Epidemiology

In the UK:

• ▶. prevalence about 1/800, annual incidence 1/8000

• ▶. 1% of people over the age of 65 years are affected

• ▶. a general practitioner will have three to four patients at any one time

• ▶. median age of onset is 60 years, with a slight male preponderance

• ▶. disease onset to death is about 15 years, twice the number of observed to expected deaths (standardised mortality ratio 2:1).

The disorder is no respecter of race or creed Literary and historical precedents to Parkinson's seminal description suggest it is unlikely to be a post-industrial disease. In common with other neurodegenerative diseases, increasing age is the major risk factor although 15% of cases present before the age of 45 years and the incidence may decrease somewhat in the ninth decade of life. Genetic factors are now considered to significantly increase risk.

Habitual non-cigarette smokers are twice as likely to develop the illness as smokers and there may also be a mildly increased risk to men who do not take any caffeine, perhaps related to dopamine's role in reward pathways, rather than due to a protective effect of nicotine or coffee. Loose associations with rural living, middle age, obesity and lack of exercise, well water ingestion and pesticide exposure have also been reported. Environmental toxins such as 1-methyl-4 phenyl 1,2,3,6 tetrahydropyridine, manganese, cyanide and toluene can produce a similar but not identical clinical picture.

Making the diagnosis

The diagnosis of parkinsonism hinges on the presence of bradykinesia (akinesia and hypokinesia are often used synonymously with bradykinesia). This may be apparent as soon as a patient enters the consulting room but in other cases early diagnosis depends on scrupulous history taking and a detailed neurological examination. A coarse pill rolling rest tremor, muscular rigidity and postural abnormalities are commonly associated physical signs which support the diagnosis. Parkinson's disease is the commonest cause of bradykinesia but there is a long list of secondary and Parkinson-plus syndromes (table 1). Symptoms come on so insidiously that patients and their family may understandably attribute the early subtle changes to chronic fatigue, depression or ageing, even when a change in demeanour, posture and speed of movement is immediately evident to strangers.

Bradykinesia is responsible for the common presenting complaints of difficulty fastening buttons, cleaning teeth, deterioration in handwriting, increased number of typing errors, weakness of one leg, and reduction in volume and slowing of speech. To elicit bradykinesia, a series of distinct motor tasks should be carried out, making each movement as large and as fast as possible, and continued for about 20 s:

• ▶. touch each finger onto the thumb in turn

• ▶. tap the index finger on to the thumb

• ▶. carry out piano playing movements

• ▶. tap the foot on the floor.

The characteristic abnormalities of delayed initiation of movement, associated with a progressive motor decrement on repetition, may occur only with one of these tasks. The patient should then be asked to write four lines of long hand in the case notes. It is common for the script in Parkinson's disease to slope upwards and the writing is crabbed and becomes progressively smaller and smaller. Semiquantitative tapping and pegboard tests may also be helpful.

Slowness and awkwardness in at least one of these tasks strongly suggests parkinsonism but pyramidal and cerebellar lesions and the slowness associated with severe retarded depression and obsessive–compulsive disorder need to be distinguished. Bradykinesia can also be extremely difficult to elicit in a limb affected by severe tremor; a helpful supporting feature here is that patients with Parkinson's disease often hold their hand in a fixed cataleptic attitude after completing each motor task rather than resuming a normal relaxed posture.

Tremor. A slow coarse pill rolling rest tremor of one hand or leg is the commonest neurological presenting symptom of Parkinson's disease but is insufficient alone to make the diagnosis without the presence of bradykinesia. Holmes tremor, severe essential tremor and dystonic and neuropathic tremors all may have a prominent rest component, while a postural and kinetic tremor is not infrequent in Parkinson's disease. Although most patients with Parkinson's disease have a tremor at some stage of their disease, it can be very mild and unobtrusive, while in others it can be severe, continuous, disabling and involve all four limbs, the lips and the jaw.

There are some rare cases of familial alcohol responsive essential tremor which after decades of stability evolve gradually into full blown Parkinson's disease. Some are erroneously given the label benign tremulous Parkinson's disease.

Rigidity. Muscular stiffness with aching discomfort may be an early complaint. Uniform resistance to passive stretch in a relaxed patient at the elbow, shoulder, knee or neck (ie, lead pipe rigidity) is the third cardinal sign of parkinsonism. A ratchety jerky resistance may also be elicited at the wrist (cogwheel phenomenon) and is a supportive finding. In contrast, spasticity is revealed by initial increased resistance to stretch followed by a sudden give way (clasp knife rigidity) and gegenhalten (an opposing voluntary resistance).

The prodromal phase

Once the diagnosis of Parkinson's disease has been made, about a quarter of patients will describe a constellation of non-specific symptoms, which with hindsight may have been early manifestations of the disease:

• ▶. A severe depressive illness can usher in the motor symptoms although a misinterpretation of the early signs of akinesia as depression is a catch.

• ▶. Profound fatigue and slight poverty of thought and mental inflexibility are striking in some instances.

• ▶. Autonomic symptoms including a defective thermostat (profound drenching sweats in cold weather), disturbances of colonic mobility and dribbling of saliva onto the pillow at night are also well recognised, as is erectile failure.

• ▶. Frozen shoulder and chronic low back pain are common rheumatological presentations, probably as a consequence of immobility and postural abnormalities.

• ▶. Idiopathic REM sleep behaviour disorder (nightmares, shouting out and thrashing violently about in sleep and falling out of bed) may be a prodromal syndrome but is not specific. A bed partner needs to be interviewed about sleep patterns to evaluate the severity of this disturbance.

• ▶. Hyposmia may be a harbinger of Parkinson's disease. Formal testing of smell with either the University of Pennsylvania smell tests kit or Sniffin Sticks pens is needed to detect it. This seems to be much more common in Parkinson's disease than the other parkinsonian syndromes and essential tremor, so although not specific may help in distinguishing Parkinson's disease.

Many of these symptoms have been considered ‘pre-motor’ and support Braak's hypothesis that the disease begins in the peripheral autonomic system, olfactory bulb and the dorsal nucleus of the vagus and then spreads rostrally up the brainstem by a prion-like mechanism before finally invading the cerebral cortex. However, the detection of subtle motor abnormalities preceding the clinical diagnosis by over a decade in some observant young onset patients (eg, Ray Kennedy the England, Arsenal and Liverpool football player) suggests caution in assuming that autonomic and olfactory signs really do occur first. The disease process, however, almost certainly begins many years before the emergence of bradykinesia, rigidity and rest tremor.

The telling of the diagnosis

This must be unhurried, truthful and provide real hope. Patients need to be reassured that Parkinson's disease is treatable and no longer a death sentence. Optimistic examples of what can be achieved are helpful and young patients particularly may benefit from being put in touch with an articulate and positive patient of similar age who is doing well, either via the Parkinson's Disease Society, Cure Parkinson's Trust, or after prior consent.

Confirming the diagnosis

There are no mandatory laboratory or imaging investigations in the workup of parkinsonism; the diagnosis can be made with confidence in most cases on clinical grounds alone.

Most patients with Parkinson's disease have a sustained excellent response to dopaminergic therapy but in the early stages of disease it may be difficult to convincingly demonstrate improvement. A baseline Unified Parkinson's Disease Rating Scale parts 2 and 3 repeated again at 3 months may be useful in determining whether dopaminergic responsiveness has actually occurred. If doubt remains, the dose of medication should be doubled and a further review carried out after a month. If there is still no tangible subjective benefit on 750 mg/day levodopa or less than a 2 point change on the Unified Parkinson's Disease Rating Scale then a formal acute levodopa challenge using 250 mg dispersible levodopa/benserazide should be carried out using finger tapping and timed walking tests at baseline and then again at 1 and 2 h. Before this challenge, all antiparkinsonian medication should be stopped overnight and if the patient has experienced nausea or dizziness on long term levodopa, domperidone 30 mg three times daily should be given for 24 h.

In patients with a predominantly bradykinetic–rigid syndrome who have failed to improve with dopaminergic treatment, an MR brain scan should be ordered looking for changes suggestive of:

• ▶. MSA (pontine and cerebellar atrophy, pontine hot cross bun sign and hypointense lesions with hyperintense rim in the putamen on axial T2 sequences).

• ▶. PSP (midbrain and superior cerebellar peduncle atrophy).

• ▶. Vascular parkinsonism (severe subcortical white matter ischaemia and striatocapsular infarcts).

• ▶. Rarer causes of secondary parkinsonism (paramagnetic signals in the basal ganglia).

In predominantly tremulous patients, a dopamine transporter single photon emission computed tomography (DAT) scan may be helpful; absence of nigrostriatal dopaminergic degeneration effectively excludes Parkinson's disease but there are problems of standardisation and interpretation.

Rarities not to be missed

There are a small group of rare causes of atypical and secondary parkinsonism where MRI and other investigations may provide the diagnosis.

• ▶. The most important are supratentorial meningiomas and communicating hydrocephalus because both are potentially surgically remediable.

• ▶. The eye of the tiger sign on MRI (T2 weighted star sequence imaging shows areas of hyperintensity surrounded by a larger area of hyperintensity in the medial globus pallidus) may point to Hallervorden–Spatz syndrome (PANK-2 mutation).

• ▶. The middle cerebellar peduncle sign on MRI (increased T2 signal in the white matter of the middle cerebellar peduncle) in a patient with tremor, ataxia and parkinsonism points to the fragile X premutation, particularly if the patient is male and there is a family history of mental retardation in a grandchild.

• ▶. Wilson's disease can present with parkinsonism in adolescence or young adult life but this is much rarer than either the dystonic or pseudosclerotic forms. These cases usually have associated neuropsychiatric problems, a Kayser–Fleischer ring visible with a hand lens on the back of the cornea, and a poor or absent response to levodopa. The diagnosis is confirmed by a very low serum caeruloplasmin and if doubt remains by a 24 h urinary copper collection, MR brain scan and liver biopsy to measure copper levels.

• ▶. Dopa responsive dystonia may sometimes have parkinsonian features and presents in young adults as well as in children. There are a number of different mutations of enzymes involved in catecholamine metabolism, including GTP cyclohydrolase, tyrosine hydroxylase and sepiapterin reductase. Useful investigations include a DAT scan, oral phenylalanine loading test, blood and spinal fluid pterin levels, and genetic testing.

• ▶. Ephedrone toxicity should be considered in young Eastern European men who present with the subacute onset of bradykinesia, severe dysarthria, a cock-like walk due to dystonia and severe postural instability with falls backwards. The repeated chronic intravenous use of methcathinone (Ephedrone) a psychostimulant prepared illicitly from the nasal decongestant pseudoephedrine (Sudafed), potassium permanganate and vinegar leads to the clinical and radiological changes of chronic manganism and has become a significant public health hazard in the former Eastern bloc. Diagnosis is supported by: hyperintense signals on T1 MR sequences in the pallidum, nigra reticularis and subthalamic nucleus with lesser involvement in the putamen and dentate nucleus; measurement of blood and pubic hair manganese; normal DAT scan; and admission of ephedrone abuse. Discontinuation of use does not always lead to improvement even when the scan appearances improve; there is an unfavourable prognosis for full recovery. Although methcathinone is used as a ‘legal high’ in the UK as a designer drug known on the street as miaou-miaou, it is not normally prepared with permanganate.

Management

Although the dopamine miracle of 40 years ago has proved to be something of a false dawn, levodopa remains the most significant and important landmark in the therapeutics of neurodegenerative disease. An illness that once led to severe physical handicap and a markedly reduced life expectancy can now be adequately controlled for more than 20 years in many patients. There has, however, been an increasing recognition that although bradykinesia, rigidity, tremor and postural instability are responsible for a great deal of physical handicap, associated symptoms such as depression, pain, insomnia and constipation may also contribute to a reduced quality of life. Fortunately, symptomatic treatments are available for many of these non-motor symptoms (table 2) and their effective management is an important part of good clinical practice.

Somewhat disappointingly, levodopa in combination with a peripheral dopa decarboxylase inhibitor (carbidopa or benserazide) remains the best symptomatic therapy and almost all patients will receive the drug at some stage of their illness. A number of prospective studies have shown there is no long term advantage in delaying levodopa, by starting treatment with an oral dopamine agonist or a selective monoamine oxidase inhibitor. Concern about daytime somnolence, ankle oedema and impulse control disorders (pathological gambling, hypersexuality, compulsive shopping, hoarding, binge eating and reckless generosity) with the dopamine agonists has swung the pendulum back towards early levodopa, even in young onset patients (table 3).

The initial maintenance dose of levodopa should start with 50 mg three times daily and not exceed 600 mg/day if the risk of long term adverse effects, particularly dyskinesias and behavioural disorders, is to be minimised. Levodopa sparing agents, including dopamine agonists (ropinirole, pramipexole tablets and rotigotine transdermal patches), selective type B monoamine oxidase inhibitors (selegiline, rasagiline) and catechol-O-methyl transferase (COMT) inhibitors (entacapone and tolcapone) can all be combined with levodopa and help to reduce end of dose deterioration and the on–off syndrome (capricious psychomotor fluctuations occurring several times a day). Combination of lower doses of levodopa with these adjuvant therapies also reduces the risk of severe disabling peak dose choreoathetosis. Amantidine may also be helpful in attenuating drug induced involuntary movements in some but not all cases, and anticholinergic drugs still have a role for off period dystonia in young onset patients.

The current trend is to start symptomatic therapy in most patients within a year of diagnosis in the hope that this will aid neuro-adaption and help compensate for progressive nigrostriatal denervation. In patients with mild motor disability, rasagiline is a reasonable and popular choice although claims that it is neuroprotective or disease modifying are not justified on the available evidence. In addition to early drug treatment, skilled physical therapy and programmed exercise are of great importance. Parkinson's disease nurse specialists have improved the overall care and support for UK patients; they should be involved early but always work closely with a neurologist for best results.

In patients with refractory motor fluctuations three highly effective treatment options are now available.

• ▶. The cheapest, safest and least invasive is waking day subcutaneous apomorphine administered from a small pump attached to a needle inserted each morning under the skin of the abdominal wall.

• ▶. Another approach is intrajejunal continuous administration of a soluble dopa gel through a gastrojejunostomy, which in the UK at least is restricted to apomorphine pump failures.

• ▶. Finally, bilateral deep brain stimulation of the subthalamic nucleus markedly reduces off periods and permits, on average, a 50% reduction in oral medication resulting in abolition of dyskinesias in many cases.

It is unclear whether any one of these approaches has major advantages over either of the others, and most specialist centres now offer all three. It seems reasonable to offer apomorphine as firstline treatment for the time being and then consider one of the other options as secondline approaches.

Once the terminal phase of the illness ensues, palliative care becomes more and more important and drug treatment should be simplified. The cause of death in many patients with Parkinson's disease remains obscure but a terminal chest infection often as a consequence of aspiration or pulmonary embolism is the commonest explanation.

The questions people with Parkinson's disease ask