Figure 14.1 Parkinson’s disease

Causes

The underlying cause of most cases of PD is not known and the term idiopathic PD is used to describe the disease. Many of the clinical features of PD can result from a variety of other conditions including vascular disease, drugs, neurodegeneration and rarely encephalitis. When this happens the condition is called parkinsonism rather than PD.

Pathophysiology

The classic features of PD are a result of degeneration of dopamine secreting substantia nigra neurones which project from the brainstem via the striatal neurones to the basal ganglia. This leads to a loss of the characteristic black pigment and the remaining dopamine secreting cells may show Lewy inclusion bodies. Clinical disease starts when the substantia nigra cell loss is >50% and striatal dopamine levels are reduced by >80%. Recent studies have shown however that the pathology in PD is more widespread and occurring much earlier than originally believed.

Clinical Diagnosis

The initial presentation of PD is often mild with up to two thirds of patients presenting at onset with an asymmetrical rest tremor, affecting one limb or difficulty with fine repetitive motor movements e.g. doing buttons or tying shoelaces. If the dominant hand is involved then writing as it crosses the page becomes noticeably smaller. The tremor is characteristically coarse, regular, occurs at rest and disappears initially on intent such as holding a cup. The tremor becomes more noticeable when the person is distracted or whilst walking. It mostly affects the limbs but can affect any part of the body including the head, chin and tongue. The typical resting tremor is a rhythmical movement of the thumb on the hand called pill rolling. This is usually accompanied by increasing bradykinesia or slowing down of movements e.g. carrying out the activities of daily living (ADL) or walking. There may be a lack of spontaneous movement and facial animation (expressionless face), (Fig. 14.1 & 2) and the blink rate is decreased.

On neurological examination, there is rigidity or stiffness of the limbs which results in increased tone throughout the full range of passive movement. This is called lead pipe rigidity or cog wheel rigidity if a tremor intrudes. Gait disturbances are usually mild in the first few years. Then posture becomes stooped and the gait is semi-flexed and shuffling with reduced arm swing and difficulty starting or stopping walking and turning (Fig. 14.1). There is a loss of postural righting reflexes which may lead to falls. The patient’s voice may become quiet and muffled or hypophonic. Smell has recently been shown to be decreased or absent, sometimes for years before the onset of the other main symptoms.

Diagnosis

The diagnosis of PD is made clinically and laboratory investigations and standard CT/MRI neuroimaging are usually not helpful. The diagnosis is made if there are at least two of the four major clinical features present (Table 14.1) and is supported if there is a rapid clinical response to treatment with dopaminergic drugs.

Key points

Treatment

Levodopa

Early Parkinson’s disease does not require any drug treatment. The main aim of treatment of PD (Table 14.2) is to reduce motor disability. Levodopa (L-dopa) does this by replacing the missing dopamine which helps to relieve the symptoms but does not prevent disease progression. L-dopa is given orally and this is later converted into dopamine in the brain by the enzyme dopa decarboxylase which comes from the remaining substantia nigra neurones. In order to prevent conversion of the inactive L-dopa to dopamine in the peripheral circulation L-dopa is given in combination with a dopa decarboxylase inhibitor, either carbidopa or benserazide. Because the dopa decarboxylase inhibitors do not cross the blood brain barrier, this will result in increased dopamine levels in the brain without similar increases in the peripheral blood. This also reduces the nausea that results from peripheral dopamine. The overall aim is to keep the daily maintenance dose of L-dopa as low as possible in order to maintain good motor function and yet reduce any long term motor complications.

Generic preparations of these are available as carbidopa/levodopa and benserazide/levodopa. Treatment is started slowly with gradual increases in dosages. The usual starting dose is in 25/100 mg tabs, either ½ or 1 tab taken three times daily taken initially with meals. The main acute side effects are nausea, vomiting, hypotension, confusion and hallucinations. These often resolve spontaneously or with concurrent administration of an antiemetic e.g. domperidone 10-20 mg tds for the first 4 weeks of treatment. If the initial response is inadequate, then the L-dopa dose can be increased slowly every 4-6 weeks by ½ tab tds to a usual maintenance dose of 25/250 mg tabs 1 tds. However, any necessary increases in dosage (½ tab tds) can be brought forward to weekly if it is clinically indicated and the patient tolerates it. Later, usually after years L-dopa may have to be given more frequently (changing from 8 to 6 to 4 to 3 hourly as necessary). A controlled release (CR) preparation may be helpful to be taken at night because of a longer duration of effect. Most patients respond very well initially but larger doses are required as the disease progresses.

In the later stages, the duration of response to each dose may shorten (the wearing off effect) and motor fluctuations may occur (the on–off phenomenon) and involuntary motor movements or dyskinesia are likely. The response to treatment may then become unpredictable and any sudden reduction or withdrawal of L-dopa is associated with deterioration.

Other drug treatments

The L-dopa/decarboxylase inhibitor combinations are the most effective symptomatic treatment for PD. Other treatments include dopamine agonists, catechol-O-methyltransferase inhibitors (COMT), NMDA antagonists, monoamine oxidase B inhibitors (MOB) and anticholinergics (Table 14.3). In general, these treatments are added on when the response to L-dopa preparations has decreased or failed. The dopamine agonists may be used early on either as first line treatment alone or in combination with L-dopa especially in younger onset PD patients. The use of dopamine agonists is associated with less dyskinesia after 3-5 years of therapy. They act postsynaptically and therefore mimic the effects of dopamine in the basal ganglia. The dopamine agonists fall into two main groups: the ergot derived group which includes bromocriptine and cabergoline and the non ergot derived group which includes ropinirole among others.

The side effect profiles are similar to dopamine except that ergotism may occur in the first group. Ergotism is a serious limitation to their long-term use as up to 3% of treated patients develop pulmonary or less frequently retroperitoneal fibrosis. The newer non-ergot agonists have been associated with hypersomnolence and impulse control disorders, including, overeating, excessive shopping, gambling and hypersexuality. Their use is contraindicated in pre-existing vascular, heart and lung disease. Amantadine is considered a useful drug to start treatment for the first 6-12 months. It has relatively few side effects but only a modest effect on motor symptoms and a limited duration of action. It is effective however, for the dyskinesia seen as a side effect of levodopa. Other useful add on drugs include the COMT inhibitor entacapone and the MOB inhibitor selegiline. These inhibit the breakdown of dopamine and prolong its activity. Their use is mainly indicated in late disease for motor fluctuations and decreasing response to L-dopa. The side effects are largely similar to levodopa. The use of anticholinergics (benzhexol) may be helpful mainly in tremor dominant disease in younger patients. The drug treatment of PD is summarised in the table below.

Non drug treatments

Physiotherapy is helpful to many patients with PD and their quality of life can be helped by the provision of simple aids to the activities of daily living. Surgical treatment is helpful when drug treatment has failed or is intolerable usually in selected younger patients. Surgery usually involves either a thalamotomy or pallidotomy or deep brain stimulation of the globus pallidus or subthalamic nucleus and accounts of these are available in larger textbooks.

Course

PD progresses slowly over many years. There is no cure and progression is variable with many patients functioning well despite the presence of the disease for years. Drug treatment is necessary for patients with motor disability and can be effective and long-lasting. As the disease progresses immobility, pain, sleep disturbance, depression and dementia (40-50%) are all very common and these may require separate management and treatment. The deterioration is slow and variable with death occurring on average 10-15 years after onset.

Key points

OTHER EXTRAPYRAMIDAL SYNDROMES

Parkinson plus syndromes

There are other uncommon or rare neurological disorders with features of parkinsonism which are briefly mentioned here. These are all disorders characterized by clinical features of parkinsonism in addition to other neurological findings more typical of the specific underlying neurological disorder. These are multiple system atrophy (MSA), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), vascular parkinsonism and dementia with Lewy bodies. MSA is characterized by parkinsonism coupled with cerebellar and/or autonomic dysfunction (hypotension) and partial initial response to L-dopa. PSP is characterized by akinetic rigidity, late onset dementia and a slowing or failure of voluntary vertical and eventually all eye movements. CBD is characterized by asymmetric bradykinesia, rigidity and limb apraxia. Vascular parkinsonism involves mainly the lower half of the body with a prominent gait disorder. Dementia with Lewy bodies is characterized by dementia, rigidity and hallucinations. A characteristic of all these disorders is either a reduced, nonsustained or absent response to levodopa treatment. Management is mostly symptomatic and supportive.

Key points

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