;53:1415.|
|17.Gibb WR. Neuropathology of Parkinson’s disease and related syndromes. Neurologic Clinics 1992;10:361.|
|18.Morrish PK, Sawle GV, Brooks DJ. An [18F]dopa-PET and clinical study of the rate of progression in Parkinson’s disease. Brain 1996;119:585.|
|19.Fearnley JM, Lees AJ. Ageing and Parkinson’s disease: substantia nigra regional selectivity. Ibid1991;114:2283.|
|20.Menza M, Forman NE, Goldstein HE, Golbe LI. Parkinson’s disease, personality and dopamine. J Neuropsychiatry Clin Neurosci 1990;2:282.|
|21.Quinn NP. Parkinson’s disease: clinical features. In: Quinn NP, editor. Parkinsonism. London: Balli?re Tindall, 1997:1.|
|22.Hughes AJ, Daniel SE, Kilford L, Lees AJ. Accuracy of clinical diagnosis of idiopathic Parkinson’s disease: a clinico-pathological study of 100 cases. J Neurol Neurosurg Psychiatry. 1992;55:181.|
|23.Rajput AH, Rozdilsky B, Rajput A. Accuracy of clinical diagnosis in parkinsonism: a prospective study. Can J Neurol Sci 1991;18:275.|
|24.Quinn N. Multiple system atrophy. In: Marsden CD, Fahn S, editor. Movement Disorders 3. Oxford: Butterworth-Heinemann; 1994:262.|
|25.Litvan I. Progressive supranuclear palsy and corticobasal degeneration. In: Quinn NP, editor. Parkinsonism. London: Balli?re Tindall; 1997:167.|
|26.Anton-Stephens D. Preliminary observations on the psychiatric uses of chlorpromazine (Largactil). J Mental Sci 1954;100:543.|
|27.Ayd FJ Jr. A survey of drug-induced extrapyramidal reactions. JAMA 1961;175:1054.|
|28.Chabolla DR, Maraganore DM, Ahlskog JE, O’Brien PC, Rocca WA. Drug-induced parkinsonism as a risk factor for Parkinson’s disease: a historical cohort study in Olmsted County, Minnesota. Mayo Clin Proc 1998;73:724.|
|29.Hallett M, Litvan I, and the Task Force on Surgery for Parkinson’s Disease. Evaluation of surgery for Parkinson’s disease. Neurology. 1999;53:1910.|
|30.Jankovic J, McDermott M, Carter J, Gauthier S, Goetz C, Golbe L, et al. Variable expression of Parkinson’s disease: a baseline analysis of the DATATOP cohort. Neurology 1990;40:1529.|
|31.Gotham AM, Brown RG, Marsden CD. Depression in Parkinson’s disease: a quantitative and qualitative analysis. J Neurol Neurosurg Psychiatry 1986;49:381.|
|32Findley L, on behalf of the Global Parkinson’s Disease Steering Committee. Investigating factors which may influence quality of life in Parkinson’s disease. Parkinsonism Rel Disord 1999;5 (suppl):S55.|
|33.Kostic V, Przedborski S, Flaster E, Sternic N. Early development of levodopa-induced dyskinesias and response fluctuations in young-onset Parkinson’s disease. Neurology 1991;41:202.|
|34.Mayeux R, Denaro J, Hemenegildo N, Marder K, Tang MX, Cote LJ, et al. A population-based investigation of Parkinson’s disease with and without dementia. Relationship to age and gender. Arch Neurol 1992;49:492.|
|35.McKeith IG, Galasko D, Kosaka K, Perry EK, Dickson DW, Hansen LA, et al. Consensus guidelines for the clinical and pathological diagnosis of dementia with Lewy bodies (DLB): report of the consortium on DLB international workshop. Neurology 1996;47:1113.|
|36.The Parkinson’s Disease Study Group. Low-dose clozapine for the treatment of drug-induced psychosis in Parkinson’s disease. N Engl J Med 1999;340:757.|
|37.Magalhaes M, Wenning GK, Daniel SE, Quinn NP. Autonomic dysfunction in pathologically confirmed multiple system atrophy and idiopathic Parkinson’s disease: a retrospective comparison. Acta Neurol Scand 1995;91:98.|
|38.Ebmeier KP, Calder SA, Crawford JR, Stewart L, Besson JA, Mutch WJ. Parkinson’s disease in Aberdeen: survival after 3.5 years. Ibid 1990;81:294.|
|39.Bennett DA, Beckett LA, Murray AM, Shannon KM, Goetz CG, Pilgrim DM, et al. Prevalence of Parkinsonian signs and associated mortality in a community population of older people. N Engl J Med 1996;334:71.|
|40.Rajput AH, Pahawa R, Pahawa P, Rajput A. Prognostic significance of the onset mode in parkinsonism. Neurology 1993;43:829.|
|41.The Parkinson’s Disease Society (UK). Meeting a need? Discussion Document. London; 1994:11.|
|42.Dodel RC, Eggert KM, Oertel WH. Costs of Parkinson’s disease: a preliminary retrospective survey. In: Stern MB, ed. Beyond the decade of the brain. Royal Tunbridge Wells: Wells Medical Ltd; 1994:59.|