CLINICAL REVIEW: The Diagnosis of Parkinson’s Disease

Written By: Sam Savage

Published Date: February 1, 2005 Last Edited: February 1, 2005

The essentials

* Some presentations of Parkinson’s diseasejriake diagnosis difficult.

* The underlying mechanism that ca uses PCHs un known._

* Bradykinesia, rigidity, tremor and postural instability are typical signs.

* Essential tremor is symmetrical and improves with alcohol.

* Parkinson plus syndromes are severe and have a poor prognosis.

1. History and epidemiology of Parkinson’s

Parkinson’s disease (PD) is a common progressive neurodegenerative condition, but patients present in a variety of ways, so sometimes the diagnosis can be difficult. Even the most experienced specialist in movement disorder is likely to misdiagnose up to a quarter of cases.

Accuracy is important, so that patients can be informed about what to expect, and to allow future planning. All patients should be referred to a specialist movement disorder clinic.

History of PD

James Parkinson first described PD in 1817, but the bradykinesia (slowness of movements) was mistaken for paralysis, and was termed ‘paralysis agitans’.

The first drug therapy, belladonna alkaloids, was used in the 186Os, but the next therapeutic advance was not made until anticholinergic drugs were introduced in the 194Os. Levodopa arrived in the 1960s, when PD patients were found to have neostriatal dopamine deficiency, after the finding that inhibition of peripheral decarboxylation of levodopa (using the decarboxylase inhibitors) improved cerebral levodopa delivery.

The first dopamine agonist (DA) bromocriptine was introduced in the 1970s. Further ergot-derived DAs were introduced in the 1980s, followed by non-ergot DAs in the 1990s. Enzyme inhibitors of monoamine oxidase B (selegiline) became available in the 1980s, and the catecholamine-O-methyltransferase inhibitor (entacapone) arrived in the 1990s.

Epidemiology

There are between four and 20 new cases of PD per 100,000 population per year. The incidence and prevalence increase with age, so a GP with a list size of 2,000 patients can expect to have about four patients.

The average age of onset of symptoms is 60 years. About 2 per cent of people over 65 years old have the condition, with men having a 1.5 times greater risk than women.

Racial differences

PD is most common in Caucasians, with the lowest rates in African races.

Patients with PD have a slightly reduced life expectancy, with a standardised mortality rate (the ratio of number of deaths in PD patients to controls) of 1.5. Parkinson’s disease is not a direct cause of death, and only half of death certificates for PD patients mention PD as an underlying contributory cause.

2. The range of possible causes

The specific cause of PD is unknown. There is loss of the pigmented dopaminergic neurones in the basal ganglia, but the underlying mechanism of this cell death remains a mystery.

What is clear is that there is a long pre-clinical phase, as symptoms only develop once there is significant depletion of striatal dopamine, and about a 50 per cent loss of pigmented neurons in the caudal substantia nigra. A delay in diagnosis is common. Many patients report symptoms well before the diagnosis is formalised.

The primary dopamine deficiency is not a simple depletion, as just replacing dopamine does not solve the problem. The basal ganglia consist of a complex network with positive and negative feedback loops involving several neurotransmitters, and the underlying pathophysiology is complex.

Genetic factors

The majority of PD cases are sporadic, but a few are inherited as a simple Mendelian trait. If an individual has a family history of PD, the risk of developing it is doubled, but still very low.

Twin studies have shown no increase in clinical PD in monozygotic twins, but functional imaging has shown reduced basal ganglia 18- fluorodopa uptake in monozygotic twins compared with dizygotic twins. This suggests that genetic factors may play a more important role than previously thought.

Environmental factors

Toxins can be involved, as demonstrated when a chemistry graduate in San Francisco manufactured a pethidine analogue for street sale that was contaminated with 1-methyl-4-phenyl-1,2,3,6- tertrahydropyridine (MPTP). Intravenous drug users injecting it developed severe parkinsonism, and active neuronal loss was found at autopsy.

Compounds structurally similar to MPTP are found in pesticides, and studies have shown a small increased risk of parkinsonism in rural areas and in those who drink contaminated well water. Heavy metals including manganese produce parkinsonism, but the clinical and pathological features are different from idiopathic PD. People drinking water containing manganese and aluminium have developed a parkinsonismdementia complex. Carbon monoxide poisoning can also induce parkinsonism.

Trauma and infection

Trauma resulting in head injury is sometimes cited as a cause of parkinsonism, but this is based on case-control cross-sectional studies, and has not been corroborated by a single prospective study.There is therefore the possibility that once Parkinson’s disease is diagnosed, patients may recall a head injury in the past (recall bias).

Early last century, post-encephalitic parkinsonism led to the suggestion of a possible viral aetiology, but the clinical and pathological features of post-encephalitic parkinsonism are different from those of the idiopathic disease.

Protective factors

Cigarette smoking imparts a reduced risk of PD, even after correcting for increased mortality in smokers. Explanations include a protective effect of nicotine, or personality factors. The loss of sense of smell in PD may contribute to stopping smoking in the early presymptomatic stages. Vitamin C has also been associated with PD.

3. The presentation of Parkinson’s

To make a diagnosis of PD using the UK Brain Bank criteria, there needs to be evidence of bradykinesia (slowness of movements), plus at least one of the following: muscular rigidity (resistance to passive movement), a tremor at rest with a frequency of 4-6Hz, and postural instability that has no other cause.

Bradykinesia

Bradykinesia is the only essential feature. Patients complain that they have slowed down, have difficulty with fine movements such as cutting food or managing buttons or zips, that their walking has deteriorated with a tendency to drag one leg and that their handwriting has become smaller.

They also have difficulty turning in bed at night. An early sign is loss of arm swing on one side.The family notice a loss of facial expression.

Generalised bradykinesia can be made from overall observations, and hand movements are examined by asking the patient to open and close the hands, to tap their index finger on the thumb (finger taps) or perform repeated wrist pronation/supination. In PD there is fatiguing of these movements with loss of amplitude, and with arrest of movement in later disease.

Leg movements are tested by asking the patient to tap the heel on the ground, lifting the foot by 5cm each time and watching for reduced amplitude and fatiguing.

Rigidity and tremor

Muscular rigidity is often described as muscle stiffness or sometimes as pain, leading to patients occasionally being misdiagnosed with an orthopaedic problem such as frozen shoulder.

Rigidity is present throughout the range of movement and can be described as ‘lead-pipe’ if smooth or ‘cog-wheel’ if tremor is superimposed. Mild rigidity can be detected by activation, that is by asking the patient to open and close the contralateral hand.

Although tremor is often the presenting feature of PD, it occurs in only 70 per cent of cases. It is typically asymmetrical, starting on one side but spreading to the other as the disease progresses. Tremor present at rest (pill-rolling) is classical of PD, but many patients also have postural tremor (demonstrated by asking patients to hold their arms outstretched and spread the fingers).This postural tremor is often latent and only emerges after a short delay, and tremors on action can also be present.

Postural instability

Postural instability develops as PD progresses, with patients complaining of poor balance and falling. It can often be detected clinically by the ‘pull test’, even early on.The patient stands with feet slightly apart and the clinician stands behind the patients and pulls sharply at both shoulders. The patient’s tendency to fall is observed, but the examiner needs to be ready to catch the patient if necessary.

The diagnosis of Parkinson’s disease remains largely clinical. Supporting features include persisting asymmetry of symptoms, a good therapy response, and the development of therapy-induced involuntary movements (dyskinesia). The diagnosis is supported by an abnormal result from presynaptic dopamine imaging.

4. Possible differential diagnoses

Essential tremor

Tremor is a common symptom, may be physiological, and can be enhanced by stress, certain drugs such as salbutamol, or diseases such as hyperthyroidism.

Management of tremor in primary care can be complex, and most difficulty lies in differentiating PD from essential tremor. In some cases functional imaging can help the diagnosis.

Essential tremor is usually present for months or years, is predominantly an action tremor, and is bilateral with symmetrical symptoms. There is of ten a positive family history, with no associated symptoms, and impr\oves with alcohol.

Treatment options

It is important to explain that it is not Parkinson’s disease, and does not affect life expectancy. Treatment may not be needed or wanted, but propranolol LA 80mg each morning can prove useful, although side-effects can outweigh the benefits. Primidone may also help but should only be used under supervision. Severe or doubtful cases should be referred.

Drug-induced parkinsonism

In epidemiological studies between a third and a half of parkinsonism is caused by medication and may be clinically indistinguishable from idiopathic PD, although a symmetrical presentation is commoner than in idiopathic PD. Neuroleptics are most commonly implicated, but the newer atypical neuroleptics are less likely to induce parkinsonism.

Anti-nausea agents such as prochlorperazine and cinnarizine are other culprits. Domperidone is the only anti-emetic which does not cross the blood-brain barrier and is often co-prescribed when initiating dopamine replacement therapy to reduce nausea, vomiting and postural hypotension. Sodium valproate, tetrabenazine, antidepressants and calcium antagonist are also reported to cause parkinsonism.

Drugs may be the sole cause of the parkinsonism, or may unmask underlying idiopathic PD. If purely drug induced, symptoms regress if the offending drug is stopped, but may persist for months or years. Sometimes it may be difficult to stop the medication or find a suitable alternative, when the severity of the symptoms and the Datient’s wishes should be taken into account.

Functional imaging can distinguish between drug-induced and idiopathic parkinsonism, and is increasingly available.

5. Other related syndromes

Vascular parkinsonism

Cerebrovascular disease can cause parkinsonism. Vascular parkinsonism has been described as classically of sudden onset, and involves the lower body, whereas idiopathic PD involves the arms more than the legs. A shuffling gait and small steps are therefore common. Structural imaging may confirm a multi-infarct state with infarction of the basal ganglia, or indicate small vessel disease that may influence the expression of parkinsonism.

However, cerebrovascular disease and idiopalhic PD may co-exisl and confuse the clinical picture. Functional imaging can then be useful to distinguish a purely vascular picture from neurodegenerative parkinsonism. This is important because neurodegenerative parkinsonism will respond to anti-parkinson therapy, but vascular parkinsonism responds poorly.

Parkinson plus syndromes

Parkinson plus syndromes represent a more widespread degenerative process of postsynaptic as well as presynaptic dopaminergic neurones, and so respond poorly to therapy. They are 10 times less common than idiopathic PD. Progression is faster, with decreased life expectancy.

Red flag signs that point to parkinson plus syndromes include axial rigidity, falls, loss of vertical gaze, dementia, and speech or swallowing problems that suggest a progressive supranuclear palsy. There may also be early autonomie features such as bladder instability and impotence, and cerebellar signs that suggest multiple system atrophy.

Parkinson plus syndromes are relatively rare but respond poorly to therapy and have a worse prognosis.

Many conditions cause parkinsonism. The diagnoses of Parkinson’s disease and parkinsonism are best confirmed by a healthcare professional with a special interest in movement disorders.

Further resources

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