Parkinson’s disease and other akinetic rigid syndromes I

Clinical features

The classical features of Parkinson’s disease are TRAP:

Tremor

Rigidity

Akinesia or bradykinesia (a- = lack of, brady- = slow, kinesia = movement)

Postural instability.

Early symptoms are often subtle. The patient may describe stiffness, difficulty in fine movements, especially writing, fatigue and a feeling of slowing down. Some patients will first notice a tremor. The onset is usually unilateral or may be limited to one limb.

The tremor, occurring in 70% of untreated patients, typically occurs at rest but may occur on sustained posture and mainly affects the hands. It is coarse and slow. The rigidity is usually best appreciated at the elbow and wrist. The increase in tone is not sustained and repeatedly gives, producing the characteristic cogwheeling.

The face is immobile and the skin may appear greasy. There may be a dysarthria, with a monotonous voice that tends to trail off. Fast repeated movements tend to slow up, so-called bradykinesia. This can be tested by asking the patient to drum their fingers on a table or repeatedly bringing index finger and thumb together (Fig. 1). Writing becomes small and spidery (Fig. 2). The posture tends to become stooped and the patient stands with slightly flexed elbows (Fig. 3). On walking there is a loss of arm swing, the steps become shorter and there may be difficulty starting or stopping. The patient may be unsteady or fall on turning. This reflects the loss of postural reflexes; these can be tested by standing behind the patient and gently pulling the patient backwards. This would normally lead to a minor adjustment in posture, but a patient with altered postural reflexes may take multiple steps backwards. In more severe disease, there may be freezing – where the patient cannot start to walk – a form of akinesia. The gait may be festinant, where the patient cannot stop once started.

Fig. 1 Tests for bradykinesia. (a) Ask the patient to tap their fingers together quickly. (b) Ask the patient to twist their hand as if polishing door knobs. With bradykinesia, the movements become smaller and slower – compare the two sides.

Fig. 2 Writing of a patient with Parkinson’s disease.

Fig. 3 Posture in Parkinson’s disease. Note the slight stoop and the position of the right arm.

Later in the disease there may be some altered higher function, sometimes a slowness of thought (bradyphrenia); a proportion, over a quarter, will go on to develop dementia. The frequency is a matter of controversy. A significant alteration in higher function early in the disease raises the possibility of alternative diagnoses (see below).

Drug treatment of Parkinson’s disease produces a range of clinical responses and adverse effects. These are considered in the next section.

Differential diagnosis

In many patients, the diagnosis is straightforward. In other patients, particularly early in the disease, diagnosis can be difficult.

The differential diagnosis depends on the pattern of the presentation. Tremor is one of the most common early symptoms. The main differential diagnosis is with essential tremor (p. 92). Essential tremor is not present when the limb is relaxed and at rest and is usually most prominent on sustained posture or with movement. However, if a patient voluntarily holds the hand in a resting position, a postural tremor may look like a rest tremor. Essential tremor may produce a yes–yes head tremor or titubation, and a trombone tremor of the tongue, features not seen with Parkinson’s disease.

The presentation with unilateral stiffness may be mistaken for a unilateral hemiparesis. The muscle stiffness may suggest muscular or rheumatic diagnoses. The fatigue and weight loss may be interpreted as features of malignancy or, combined with the slowness of thought and deed, as depression.

The gait patterns most commonly mistaken for Parkinson’s disease are the ‘marche à petit pas’ of diffuse cerebrovascular disease and, less frequently, the apraxic gait of normal pressure hydrocephalus (p. 63).

A common, and usually easily identified, cause of Parkinsonism is drug-induced Parkinsonism. This is produced to varying degrees by different dopamine antagonists such as the phenothiazines and other antipsychotics.

In younger patients, Wilson’s disease is a rare but important differential diagnosis (p. 92).

There are a range of syndromes that share several features with Parkinson’s disease, but which have different pathological findings. These have been referred to as ‘Parkinson’s plus’ syndromes. These are all relatively rare. However, together there are a significant number of affected patients; indeed, in a series of 100 postmortem examinations of patients considered to have Parkinson’s disease, 20% were found to have other forms of Parkinsonism. The most common such syndromes are (i) multisystem atrophy, where there is autonomic failure, cerebellar signs and signs of upper motor neurone involvement, and (ii) progressive supranuclear palsy (or Steele–Richardson syndrome), where there is a supranuclear palsy (reduced ability to move the eyes voluntarily, with preserved movements on doll’s head testing; p. 19), prominent loss of postural reflexes and dysarthria. Both these syndromes tend to respond poorly to treatment and have a worse prognosis than idiopathic Parkinson’s disease. In initially assessing someone with suspected Parkinson’s disease it is therefore worthwhile testing eye movements carefully and measuring standing and lying blood pressure. In patients with a significant loss of higher function and prominent hallucinations on low-dose therapy, Lewy body dementia should be considered (p. 55). Given the common pathology, this probably reflects a different clinical manifestation of the same underlying disease.

Pathology and pathogenesis

The characteristic pathological feature of Parkinson’s disease is the loss of the pigmented dopaminergic cells of the zona compacta of the substantia nigra. In some of the remaining neurones there are eosinophilic cytoplasmic inclusions called Lewy bodies which are made up of alpha-synuclein (Fig. 4). Similar changes are seen elsewhere in the brain stem, such as the locus ceruleus and the dorsal motor nucleus of the vagus. The same pathology is seen through the cortex in Lewy body dementia.

Fig. 4 Lewy body in substantia nigra.

The cause of Parkinson’s disease is not known. There are a few clues.

In the early part of this century, there was an epidemic of encephalitis lethargica (EL), thought to be a viral infection. Following recovery, patients developed Parkinsonism either directly or over 20 years later. In some modern cases of EL, anti-basal ganglia antibodies have been found. More recently, a designer drug – MPTP – has been found to cause Parkinsonism in humans and other primates. Pathologically, MPTP-induced Parkinsonism mimics idiopathic Parkinson’s disease very closely, and even Lewy bodies are found. These observations suggest there may be an environmental factor in the aetiology of the disease.

There are suggestions that there may be genetic factors, particularly in the mitochondrial function, that make some individuals more likely to develop Parkinson’s disease. There are several rare inherited forms, which usually have younger onset and sometimes subtle differences in clinical presentation, including defects of Parkin and alpha-synuclein.

Investigations

There are no specific diagnostic investigations for Parkinson’s disease, which is a clinical diagnosis. A diagnostic test based on the response to apomorphine, a dopamine agonist, has been used with limited effectiveness.

Where diagnostic uncertainty exists, investigation is aimed at eliminating alternative diagnoses, for example CT or MRI scanning to look for normal pressure hydrocephalus or small vessel disease. Some investigators have tried to use the response to certain drugs as a diagnostic test, with limited success (see next section). Positron emission tomography using radiolabelled levodopa is a research technique that may be useful. An isotope ‘DAT’ scan can show deficits of dopaminergic pathways and help distinguish between Parkinsonism and essential tremor or drug-induced Parkinsonsim, but not differentiate between different causes of degenerative Parkinsonism.

Parkinson’s disease and other akinetic rigid syndromes I

Parkinsonism is the clinical syndrome of tremor, rigidity, bradykinesia and postural instability.

The most common cause of Parkinsonism is idiopathic Parkinson’s disease.

The characteristic neuropathological feature of Parkinson’s disease is a loss of pigmented dopaminergic cells from the substantia nigra.