1. Epidemiology and aetiology
Parkinson’s disease is the second most common degenerative neurological disease after Alzheimer’s disease and has a prevalence of between 100 and 180 per 100,000. At least 120,000 people in the UK have Parkinson’s. Its incidence and prevalence increases with age and the average age of diagnosis is about 60 years. Men have a one-and-a-half-times-greater risk of developing Parkinson’s than women.
Its precise aetiology remains unknown, but it is believed that Parkinson’s is not a single disease entity, but a spectrum of diseases with a similar clinical picture. There is a complex interplay between genetic and environmental factors.
About 5 per cent of patients have an inherited condition. Several genes have been identified, some autosomal dominant (the most common is PARK 8, which is indistinguishable from idiopathic Parkinson’s), and some autosomal recessive, for example PARK 2. Patients with this gene have an earlier age of onset and clinical features are more symmetrical than in classical Parkinson’s.
After advancing age, a family history of Parkinson’s is the second largest risk factor for developing the condition and 15 per cent of patients will have a positive family history.
Environmental factors such as the drinking water, heavy metals and infectious agents have all been considered as possible causes, but evidence for these factors is limited and there is a lack of prospective studies.
This is one condition where smoking is protective — people who smoke are less likely to develop Parkinson’s than non-smokers.
It can be classified by the predominant symptoms: tremor dominant, akinetic rigid or mixed. Tremor-dominant cases have a slower rate of progression.
Identifying Parkinson’s may not be straightforward and misdiagnosis can occur. In a study, 50 per cent of patients on anti-Parkinson medication when examined by a specialist were given an alternative diagnosis. Of patients attending specialist clinics and in clinical trials with a definite diagnosis of Parkinson’s, between 4 and 14 per cent had normal dopamine functional imaging, which brings the diagnosis into doubt. NICE recommends that all patients with suspected Parkinson’s be referred to a specialist movement disorder clinic.
At specialist clinics, the diagnosis is generally based around the UK Brain Bank Criteria, which improve diagnostic accuracy.
Until recently, the focus has been on these motor features of Parkinson’s disease, but increasingly the multitude of non-motor features is receiving attention. These are often equally important to the patient.
Some non-motor symptoms predate the onset of motor features, for example depression, constipation, loss of sense of smell, and REM sleep disorder (in which patients act out their dreams and can have violent movements while still asleep).
The diagnosis remains primarily clinical. Investigations are undertaken to exclude other causes, and include thyroid function test, caeruloplasmin (Wilson’s disease) and structural neuroimaging (largely looking for a cerebrovascular disease. Recently, there is an increased use of functional imaging in specialist centres.
The most common functional imaging is an FP-CIT SPECT scan (DaTSCAN), which measures presynaptic dopamine transporters. Uptake is reduced in degenerative parkinsonism (Parkinson’s disease and ‘Parkinson plus’ disorders), but uptake is normal in non-degenerative parkinsonism (for example benign tremors, drug-induced parkinsonism).
NICE recently published guidelines on the management of Parkinson’s. There remains no cure and no treatments are proven to slow disease progression.
A multidisciplinary approach, including a specialist nurse (where available), physiotherapy, speech therapy and occupational therapy is best. Patients should have enough information to be actively involved in management decisions.
Drug treatment is started when necessary from a functional viewpoint, although clinical trials are currently examining whether there would be an advantage in starting treatment earlier in the disease course.
NICE advises that initial treatment can be with a dopamine agonist, can be levodopa based or can be with monoamine oxidase B inhibitor (MAOBI). There is insufficient evidence to recommend any one as the initial drug of choice.
As a general rule either a dopamine agonist or an MAOBI is often used in younger patients (as these delay the onset of motor complications compared with levodopa).
In patients with significant comorbidity (for example vascular disease or cognitive impairment), levodopa is the usual drug of choice.
Entacapone is a catechol-O-methyl transferase inhibitor (COMTI) that functions as a levodopa extender and is useful for symptoms related to the short half-life of levodopa.
In later disease, combinations of these drug classes are used, although many more advanced patients cannot tolerate non-levodopa agents. Levodopa remains the most effective treatment for improving motor symptoms.
Anticholinergic drugs are less commonly used because of side-effects such as dry mouth, constipation, and blurred vision. In particular, they are associated with confusion and cognitive impairment.
Amantadine has some efficacy as an anti-dyskinetic agent, but the benefit is limited. There are no good oral anti-dyskinetic drugs.
Tolcapone is a COMTI licensed in Europe after being withdrawn previously because of hepatotoxicity. It is only recommended as second line to entacapone and requires careful liver-function monitoring.
A patch formulation of the dopamine agonist rotigotine has recently been introduced. It is not recommended by the Scottish Medicines Consortium. A second MAOBI, rasagiline, is now available. This is a once daily oral preparation with a single dose of 1mg.
For patients with advanced Parkinson’s, a gel formulation of levodopa is available, which is infused via percutaneous endoscopic gastrostomy tube into the jejunum.
UK Brain Bank clinical diagnostic criteria for Parkinson’s disease
Step 1. Diagnosis of Parkinsonian syndrome
At least one of the following
- Muscular rigidity.
- 4–6Hz rest tremor.
- Postural instability not caused by primary visual, vestibular, cerebellar, or proprioceptive dysfunction.
Step 2. Exclusion criteria for Parkinson’s disease
- History of repeated strokes with stepwise progression of parkinsonian features.
- History of repeated head injury.
- History of definite encephalitis.
- Oculogyric crises.
- Neuroleptic treatment at onset of symptoms.
- More than one affected relative.
- Sustained remission.
- Strictly unilateral features after three years.
- Supranuclear gaze palsy.
- Cerebellar signs.
- Early severe autonomic involvement.
- Early severe dementia with disturbances of memory, language and praxis.
- Babinski’s sign.
- Presence of cerebral tumour or communication hydrocephalus on imaging study.
- Negative response to large doses of levodopa in absence of malabsorption.
- MPTP exposure.
Step 3. Supportive prospective positive criteria for Parkinson’s disease
Three or more required for diagnosis of definite Parkinson’s disease in combination with step one
- Unilateral onset.
- Rest tremor present.
- Progressive disorder.
- Persistent asymmetry affecting side of onset most.
- Excellent response (70–100%) to levodopa.
- Severe levodopa-induced chorea.
- Levodopa response for five years or more.
- Clinical course of 10 years or more.