Clinical Review - Parkinson's disease

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

Surgeons implant electrodes for deeper brain stimulation of a patient's subthalamic nucleus (photograph: spl)
Surgeons implant electrodes for deeper brain stimulation of a patient's subthalamic nucleus (photograph: spl)

Section 1: Aetiology and epidemiology
Parkinson's disease (PD) is one of the most common neurodegenerative diseases, and is principally due to the progressive loss of dopaminergic neurons in the substantia nigra of the brainstem.

Its prevalence is 100-190 per 100,000. The incidence increases with age: it is uncommon below 50 years, but rises progressively thereafter, to 300 per 100,000 in those aged over 80.1

While there is some variation between studied populations, it is not clear how much of this is due to methodological differences.

In general, however, it appears that PD occurs with a similar frequency across the world, although it is probably more common in men.

Genetic susceptibility
As with many conditions, PD is thought to be the result of an interaction between genetic susceptibility and environmental factors.

In those relatively rare cases with onset below 50 years of age, genetic susceptibility plays a much more dominant role than in typical, sporadic, late-onset disease.2

Studies of familial PD have identified several genes which may cause PD with Mendelian inheritance, especially in young (<50 years) onset disease.

While uncommon compared with sporadic late-onset PD, the genes involved have highlighted potential pathogenic mechanisms which may turn out to be relevant to idiopathic PD, including oxidative stress, mitochondrial dysfunction and abnormal cellular protein handling.

Twin studies have failed to show a higher concordance for the diagnosis of PD in monozygotic versus dizygotic pairs, suggesting that environmental factors are more important in late-onset PD.1

Neurotoxins
In the 1980s, a group of illicit drug users developed a severe Parkinsonian syndrome after injecting narcotics contaminated with the neurotoxin MPTP, leading to its use in experimental models of PD, and furthermore stimulating the search for other environmental toxins relevant to human disease.

Epidemiological studies suggest it is possible that agrochemicals act as neurotoxins, with rural residence and drinking of well water increasing the risk of PD.

Several herbicides and pesticides have been implicated, although a major causal effect remains unproven.2

Protective factors
Two potential 'protective' factors are notable: the most robust epidemiological phenomenon in PD, other than the influence of age, is the negative association with smoking.

When compared with non-smokers, PD is less common in current smokers, recent ex-smokers and those who smoked in early adult life but stopped. The reason is unknown. It is postulated that a biologically determined factor, which makes people less likely to smoke, is linked to a higher risk of PD.

Controversy exists as to whether exposure to NSAIDs may protect against PD.2

Section 2: Making the diagnosis
PD is characterised clinically by four cardinal motor symptoms, represented by the acronym TRAP (tremor, rigidity, akinesia, and postural instability).3

The typical patient presents with an asymmetric, upper limb, tremor-dominant akinetic-rigid syndrome.

Tremor and rigidity
Tremor usually manifests at rest, such as sitting watching television, but may also occur with posture or movement of the limb (kinetic or action tremor), although it is usually worse at rest.

Rigidity is an increased resistance to the passive movement of a limb and has a 'leadpipe' quality. The superimposition of rest tremor on rigidity gives the characteristic 'cogwheeling'.

Akinesia, or more accurately bradykinesia, is a slowness of initiating and executing voluntary movement, often associated with additional difficulty performing sequential motor tasks. It is the principal motor symptom/sign in PD, and its absence should lead to reconsideration of the diagnosis (see box, below).

Postural instability is common in PD, and may lead to falls, but not usually until later in the course of the disease.

Non-motor symptoms
In recent years, the importance of non-motor symptoms in PD has been increasingly recognised; indeed these may be more important causes of morbidity than motor symptoms, compounded by their usual resistance to dopaminergic therapy.

Symptoms include hyposmia (reduced sense of smell), constipation and sleep disorders, any of which may predate the onset of classic motor PD, possibly by years or even decades. Pain and other sensory symptoms are also common in PD.

Other non-motor symptoms, such as autonomic dysfunction, usually occur later in disease, while dementia in PD, characterised by visual hallucinations, daytime somnolence and fluctuating cognitive performance, occurs in at least 80 per cent eventually.

Dementia preceding or occurring within one year of the onset of motor symptoms is called dementia with Lewy bodies (DLB), whereas if more than one year has elapsed, the term Parkinson's disease dementia (PDD) is used - the common pathology is extensive cortical Lewy body disease.

Imaging
The diagnosis of PD is predominantly clinical. Imaging (usually MRI) may be helpful in excluding other conditions.

Diagnostic uncertainty may sometimes be resolved with nuclear medicine studies, which measure (indirectly) striatal dopamine. The imaging above shows the typical appearance, with the characteristic asymmetric loss of tracer uptake.

UK Brain Bank Criteria for the diagnosis of Parkinson's3

Step 1: Bradykinesia
At least one of the following criteria:

  • Rigidity.
  • Four to six Hz rest tremor.
  • Postural instability not caused by primary visual, vestibular, cerebellar or proprioceptive dysfunction.

Step 2: Exclude other causes of Parkinsonism.

Step 3: At least three of the following supportive (prospective) criteria:

  • Unilateral onset.
  • Rest tremor.
  • Progressive disorder.
  • Persistent asymmetry primarily affecting side of onset.
  • Excellent response (70-100 per cent) to levodopa.
  • Severe levodopa-induced chorea (dyskinesia).
  • Levodopa response for five years or more.
  • Clinical course of 10 years or more.

Section 3: Managing the condition
PD cannot currently be prevented or cured, but reasonably effective symptomatic treatment of the motor symptoms is achievable, at least for the first few (usually four to six) years.

After this, motor complications, which may be treatment related, cause management to become difficult.

The onset of neuropsychiatric symptoms (hallucinations, cognitive impairment and later dementia) is particularly problematic, and severely restricts the physician's pharmacological options.

Side-effects
The choice of initial treatment is usually between levodopa (L-dopa) or a dopamine receptor agonist.4 L-dopa produces a superior symptomatic effect to an agonist, and can have fewer side-effects.

After, on average, four to six years' use this 'honeymoon' period is replaced by motor fluctuations, where patients may rapidly enter an 'off' state (freezing), while at other times manifest an excess of movement - dyskinesias (usually chorea).

To some extent, these fluctuations can be smoothed out by fractionation of the total dose with more frequent dosing, or by the addition of a catechol-O-methyltransferase (COMT) inhibitor (entacapone or tolcapone), which delays L-dopa degradation and hence prolongs its duration of action. Tolcapone requires monitoring of liver biochemistry.

Most neurologists deploy a dopamine agonist initially in younger patients (under 70) to delay the need for L-dopa, and hence the time to motor complications. Older patients do not usually tolerate agonists due to neuropsychiatric side-effects, and L-dopa is preferred.

The situation has become even more complicated, as agonists have been linked with a number of potentially destructive behavioural side-effects (impulse control disorders), including pathological gambling and compulsive shopping.

Antipsychotics
Antipsychotics are all dopamine receptor antagonists to some degree, and will therefore almost invariably lead to deterioration in PD motor features if deployed to treat hallucinations or delusions.

'Typical' neuroleptics, such as haloperidol, may be fatal if given to patients with PD (or DLB).

Abrupt discontinuation of treatment in PD may provoke a similar crisis and should be avoided. Newer 'atypical' anti psychotics worsen PD motor symptoms far less, and an acceptable balance between motor and psychiatric symptoms may be obtained: the usual choice is quetiapine.

Cognitive impairment and/or hallucinations may improve with an anticholinesterase inhibitor, such as rivastigmine.

Freezing may be treated by a subcutaneous bolus of apomorphine, administered by patient or carer, and moderate to severe motor fluctuations may improve with a continuous ambulatory subcutaneous apomorphine infusion.

If this fails, patients may be referred for subthalamic nucleus surgery, where a stereotactically inserted electrode is attached to a subcutaneous stimulator device, similar to a pacemaker.4

Section 4: Prognosis
PD is incurable and no convincing neuroprotective therapy exists. The median survival after symptom onset is around 15 years (compared with symptomatic survival in the so-called Parkinson's plus syndromes of seven to eight years).

PD will therefore probably shorten a patient's life, if they do not succumb to another disease first.

Motor complications
Those with a younger onset can have a more indolent course, but may experience worse motor complications.

This may in part be due to physicians' more aggressive treatment with higher doses of medication earlier in the disease. Those with a tremor at onset also do better, while older patients, and those with early gait disorder often fare poorly.

The onset of neuropsychiatric symptoms usually marks an extended palliative phase of the disease, in which treatment options are restricted.

Specialist care
The NICE guidelines on PD recommend referral to a physician with a specialist interest in the condition,5 invariably a neurologist or geriatrician.

The specialist will then usually be responsible for follow-up, reviewing the diagnosis, and orchestrating treatment in cooperation with the primary care physician.

The guidelines maintain that PD patients should have access to a specialist PD nurse, speech and language and occupational therapy, physiotherapy and ultimately palliative care.

Resources

1. Schrag A. Epidemiology of Movement Disorders. In Parkinson's Disease and Movement Disorders (5th Ed). Jankovic J, Tolosa E (Ed). Lippincott Williams & Wilkins, 2007

2. Current Concepts on the Etiology and Pathogenesis of Parkinson Disease. In Principles and Practice of Movement Disorders. Fahn S, Jankovic J (Ed). Churchill Livingstone

3. Jankovic J. Parkinson's disease: clinical features and diagnosis. J Neurol, Neurosurg Psychiatry 2008; 79: 368-76.

4. Clarke C E. Parkinson's disease in Practice (2nd Ed). Royal Society of Medicine Press.

5. Parkinson's disease: Diagnosis and management in Primary and Secondary Care: Quick Reference Guide. National Institute for Health and Clinical Excellence, June 2006.

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