Examine this patient.



· Tremor: usually unilateral at onset; usually starts in upper limbs. Also seen in the legs and jaws.

· Rigidity: ask about history of falls, poor balance, pain and muscle stiffness.

· Poverty of movement: ask about drooling of saliva, difficulty in writing (micro-graphia), difficulty in turning in bed and change in

voice (softness of voice).

· Family history of disease.

· History of encephalitis.

· History of exposure to manganese dust, carbon disulphide, or carbon monoxide.

· Use of MTP for recreational purposes.

· Elicit a drug history, particularly regarding neuroleptics (reserpine, metoclopramide).


Usually florid cases are seen in the examination and the striking abnormalities are:

· An expressionless or 'mask-like' face (fixed stare, infrequent blinking and ironed-out wrinkles).

· Drooling of saliva.

· Resting or pill-rolling movement (most common in the distal extremities).

Proceed as follows:

· Comment on the expressionless face, pill-rolling movement and drooling of saliva so that the examiner knows that you have

observed these abnormalities. Elicit bradykinesia by asking the patient to touch her thumb with each finger in turn.

· Examine the tone, in particular at the wrist for cog-wheel rigidity.

· Proceed to do the glabellar tap. Tap the forehead just above the bridge of the nose repeatedly (about twice per second): in

normal subjects the blinking will stop whereas the patient with Parkinson's disease continues to blink - referred to as Myerson's

sign. It must be remembered that this sign is unreliable.

· Ask the patient to walk, and comment on the paucity of movement including the absence of arm swing and festinating gait (the

patient walks with a stooped posture as if trying to catch up with her centre of gravity). The feet may scrape the floor in taking

steps so the patient trips easily (be prepared to prevent the patient from falling when examining the gait).

· Tell the examiner that you would like to:

-Ask the patient a few questions with a view to assessing her speech.

-Assess handwriting (tremulous and small, micrographia).

· Tell the examiner that you would like to look for:

-Postural hypotension (Shy-Drager syndrome, L-dopa treatment).

-Impaired vertical gaze (Steele-Richardson-Olzewski syndrome).

· Seborrhoea.

Note. The diagnosis of Parkinson's disease is entirely clinical but the results of certain investigations may help in recognizing

alternative causes for parkinsonism.


This patient has features of Parkinson's disease (lesion) which is due to long-standing use of phenothiazines (aetiology). The patient

is severely disabled by the bradykinesia (functional status).


What comprises Parkinson's disease?

Upper body dyskinesia

This must be present - it is a symptom complex containing many of the following features:

· Slowness of movement (bradykinesia).

· Poverty of movement (mask-like facies, diminished arm swing).

· Difficulty in initiating movement.

· Diminished amplitude of repetitive alternative movement.

· Inordinate difficulty in accomplishing some simultaneous or sequential motor acts.


This is usually but not always present:

· Leadpipe rigidity, where the increase in tone is equal in flexors and extensors of all four limbs but slightly more in flexors,

resulting in a part flexed 'simian' posture.

· Cog-wheel rigidity is due to superimposed or underlying tremor.

Postural instability

Usually a late feature.


Absent in about one third of patients with Parkinson's disease at presentation and throughout its course in some.

· Resting, 3-5 Hz pill, pronation and supination rolling tremor of the upper limb.

· Tremor is intermittent (can usually be brought about by getting the subject to count backwards with the eyes closed and hands

dangling over the armrests of the seat).

· The tremor is intensified by emotion or stress and disappears during sleep.

· The legs, head and jaw may shake as well. Jaw tremor is rare but is most distressing; the teeth may pound together until they

become unbearably painful.


What are the causes of Parkinson's disease?

· True parkinsonism:

-Idiopathic (due to degeneration of the substantia nigra) - also known as

Parkinson's disease.

-Drug-induced (chlorpromazine, metaclopramide, prochlorperazine).

- Anoxic brain damage such as cardiac arrest, exposure to manganese and carbon monoxide.

-Postencephalitic - as a result of encephalitis lethargica or von Economo's


- 1-Methyl-4-phenyl- 1,2,3,6-tetrahydropyridine toxicity - seen in drug abusers. -Multiple system atrophy. -Progressive supranuclear


- Familial.

-Mutation of the alpha-synuclein gene or linkage to a region on chromosome 2.

· Pseudoparkinsonism:

-Essential tremor.

-Atherosclerotic (vascular) pseudoparkinsonism (mention that in the past atherosclerosis was thought to be a cause of Parkinson's

disease but this is no longer accepted as a cause).

· Hemiparkinsonism (presenting feature of a progressive space-occupying lesion).

What are the pathological changes in Parkinson's disease?

The most typical pathological hallmarks of Parkinson's disease are:

· Neuronal loss with depigmentation of the substantia nigra.

· Lewy bodies, which are eosinophilic cytoplasmic inclusions in neurons con-sisting of aggregates of normal filaments.

The following associations have been made with clinical features and pathological changes:

What is the mental status of patients with Parkinson's disease?

· In the initial stages, intellect and senses are usually preserved. Many patients have some intellectual deterioration - a slowness

of thought and of memory retrieval (bradyphrenia), and subtle personality changes.

· Global dementia may develop in one fifth of patients.

· Depression occurs in one third of patients.

· Acute confusion can be precipitated by drug therapy.

Note. Parkinson's disease must be kept in mind in elderly patients presenting with a history of frequent falls.

What is the difference between rigidity, spasticity and gegenhalten?

· Rigidity indicates increased tone affecting opposing muscle groups equally and is present throughout the range of passive

movement. When smooth it is called 'leadpipe' rigidity, and when intermittent is termed 'cog-wheel' rigidity. It is common in

extrapyramidal syndromes, Wilson's disease and Creutzfeld-Jakob disease.

· Spasticity of the clasp-knife type is characterized by increased tone which is maximal at the beginning of movement and

suddenly decreases as passive move-ment is continued. It occurs chiefly in the flexors of the upper limb and extensors of the

lower limb (antigravity muscles).

· Gegenhalten, or paratonia, is where the increased muscle tone varies and becomes worse the more the patient tries to relax.

What do you understand by the 'wheelchair sign' in Parkinson's disease?

Patients with advanced disease and 'on-off' motor fluctuations require a wheelchair when 'off' and when 'on' are seen to walk about

(sometimes pushing the chair!). These patients are rarely permanently wheelchair-bound; in contrast, those who never leave their

wheelchair usually do not have Parkinson's disease.

What is the role of protein diets in patients who have episodes of sudden and substantial loss of mobility?

High-protein diets should be avoided in these patients, because a large influx of dietary amino acids can interfere with the transport

of L-dopa into the brain (N Engl J Med 1967; 276: 374-9).

How is the severity of Parkinson's disease graded?

The Hoehn-Yahr staging grades Parkinson's disease into five stages:

· Newly diagnosed disease - Stage I.

· Moderately severe disease - Stages II and III.

· Advanced disease - Stages IV and V.

How would you manage a patient with Parkinson's disease?

Symptomatic therapy:

· When tremor is the main problem - anticholinergic drugs such as trihexyphenidyl, benzatropine, biperiden, cycrimine,

procyclidine, phenoxene, orphenadrine.

· When bradykinesia is the main problem - [-dopa with a decarboxylase inhibitor such as carbidopa or benserazide. Other drugs

include amantadine and synthetic dopamine agonists (bromocriptine, pergolide). In early Parkinson's disease levodopa-sparing

agents may be desirable to prevent dyskinesia. Bromocriptine alone improves about 50% of patients during the first year of

treatment but there is a gradual loss thereafter with only 10% responding at 5 years; other dopamine agonists have similar

effects. Ropinirole and pramipexole are dopamine agonists that are not derived from ergot and are more selective, have fewer

adverse effects and tend to produce greater therapeutic response which is longer-lasting than that of the older ergot

derivatives. In the elderly, L-dopa is the first line of treatment as it has the best therapeutic index.

Protective therapy:

Selegiline, a monoamine oxidase B inhibitor, is said to retard the progression of early Parkinson's disease (N Engl J Med 1993; 328:

176-83); it delays the need for levodopa by a mean of 8 months. One study found increased mortality in patients taking levodopa in

combination with selegiline (BMJ 1995; 311: 1602-7) but a subsequent study has refuted this finding.

What is the role of ropinirole in early Parkinson's disease?

A 5-year study shows that the early use of the dopamine D2 receptor agonist ropinirole significantly reduces the risk of dyskinesia in

patients with Parkinson's disease. When all patients randomly assigned to ropinirole were compared with those randomly assigned

to levodopa, the risk of dyskinesia was lower by a factor of almost three in the ropiimolc group. The overall incidence of dyskinesia at

5 years was 20% in the ropinirole group compared to 45% in the levodopa group. This difference was even more striking among

patients who did not require supplementary levodopa (rates of dyskinesia: ropinirole group, 5%; levodopa group, 36%). The reason

why the early use of ropinirole reduced the risk of dyskinesia remains unclear. The early use of ropinirole did not reduce the

occurrence of wearing-off and freezing during walking to the same extent as it did the occurrence of dyskinesia. However, delaying

treatment with levodopa to prevent dyskinesia can be justified only if the underlying symptoms of Parkinson's disease are sufficiently

controlled (N Engl J Med 2000; 342: 1484-91).

In which condition is L-dopa absolutely contraindicated?


What do you know about 'drug holidays' in levodopa therapy?

Drug holidays (i.e. discontinuation of therapy) were previously claimed to enhance the efficacy of treatment when it was resumed;

this is now known to be dangerous (deaths have occurred) and of doubtful value.

What do you know about dopamine receptors?

At least four types of receptors have been reported: D1 and D2 are the two major families of dopamine receptors. For

neurotransmission to occur, a complex con-sisting of a dopamine receptor and G protein (guanine nucleotide-binding protein) must

be formed. This complex then usually couples to the enzyme adenylate cyclase which controls the formation of the second

messenger, cyclic AMP. Alteration of the second messenger leads to a cascade of events that ultimately determines the transfer of

information between nerve cells. The D2A receptor is involved in the thera-peutic response elicited by dopaminergic agonists in

parkinsonism, although the mechanism at the physiological level is not clear. The role of the D1 family is unclear; it is not certain

whether the activation of these receptors leads to useful effects (i.e. reduction of parkinsonian deficits), undesirable effects (e.g.

dyskinesia), or both. Bromocriptine, pergolide and lisuride all stimulate D2 receptors, whereas bromocriptine and lisuride are D1

receptor antagonists and pergolide is a D1 receptor agonist.

Mention some newer drugs used in the treatment of Parkinson's disease.

· Dopamine antagonists: cabergoline, ropinirole, pramipexole.

· lnhibitors of catechol O-methyltransferase (COMT): entacapone, tolcapone. COMT inhibitors increase 'on' time and reduce the

duration of the 'off' time and thus allow reduction of the daily dose of L-dopa.

· Inhibitors of glutamate receptors: CPP (3-(2-carboxy-piprazin-4-yl)propyl-I-phosphonate), lamotrigine.

· GM-1 ganglioside: when monkeys were treated with this drug from cow's brain their motor function was returned to normal.

What is the role of fetal tissue in Parkinson's disease?

Parkinson's disease is characterized by loss of midbrain dopamine neurons that innervate the caudate and putamen. Patients tend

to have a reduced response to levodopa after 5-20 years of therapy, with 'on-off' fluctuations consisting of dyskinesia alternating with

immobility. Animal experiments have suggested that

fetaldopaminergic neurons can survive transplantation and restore neurological function. Trials are underway to determine whether

fetal grafts can improve motor function in patients with Parkinson's disease. Fetal ventral mesencephalic tissue is implanted in the

patient's postcommissural putamen (N Engl J Med 1995; 332: I 118-24).

What is the role of thalamotomy in Parkinson's disease?

Thalamotomy used to be the main treatment until 1950, but with the introduction of levodopa it became less popular. However, there

has been a revival of stereotactic surgery prompted by the failure of levodopa in four main aspects: in severe tremor,

levodopa-induced dyskinesia, advanced Parkinson's disease and akinetic-rigid syndromes (BMJ 1998; 316:1259 60). Four types of

stereotactic surgery are practised:

· Thalamotomy for intractable tremor, where a radiofrequency lesion is placed in the venterointermediate nucleus (VIM) of the

thalamus. It is unsuitable for bilateral tremor as bilateral thalamotomy tends to cause impairment of speech.

· Thalamic stimulation with a fine electrode in the VIM nucleus and a pacemaker inserted under the skin on the chest. This

relieves tremor and can be performed bilaterally. Neither procedure improves akinesia, the most disabling aspect of

Parkinson's disease.

· Deep-brain stimulation of the globus pallidus and subthalamic nucleus may result in striking improvements in parkinsonism and

dyskinesia, resulting in large reductions of levodopa dose and thus improvements in levodopa-induced dyskinesias

(Lancet 1995; 345: 91-5).

· Unilateral posteroventral medial pallidotomy - ameliorates contralateral parkinsonian symptoms and medication-related

dyskinesia and is sustained for up to 5 1/2, years. Improvements in ipsilateral and axial symptoms are not sustained and many

patients undergo a second contralateral procedure (N Engl J Med 2000; 342: 1708-14).

Note. Patients with dementia and hallucinations tolerate all surgical procedures poorly and any benefit in patients with rapidly

progressive parkinsonism is likely to be short lived.

What are Parkinson plus syndromes?

Some patients have other neurological deficits in addition to Parkinson's disease. Examples of these so-called 'Parkinson plus

syndromes' are:

· Steele-Richardson-Olszewski disease (akinesia, axial rigidity of the neck, bradyphrenia, supranuclear palsy).

· Multiple system atrophy. Olivopontocerebellar degeneration. Strionigral degeneration.

Progressive autonomic failure (Shy Drager syndrome).

· Basal ganglia calcification.

What is tardive dyskinesia?

Tardive dyskinesia is seen in patients taking neuroleptics. Its manifestations are orofacial dyskinesia such as smacking, chewing lip

movements, discrete dystonia or choreiform movements and, rarely, rocking movements. Withdrawal of the

offendingdrug will improve these symptoms over a period of 3-4 years, except in a small minority of patients.

What is the drug of choice when these patients develop psychosis and delusions?


Mention some heredo-degenerative parkinsonian disorders.

· Hallervorden-Spatz disease: autosomal recessive; patients also have dementia, dystonia, choreoathetosis, retinitis pigmentosa.

There is increased iron deposition and increased cysteine in the globus pallidus.

· Fahr's disease or familial basal ganglia calcification: patients also have chorea, dementia and palilalia.

· Olivopontocerebellar and spinocerebellar degenerations: autosomal dominant, associated cerebellar ataxia and retinitis


James Parkinson (1755-1824) first reported six cases of this syndrome in 1817 (at the age of 62 yea rs).

J.C. Steele, J.C. Richardson and J. Olszewski were all US neurologists.

K. von Economo (1876-1931), an Australian neurologist, also wrote on Wilson's disease.

C.D. Marsden, contemporary Professor of Neurology, National Hospital, Queen's

Square, London; his chief interest is Parkinson's disease and movement disorders.