Parkinson's disease

Contributed by Professor Adrian Williams, professor of clinical neurology and Dr Mark Willmot, specialist registrar in neurology at Queen Elizabeth Hospital, Birmingham.

1. Epidemiology and aetiology
Idiopathic Parkinson's disease is the second most commonly encountered neurodegenerative disorder after Alzheimer's disease. It is rare before the age of 50.

Prevalence of Parkinson's in the developed world is about 0.3 per cent, although incidence appears to be increasing in older age groups. There may be a lower prevalence in non-caucasian populations, but epidemiological studies have been limited by methodological issues and by factors affecting incidence such as emigration or adoption of a western lifestyle.

Parkinson's disease is more common in men than women. It is unclear why this is so, but differences in hormonal or environmental exposures may be involved.

Multiple causes
The exact causes of Parkinson's are unknown, however, environmental and genetic factors are both believed to contribute to its development.

The compound N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), a by-product of illegally manufactured meperidine, was identified as the factor responsible for a small epidemic of parkinsonism during the 1980s.

Dietary deficiency has been implicated in other epidemics. For example, niacin deficiency can cause parkinsonism in cases of pellagra. This is because it affects the coenzymes required for the reduction/oxidation reaction (redox) involved in cell respiration.

Genetic factors
More than eight mutations in different Park genes have been correlated with a propensity to the condition, and twin studies support a genetic component in Parkinson's risk, at least in younger patients.

Mitochondrial dysfunction has also been implicated as a cause of Parkinson's disease. Either because of an imbalance in the supply of reductive raw materials, or because of structural damage to the mitochondria, the redox process by which mitochondria transform glucose and oxygen into ATP can become inefficient. This can result in the production of too many oxygen radicals, causing oxidative stress and an increased risk of neuro-degenerative diseases.

2. Making the diagnosis
Classical Parkinson's disease presents with a triad of tremor, hypokinesia and rigidity. Tremor is the presenting symptom in most cases. It is typically unilateral, worst at rest and has a 'pill rolling' rotary component. Over time, the tremor spreads to other limbs.

Hypokinesia is the inability to initiate and maintain repetitive movement. It manifests as shuffling gait, micrographia, loss of facial expression and difficulty in rising from a seated position.

Rigidity is a clinical sign that can be detected by passively moving the upper limb at the wrist and elbow. Postural instability can lead to poor balance and falls.

REM sleep disorders and depression are also common early symptoms of Parkinson's.

Other features
Other features include drooling, monotonous speech, autonomic dysfunction presenting as constipation, postural hypotension, sweating abnormalities, sexual dysfunction, seborrhoeic dermatitis and dementia. Advanced Parkinson's patients can develop dyskinesias and unpredictable motor fluctuations as a result of waning drug treatment efficacy.

Investigations
If the presentation is typical, diagnosis can be made on clinical grounds alone. Patients with atypical features or who are under 40 years old should be investigated to confirm the diagnosis. A clinical diagnosis of Parkinson's disease can be wrong in up to a quarter of patients because it is mimicked by a number of akinetic rigid syndromes. Essential tremor is the condition most often misdiagnosed as Parkinson's. Dopamine transporter scanning can be used to differentiate.

Diagnostic certainty can be improved by using criteria such as those from the UK Parkinson's Disease Society. Genetic testing for familial cases is not yet widely available and, as with other screening tests for untreatable genetic diseases, is of dubious value.

Differential diagnosis of Parkinson's disease

  • Essential tremor - symmetrical, postural, improves with alcohol, no rigidity or hypokinesia;
  • Drug-induced parkinsonism - from neuroleptics, some antiemetics and antidepressants;
  • Vascular parkinsonism - symmetrical, lower body/gait only, tremor uncommon, poor response to levodopa;
  • Multiple system atrophy - early pronounced autonomic features, parkinsonism, poor response to levodopa, cerebellar signs, pyramidal signs;
  • Progressive supranuclear palsy - early falls, parkinsonism, poor response to levodopa, loss of vertical eye movements, speech and swallowing problems, early dementia;
  • Corticobasal degeneration - asymmetrical parkinsonism, poor response to levodopa, early dementia, limb apraxia, cortical sensory loss, pyramidal signs;
  • Wilson's disease - young onset parkinsonism or trembly/dystonic movement disorder, liver disease, psychiatric features, Kayser-Fleischer rings;
  • Lewy body dementia - early dementia, fluctuating cognitive function, visual hallucinations, parkinsonism;
  • Normal pressure hydrocephalus - gait apraxia, cognitive impairment, urinary incontinence, parkinsonism, no response to levodopa.

3. Management
There is no evidence to support one particular drug as the initial choice in treating Parkinson's disease.

First-line treatment
Levodopa (given with a peripheral decarboxylase inhibitor) is the most effective parkinsonism drug but is associated with motor fluctuations and dyskinesias after a few years. Its early use is recommended in older patients as they are less prone to motor complications and more sensitive to neuropsychiatric effects of other agents.

Non-ergot dopamine agonists, such as ropinirole and pramipexole, are effective in early Parkinson's. They carry a lower risk of motor complications than levodopa, but a greater risk of neuropsychiatric effects. Continuous dopaminergic stimulation can be provided using rotigotine. Ergot-derived dopamine agonists are not recommended first line as they increase the risk of fibrotic reactions.

MAO-B inhibitors can be used as first-line therapy. Although they have only modest anti-parkinsonian effects, they could be neuroprotective.

Dual therapy
Monotherapy will eventually fail to control motor symptoms in many patients. In the absence of motor fluctuations, dyskinesias and neuropsychiatric features, dual therapy with levodopa and a dopamine agonist is recommended. For patients on a MAO-B inhibitor, either a dopamine agonist or levodopa can be added. If motor fluctuations, dyskinesias or neuropsychiatric features are present management needs specialist input.

Other treatments that can be added include MAO-B inhibitors, dopamine agonists, and controlled-release levodopa. Anticholinergics may also be effective, although these are not recommended as a first choice because of side-effects.

Motor fluctuations can also be managed by adjusting the frequency of daytime levodopa, avoiding administration at mealtimes or switching the patient to a low-protein diet. If these measures fail then consideration should be given to subcutaneous apomorphine, deep brain stimulation (DBS) or levodopa enteric gel.

Dyskinesias can be managed by adding amantadine, reducing levodopa or MAO-B or COMT inhibitors. If these measures are ineffective, the patient should be considered for apomorphine infusion or DBS, to facilitate reduction of levodopa.

Depression should be treated with SSRIs or tricyclics while optimising anti-parkinsonian medication.

Drugs aggravating dementia such as anticholinergics or amantadine, should be discontinued; cholinesterase inhibitors may help to improve cognitive function.

A patient who develops psychotic symptoms should be examined for sepsis or a metabolic disorder. If these are absent, anti-parkinsonian drugs should be reduced.

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