Parkinsonism and Parkinson's disease

What are Parkinsonism and Parkinson's disease?¹

Parkinsonism is a general term for the clinical features of bradykinesia plus at least one of tremor, rigidity, and/or postural instability. Parkinson's disease is the most common form of Parkinsonism. Other causes of Parkinsonism include drug-induced Parkinsonism, cerebrovascular disease, Lewy body dementia, multiple system atrophy, and progressive supranuclear palsy.

Parkinson's disease is a movement disorder characterised by:²

• Tremor at rest.

• Rigidity.

• Bradykinesia.

The diagnosis is almost entirely based on clinical examination. It is caused by degeneration of the dopaminergic pathways in the substantia nigra. Although Parkinson's disease is mainly caused by dysfunction of dopaminergic neurons, nondopaminergic systems are also involved.³

The exact cause of Parkinson's disease is unknown. The majority of cases are thought to arise sporadically, but up to 20% of people with Parkinson's disease have a family history of Parkinson's disease in a first-degree relative.

Pathogenesis

• The ventral tier of the zona compacta of the substantia nigra is particularly affected with reduction of dopamine in the striatum.

• Parkinson's disease is used to describe the idiopathic syndrome of Parkinsonism.

• Drug-induced Parkinsonism is caused by drugs that block the dopamine receptors or reduce storage of dopamine. This is mainly the major tranquilisers used to treat psychosis but the condition can also be seen with drugs used to treat nausea - eg, metoclopramide.⁴

• Parkinsonism may also occur following encephalitis or exposure to certain toxins - eg, manganese dust, carbon disulfide, severe carbon monoxide (CO) poisoning.

How common is Parkinson's disease? (Epidemiology)⁵

• Parkinson's disease is the second most common neurodegenerative disorder after Alzheimer's disease.

• The prevalence increases with age: 4–5 per 100,000 people in people aged 30-39 years; 1,700 per 100,000 people aged 80-84 years.¹

• About 0.3% of the general population is affected, and the prevalence is higher among men than women, with a ratio of 1.5 to 1.

• Parkinson's disease may be more common among white people than those of Asian or African descent but the data are conflicting.

Risk factors

• Increasing prevalence with age, and slightly more common in men.

• Another recognised factor includes pesticide exposure.

• Small-scale studies have suggested that patients born in the spring have a higher incidence of Parkinson's disease.

Parkinson's disease symptoms^{1 5}

Parkinson's disease is a slowly progressing neurodegenerative disorder, causing impaired motor function with slow movements, tremor and gait and balance disturbances.

Non-motor symptoms are common and include disturbed autonomic function with orthostatic hypotension, constipation and urinary disturbances, sleep disorders and neuropsychiatric symptoms.^{6 7}

Onset is insidious with peak age of onset at 55-65 years. It commonly presents with impairment of dexterity or, less commonly, with a slight dragging of one foot. A fixed facial expression is characteristic with infrequent blinking. There may also be saliva drooling from the mouth, often due to impaired swallowing, and a quiet voice.

Main features are resting tremor, rigidity and bradykinesia:⁸

• Tremor at 4-6 Hz is seen at rest and, if not immediately apparent, may be induced by concentration - eg, asking the patient to recite months of the year backwards. It is absent during activity - eg, tipping water from cup to cup. Tremor is usually apparent in one limb or the limbs on one side for months or even years before becoming generalised.

• Rigidity presents as an increase in resistance to passive movement that can produce a characteristic flexed posture in many patients. It may be increased by asking the patient to perform an action in the opposite limb - contralateral synkinesis.

• Bradykinesia presents as a slowness of voluntary movement and reduced automatic movements. It is particularly noticeable in a reduced arm swing whilst walking. It can also be seen as a progressive reduction in the amplitude of repetitive movements - eg, asking the patient to repeatedly oppose middle finger and thumb. Patients may still retain the ability to move quickly in an emergency situation.

Typically, muscles are of normal strength if given time to develop power. There is no alteration in tendon reflexes or plantar responses.

Later features

Gait disturbance: the patient may have difficulty in rising from a sitting position and starting to walk. Gait is characterised by small shuffling steps with unsteadiness on turning (taking several steps to turn) and difficulty in stopping ('festination'). There may be a tendency to fall.

When patients have a gait disorder without other Parkinsonian features, the most likely diagnosis is gait apraxia, which is more common and usually caused by small-vessel cerebrovascular disease.

Gait disorders and postural instability are the leading causes of falls and disability in Parkinson's disease. Cognition plays an important role in postural control and may interfere with gait and posture. It is very important to recognise gait, posture and balance dysfunction⁹ .

Criteria for the diagnosis of Parkinson's disease¹⁰

Suspect Parkinson's disease in people presenting with tremor, stiffness, slowness, balance problems and/or gait disorders. If Parkinson's disease is suspected, refer people quickly and untreated to a specialist with expertise in the differential diagnosis of this condition.¹¹ :

Step 1: diagnosis of Parkinsonian syndrome
Bradykinesia (slowness of initiation of voluntary movement with progressive reduction in speed and amplitude or repetitive actions) and at least one of the following:

• Muscular rigidity.

• 4- to 6-Hz resting tremor.

• Postural instability not caused by primary visual, vestibular, cerebellar or proprioceptive dysfunction.

Step 2: exclusion criteria for Parkinson's disease

• History of repeated strokes with stepwise progression of Parkinsonian features.

• History of repeated head injury.

• History of definite encephalitis.

• Oculogyric crises.

• Neuroleptic treatment at onset of symptoms.

• More than one affected relative.

• Sustained remission.

• Strictly unilateral features after three years.

• Supranuclear gaze palsy.

• Cerebellar signs.

• Early severe autonomic involvement.

• Early severe dementia with disturbances of memory, language and praxis.

• Babinski's sign.

• Presence of a cerebral tumour or communicating hydrocephalus on CT scan.

• Negative response to large doses of L-dopa (if malabsorption excluded).

• Exposure to MPTP.

Step 3: supportive prospective positive criteria of Parkinson's disease
Three or more are required for the diagnosis of definite Parkinson's disease:

• Unilateral onset.

• Rest tremor present.

• Progressive disorder.

• Persistent asymmetry affecting the side of onset most.

• Excellent response (70-100%) to L-dopa.

• Severe L-dopa-induced chorea.

• L-dopa response for five years or more.

• Clinical course of ten years or more.

• Hyposmia.

• Visual hallucinations.

Long-term problems¹

After an initial 'honeymoon period', the majority of people who have received L-dopa for 5-10 years may experience the following:

Motor fluctuations

• When Parkinson's disease patients are moving well, they say they are 'on'. When they are stiff and bradykinetic, they say they are 'off'.

• Wearing off of the treatment (before the next dose is due) may start to occur as well as 'on-off' fluctuations, which occur randomly.

• Patients may also experience involuntary movements whilst 'on'. These are dyskinesias.

• Motor fluctuations are difficult to treat and are best managed by a specialist.

Axial problems not responding to treatment

• Axial problems are balance, speech and gait disturbance which do not respond to Parkinson's disease medication.

• It is thought to be as a consequence of axonal degeneration outside the substantia nigra where dopamine is not the neurotransmitter.

• If a patient cannot walk or speak well but has no limb Parkinsonism (ie is otherwise well medicated), they will not be improved by increasing their dose.

• Their treatment options include physiotherapy, occupational therapy and speech and language therapy (SALT).

Parkinson's disease dementia

This is dementia occurring more than one year after diagnosis of Parkinson's disease. It is similar to Alzheimer-type dementia but has three typical features:

• Presence of Parkinsonism in the limbs.

• Frequent visual hallucinations.

• Frequent fluctuations in lucidity.

Sudden deteriorations may be mistaken for intercurrent illness - eg, urinary tract infection - but the midstream specimen of urine is negative, and the patient becomes better.

Parkinson's disease dementia is difficult to treat, as confusion and hallucinations may be worsened by the treatment of Parkinson's disease - dopamine agonists. Atypical antipsychotics (eg, quetiapine), are effective without worsening the Parkinsonism.

Differential diagnosis¹

• Benign essential tremor - far more common; tremor is worse on movement (eg, while trying to hold a cup of tea) and rare while at rest.

• Drug- or toxin-induced - numerous drugs or toxins may cause tremor, notably selective serotonin reuptake inhibitors (SSRIs), caffeine, amfetamines, beta-adrenergic blockers, tricyclics, and lithium. Neuroleptics (eg, haloperidol, chlorpromazine) and anti-emetics (eg, prochlorperazine) can cause Parkinsonian features which look identical to Parkinson's disease.

• Huntington's disease - can present earlier with rigidity instead of chorea when Parkinsonism is not expected. Normally, there is family history.

• Wilson's disease - earlier onset with characteristic Kayser-Fleischer rings and hepatitis.

• Corticobasal degeneration - manifest by obvious signs of cortical dysfunction - eg, apraxia, dementia and aphasia.

• Creutzfeldt-Jakob disease (CJD) - dementia usually apparent with myoclonic jerking, ataxia and pyramidal signs common.

• Multi-infarct dementia - this is characterised by cognitive impairment, spasticity, and extrapyramidal signs.

• Lewy body dementia - often mimics Parkinsonian features.

• Pick's disease - affects the frontal and/or temporal lobes. Level of consciousness is not affected (unlike in Alzheimer's disease) and Parkinsonism is usually mild.

• Cerebellar tremor - this presents as a unilateral or bilateral, low-frequency intention tremor. It may be caused by stroke, brainstem tumour, or multiple sclerosis.

• Pyschogenic tremor - the tremor is variable, increases under direct observation, decreases with distraction and changes with voluntary movement of the contralateral limb.

The 'atypical Parkinsonism syndromes' are a group which look like Parkinson's disease but are much more severe. Median survival is only seven years compared with the normal lifespan in Parkinson's disease. They include:

• Multiple system atrophy - may also present with Parkinsonian symptoms, often with a poor or temporary response to levodopa therapy. See separate Multiple System Atrophy article.

• Progressive supranuclear palsy - characterised by paresis of conjugate gaze with initially problems looking up and down on request, advancing to difficulty in following objects up and down.

Referral¹

Refer people with suspected Parkinson's disease quickly (and untreated) to a specialist (with expertise in the differential diagnosis of this condition) for diagnosis.

The National Institute for Health and Care Excellence (NICE) also recommends: consider referring people at any stage of Parkinson's disease to the palliative care team to give them and their family members or carers (as appropriate) the opportunity to discuss palliative care and care at the end of life.¹¹

Investigations^{10 11}

The diagnosis is clinical. Other investigations focus on excluding other causes of the presentation:

• CT or MRI brain scan:
  

  • For patients who fail to respond to therapeutic doses of L-dopa (at least 600 mg/day) administered for 12 weeks.

  • MRI scanning is needed to exclude rare secondary causes (eg, supratentorial tumours and normal pressure hydrocephalus) and extensive subcortical vascular pathology.²

  • Functional MRI and CT imaging are useful research tools. Blood flow changes monitored by these methods and correlated with functional disability are providing useful clues as to the structural abnormalities which cause Parkinsonism and Parkinson's disease.¹²

• ¹²³I-FP-CIT single photon emission computerised tomography (SPECT) should be considered for people with tremor if essential tremor cannot be clinically differentiated from Parkinsonism.

• Positron emission tomography (PET) scanning with fluorodopa can localise dopamine deficiency in the basal ganglia, while autonomic tests and sphincter electromyography may support a diagnosis of multiple system atrophy.

• Structural MRI may be considered in the differential diagnosis of other Parkinsonian syndromes.

• Transcranial sonography has been recommended for the differentiation of Parkinson's disease from atypical and secondary Parkinsonian disorders, for the early diagnosis of Parkinson's disease and for the detection of subjects at risk for Parkinson's disease. However, the technique is not universally available and requires some expertise.

• Genetic testing may be required - eg, Huntington's gene. Fewer than 5% of all Parkinson's disease cases are caused by known single-gene mutations.

• Olfactory testing to help differentiate Parkinson's disease from other Parkinsonian disorders.

• Further investigations for young-onset or atypical disease may include measurement of ceruloplasmin levels (Wilson's disease) and syphilis serology.

Associated diseases

• Dementia: the prevalence of dementia in Parkinson's disease ranges from 20-40%, with a 2- to 6-fold increased risk compared with control populations.

• Depression: occurs in approximately 45% of all patients with Parkinson's disease, does not correlate with the stage of motor deficits and reduces the quality of life independently of motor symptoms.¹³

Parkinson's disease treatment and management

See the separate Parkinson's Disease Management article.

Monitoring symptoms¹⁴

NICE has approved a few devices to help monitor symptoms. Kinesia 360, KinesiaU, PDMonitor, Personal KinetiGraph (PKG) and STAT-ON are conditionally recommended as options for remote monitoring of Parkinson's disease.

Complications¹

Motor complications are usually related to the use of anti-parkinsonian medication, and include deteriorating function, loss of drug effect, motor fluctuations, dyskinesia, freezing of gait and falls.

Non-motor complications include:

• Mental health conditions: depression, anxiety, and apathy; dementia and cognitive impairment; impulse control disorders and psychotic symptoms (delusions and hallucinations).

• Autonomic dysfunction: constipation, orthostatic hypotension, dysphagia and weight loss, excessive salivation and sweating, bladder and sexual problems.

• Other complications: nausea and vomiting, pain, sleep disturbance and daytime sleepiness, aspiration pneumonia, pressure sores.

Prognosis¹

Parkinson's disease is typically slowly progressive, but the rate of progression is variable. The mortality rate for elderly people aged 70-89 years with Parkinson's disease is 2-5 times higher than for age-matched controls in some studies. The risk of dementia is about 2-6 times higher in people with Parkinson's disease than in healthy controls.