Elsevier

The Lancet

Volume 373, Issue 9680, 13–19 June 2009, Pages 2055-2066
The Lancet

Seminar
Parkinson's disease

https://doi.org/10.1016/S0140-6736(09)60492-XGet rights and content

Summary

Parkinson's disease is a common progressive bradykinetic disorder that can be accurately diagnosed. It is characterised by the presence of severe pars-compacta nigral-cell loss, and accumulation of aggregated α-synuclein in specific brain stem, spinal cord, and cortical regions. The main known risk factor is age. Susceptibility genes including α-synuclein, leucine rich repeat kinase 2 (LRRK-2), and glucocerebrosidase (GBA) have shown that genetic predisposition is another important causal factor. Dopamine replacement therapy considerably reduces motor handicap, and effective treatment of associated depression, pain, constipation, and nocturnal difficulties can improve quality of life. Embryonic stem cells and gene therapy are promising research therapeutic approaches.

Introduction

James Parkinson hoped that his monograph entitled An Essay on the Shaking Palsy, in which he detailed six patients with “involuntary tremulous motion with lessened muscular power, in parts not in action even when supported, with a propensity to bend the trunk forward and to pass from a walking to a running pace”, would persuade nosologists that he had described an unrecognised disorder.1, 2 In acknowledgment of the London apothecary's clear description, Jean Martin Charcot, the father of neurology, proposed that the syndrome should be called maladie de Parkinson (Parkinson's disease).

The incidence of the disease rises steeply with age, from 17·4 in 100 000 person years between 50 and 59 years of age to 93·1 in 100 000 person years between 70 and 79 years, with a lifetime risk of developing the disease of 1·5%.3, 4 The median age of onset is 60 years and the mean duration of the disease from diagnosis to death is 15 years, with a mortality ratio of 2 to 1.5 Because of ageing of western populations, an increased frequency above the current 1 in 800 can be anticipated. The precise mode of death is difficult to identify in most cases, but pneumonia is the most common certificated cause. Although good evidence exists that men are about 1·5 times more likely than women to develop Parkinson's disease, this difference is not the same across different studies, and is more pronounced in, and might be restricted to, people older than 70 years of age in western populations.6

Parkinson's disease is not related to race or creed, and literary and historical precedents before the publication of Parkinson's monograph make it unlikely to be a postindustrial condition.7 The cause remains as elusive as when it was first described in 1817, but important genetic and pathological clues have recently been found.

Section snippets

Pathogenesis

Although Parkinson's disease is regarded as a sporadic disorder, remarkably few environmental causes or triggers have so far been identified.8, 9, 10 Similar to other neurodegenerative diseases, ageing is the major risk factor, although 10% of people with the disease are younger than 45 years of age. The incidence seems to decrease in the ninth decade of life,9 which could be artifactual or related to underdiagnosis of elderly people of that age, or could be a real decline, similar to what

Clinical features

Parkinson's disease commonly presents with impairment of dexterity or, less commonly, with a slight dragging of one foot. The onset is gradual and the earliest symptoms might be unnoticed or misinterpreted for a long time. Fatigue and stiffness are common but non-specific complaints. Work colleagues or family members might notice a lugubrious stiff face, a hangdog appearance, a flexion of one arm with lack of swing, a monotonous quality to the speech, and an extreme slowing down. These changes

Diagnosis

The diagnosis of Parkinson's disease cannot be made without the detection of unequivocal bradykinesia, although individuals with monosymptomatic rest tremor who have abnormalities of striatal dopamine on functional imaging exist. Bradykinesia might be apparent as soon as the patient enters the consulting room or when the patient undresses to be examined. Facial expression can be immobile and rigid, and the ability to express emotions is slow. The speech might also be slow, quiet, and lacking in

Neuropathological lesions

A region-specific selective loss of dopaminergic, neuromelanin-containing neurons from the pars compacta of the substantia nigra is the pathological hallmark of Parkinson's disease. However, cell loss in the locus coeruleus, dorsal nuclei of the vagus, raphe nuclei, nucleus basalis of Meynert, and some other catecholaminergic brain stem structures including the ventrotegmental area also exists.64 This nerve-cell loss is accompanied by three distinctive intraneuronal inclusions: the Lewy body,

Treatment

Parkinson's disease is still an incurable progressive disease, but treatment substantially improves quality of life and functional capacity. L-dopa, in combination with a peripheral dopa decarboxylase inhibitor (benserazide or carbidopa), is the most effective therapy and should always be the initial treatment option, whatever the age of the patient. Most people can be maintained over the first 5 years of the disease on 300–600 mg/day L-dopa. Although prediction of the therapeutic response in

Future perspectives

Although life expectancy and control of bradykinesia and tremor have improved with new treatments for Parkinson's disease, postural instability and cognitive impairment have become increasingly important unmet therapeutic needs. Furthermore, no neuroprotective treatment can arrest the underlying disease process, and dopaminergic therapy is far from perfect in controlling motor handicap. Long-term physiological dopamine release can be achieved by fetal mesencephalic dopamine cell implantation.120

Conclusions

Although shaking palsy remains as much an enigma as when James Parkinson first described its clinical features, the current knowledge of the disease continues to evolve and be challenged by scientific discovery. Severe damage to most catecholaminergic-containing nerve cells in the brain stem is a characteristic pathological finding, although damage is not restricted to these structures. Terms such as Lewy body disease or synucleinopathy can be helpful for molecular pathologists, but are

Search strategy and selection criteria

We searched PubMed for papers published in English between 1998 and 2008 with the terms “Parkinson's disease” and “gene therapy”, “implantation”, “treatment”, “diagnosis”, “imaging”, “epidemiology”, “pathology”, and “genetics”. We also reviewed historical textbooks and monographs. We have used the American Academy of Neurology (AAN) treatment guideline parameters, the Movement Disorder Society Evidence Based Review (EBR), and the National Institute for Health and Clinical Excellence

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