Parkinson's disease is a neurological disorder that is the most common cause of parkinsonism.

Causes and incidence 

Parkinson’ s disease is caused by degeneration of, or damage to, cells in the basal ganglia of the brain. As a result, there is a deficiency of the neurotransmitter dopamine (which is needed for the control of movement). The condition occurs mainly in elderly people and is more common in men. 

Symptoms and signs

The main symptoms develop gradually, over several months or even years. The disease usually begins as a slight tremor of one hand, arm, or leg, which is worse when the hand or limb is at rest. Later, both sides of the body are affected, causing stiffness, weakness, and trembling of the muscles. Symptoms include a stiff, shuffling walk that may break into uncontrolled, tiny running steps; constant hand tremors, sometimes accompanied by shaking of the head; a permanent rigid stoop; and an unblinking, fixed expression. Everyday activities such as eating, washing, and dressing become very difficult. The intellect is unaffected until late in the disease, although the affected person’ s speech may become slow and hesitant, and the handwriting usually becomes very small. Depression is a common complication.

Treatment

There is no cure, but drug treatment, physiotherapy, and, rarely, surgery can help to relieve symptoms. In the early stages of Parkinson’ s disease, exercises, special aids in the home, and support can improve the affected person’ s morale and mobility. Drug treatment is used to minimize symptoms in later stages. These treatments cannot halt the degeneration of brain cells, but can minimize the symptoms by helping to correct the chemical imbalances in the brain. In some cases, an anticholinergic drug such as trihexyphenidyl (benzhexol) may initially be given to reduce tremor. Anticholinergic drugs can be effective for several years, but may cause side effects such as dry mouth, blurred vision, and difficulty in passing urine.

Levodopa, which the body converts into dopamine, is usually the most effective drug. It may, however, cause side effects such as nausea and vomiting; therefore, the dose is increased gradually, and the drug may be given in combination with benserazide or carbidopa. Levodopa is usually effective for several years, but the effects gradually wear off. Drugs that may be used in conjunction with it, or as substitutes for it, include amantadine and bromocriptine.

Surgical operations on the brain are occasionally performed, if the affected person is young and otherwise in good health. New therapies that are still being assessed include replacement of damaged tissue with transplanted brain cells, and deep brain stimulation with electri-cal impulses to reduce tremor.

Outlook

If left untreated, the disease progresses over 10 to 15 years, leading to severe weakness and incapacity. Some sufferers eventually develop dementia. Modern drug treatments, however, can provide considerable relief from the symptoms and give affected people a much improved quality of life.

Read more:

• Parkinson's disease in more detail- non-technical
• Cardinal features of Parkinson's disease - technical
• Treatment of Parkinson's disease with levodopa - technical
• Dementia in Parkinson's disease in detail - technical

Parkinsonism and other extrapyramidal diseases in detail - technical

Essentials

The human basal ganglia is a complex functional organization, with important interconnections with the nigrostriatal pathway, which dominates the dopaminergic innervation of the striatum (caudate nucleus and the putamen). Additionally, the globus pallidus, thalamic nuclei, the subthalamic nucleus and the pedunculopontine nucleus all play important regulatory and excitatory/inhibitory roles. Neuronal loops also interconnect the basal ganglia with the cerebellum as well as the cortex, and function is mediated by dopamine as well as a complex array of neuropeptides such as serotonin, acetylcholine, catecholamines, adenosine and gamma aminobutyric acid. See Chapter 24.7.1 for further discussion.

The principal clinical syndromes are Parkinson’s disease; other syndromes with Parkinsonian features (including drug-induced Parkinsonism); progressive supranuclear palsy; multisystem atrophy; Dementia with Lewy bodies; neuroacanthosis; torsion dystonia, and chorea. Apart from the use of dopaminergic agents, several drugs have beneficial effects in the management of Parkinsonism and other extrapyramidal diseases.

Parkinson's disease

Parkinson’s disease was first described by the celebrated London physician James Parkinson in 1817, and later named after him by Charcot. Parkinson’s disease is one of the most important disabling illnesses of later life. It is estimated to affect 1% of those aged 70 years, but is also seen in younger people, with 10% of cases occurring before the age of 50.

Epidemiology, incidence, and prevalence

The exact estimation of the incidence and prevalence of Parkinson’s disease is problematic, because there is no ‘in-life’ marker for idiopathic Parkinson’s disease; estimates of the annual incidence of Parkinson’s disease are in the range of 4 to 20 per 100 000 individuals. A widely accepted figure for the prevalence of Parkinson’s disease is approximately 200 per 100 000 population. In the United Kingdom, there are approximately 120 000 to 130 000 diagnosed cases, but there may be many more who remain undiagnosed. In the United States of America, it is estimated that between 750 000 and 1.5 million people have the condition.

Both the incidence and prevalence of Parkinson’s disease increase with age, and the prevalence may be as high as 1 in 50 for patients over the age of 80 years. Men are 1.5 times more likely than women to develop the condition. Hospital-based studies and a limited number of epidemiological surveys in Africa have suggested that Parkinson’s disease is less common in the black population, although this observation remains controversial.

Risk factors

Although Parkinson’s disease was first described almost 200 years ago, it remains difficult to define exactly which individuals are at risk. The ageing process is related to the development of Parkinson’s disease but is not solely responsible, because some patients develop the disease early in life. Furthermore, the type of dopamine cell loss in normal ageing differs from that in Parkinson’s disease. Certain personality traits and environmental factors may increase the risk of Parkinson’s disease (Bullet list 1). People with a family history of Parkinson’s disease, particularly first-degree relatives, are also at higher risk of developing the disease.

It has been postulated that people may be affected differently by a combination of genetic and environmental factors. A possible role of an environmental toxin was triggered by the fascinating observation that 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), accidentally consumed as a heroin contaminant in the United States of America in the late 1970s and early 1980s, caused an outbreak of levodopa-responsive parkinsonism. This led to the development of MPTP as an experimental agent to cause selective nigrostriatal cell loss in animal models. Recently, similar observations have been made in people in the welding trade, fuelling the hypothesis that manganese may be a causative factor. There have been conflicting reports about environmental agents that may predispose to Parkinson’s disease. These are listed in Box list 1.

Bullet list 1 Personality trends and environmental factors

Genetic factors

Individuals with a positive family history have twice the risk of developing Parkinson’s disease and the risk for siblings is increased significantly if there is an affected sibling with young-onset Parkinson’s disease. The risk increases further to 12 to 24% if both a sibling and a parent are affected (see Bullet list 1). α-Synuclein was the first gene to be identified in a multigeneration Italian–American family (the Contursi family) as causing an aggressive parkinsonism. Since then several genes have been identified, with Parkin and LRRK2 being the most prevalent ones (Table 1 below). LRRK2 stands for leucine-rich repeat kinase 2 and is part of the family of Roco genes; it encodes for the protein dardarin. LRRK2 has been associated with familial late-onset Parkinson’s disease and a few cases of sporadic late-onset Parkinson’s disease. However, routine genetic testing for Parkinson’s disease is not available, nor is genetic counselling currently possible. The precise function of these genes is unknown, although α-synuclein is the core protein in Lewy bodies whereas parkin may be active through the ubiquitin pathway.

Table 1  Genetics of parkinsonism

Symbol	Inheritance	Product	Location	Gene
PARK1	AD	α-Synuclein	4q21.3–q23	SNCA
PARK2	AR, juvenile onset	Parkin	6q25.2–q27	Parkin
PARK3	AD, Lewy body		2p13	–
PARK4	AD, Lewy body		4p15	–
PARK5	AD	Ubiquitin C-terminal esterase L1	4p14	UCHL1
PARK6	AR, early onset		1p35–p36
PARK7	AR, early onset		1p36
PARK8	AD	Dardarin	12p11.2–q13.
PARK9	AR		1p36	–
PARK10			Unspecified	–
PARK11			2q36

AD, autosomal dominant; AR, autosomal recessive.

Pathophysiology

The main pathological feature of Parkinson’s disease is the degeneration of neuromelanin-containing neurons in the pars compacta of the substantia nigra (SN), which leads to deafferentation of the striatum. Normally, it has been suggested that the basal ganglia exert their motor and nonmotor effects through a complex circuitry. The two main pathways are the direct (stimulatory) and indirect (inhibitory) pathways, a balance in favour of the direct pathway being kept by regulatory control exerted by dopamine manufactured in the SN. In Parkinson’s disease, dopamine cell degeneration leads to overexcitation of the direct circuit, and the resultant bradykinesia, by a complex pathway that also involves paradoxical excitation of the subthalamic nucleus and internal segment of the globus pallidus. The net result of both the direct and indirect pathways in the absence of dopamine is overexcitation of the medial globus pallidus, leading to excessive inhibition of the thalamus. Thalamic input to the motor cortex is excitatory and thus thalamocortical inhibition leads to akinesia and other symptoms of Parkinson’s disease.

Lewy bodies are intracytoplasmic eosinophilic inclusion bodies, typically found in the neurons of the SN. The pathophysiological basis of Parkinson’s disease has recently been re-explored by seminal and somewhat controversial work by Heiko Braak, who has suggested that Lewy body formation, a hallmark of dopaminergic cell degeneration in Parkinson’s disease, actually occurs in the brainstem, in the lower medulla and the olfactory bundle. In stage 2 more dorsal medulla and pons are involved whereas it is at stage 3 that the midbrain and the SN are involved. According to this hypothesis, therefore, clinical Parkinson’s disease is being detected only at stage 3. In support of this observation is the fact that several nonmotor features of Parkinson’s disease, e.g. olfactory loss and sleep disorders such as rapid eye movement disorder (RBD), seem to occur from the brainstem and olfactory bundle involvement, and in fact precede the development of motor Parkinson’s disease. A list of such nonmotor features that may actually precede the development of motor signs of Parkinson’s disease and may in fact in future detect people ‘at risk’ of Parkinson’s disease is listed in Bullet list 2.

A recent twist to the pathophysiological basis of Parkinson’s disease is the observation that positron emission tomography (PET) of the brain in Parkinson’s disease identifies neuroinflammation in the brainstem, suggesting that the pathological process in Parkinson’s disease may be initiated by an inflammatory process within the glial cells.

Symptoms and signs

Parkinsonism is a clinical syndrome and typically, when the condition appears to be idiopathic and in particular responds to levodopa therapy, it is referred to as Parkinson’s disease. Often the presenting symptom is a slow resting tremor, worse at rest (4–7 Hz) and often unilateral, although up to 30% of cases do not have a tremor at onset of the disease. The presence of an obvious tremor often leads both patients and their carers to suspect Parkinson’s disease and self-referral. In this context, it is important to differentiate an essential tremor from a parkinsonian tremor because the former carries a more benign prognosis and is twice as common, with a prevalence of at least 400 per 100 000 (Table 2).

Bradykinesia/akinesia is difficulty in initiating and slowness in executing, movement. It is the most disabling and progressive motor sign of Parkinson’s disease and is a core feature for diagnosis of Parkinson’s disease using the United Kingdom Parkinson’s Brain Bank criteria (Bullet list 3). It first affects fine movements such as fastening buttons, and handwriting, which becomes smaller and may progressively trail off (micrographia). Associated movements suffer and one or both arms may stop swinging when walking.

Diagnosis of parkinsonism

Gait is affected in Parkinson’s disease, with difficulty starting walking, small steps, and shuffling. ‘Festination’ occurs when the patient appears to hurry and then stops suddenly as if rooted to the ground. The face often becomes expressionless (masked face or hypomimia) with reduced blinking. Bradykinetic laryngeal movement leads to quiet, monotonous speech that is low in volume and sometimes repetitive (palilalia).

Rigidity is usually detected on examination and patients tend to complain of muscular stiffness and pain. Parkinsonian rigidity, which can be activated by performing mirror movements in the opposite limb, presents as one of two types:

1. 1 ‘lead-pipe’ rigidity—a constant resistance to passive movement, in the absence of tremor
2. 2 ‘cogwheel’ rigidity—a superimposed clicking resistance similar to a ratchet, in the presence of tremor

Clinical assessment of Parkinson’s disease is possible using several validated Parkinson’s disease-specific scales and questionnaires. These include the self-rated, 30-item, nonmotor questionnaire (NMSQuest), the simple 8-item, Parkinson’s disease quality-of-life questionnaire (PDQ-8), the motor scale (Unified Parkinson’s disease rating scale, UPDRS), and the nonmotor scale (NMSS).

The nonmotor symptom complex

A wide range of nonmotor symptom complexes (NMSs) is also seen in Parkinson’s disease from an early stage, all of which are likely to have a major effect on the health-related quality of life of patients. These symptoms include depression, dementia, sleep disorders, bowel and bladder problems, fatigue, apathy, pain, and autonomic dysfunction (see Bullet list 2).

Confirmation of diagnosis

There are no specific tests for the diagnosis of Parkinson’s disease, which remains clinical.

DaTSCAN

This is single photon emission computed tomography (SPECT) using the labelled cocaine derivative N-ω-fluoropropyl-2β-carboxymethoxy-3β-(4-iodophenyl)tropane (¹²³I-labelled β-CIT and ¹²³I-labelled FP-CIT (DaTSCANn), and is recommended in guidelines from the National Institute for Health and Clinical Excellence (NICE) and widely used to support diagnosis and differentiate Parkinson’s disease from essential tremor. It labels the presynaptic dopamine transporter and this provides assessment of the presynaptic neurons, which degenerate in Parkinson’s disease. Essential tremor is likely to show a normal DaTSCAN whereas in Parkinson’s disease there is diminished uptake of the ligand, usually correlating with the clinically affected side, and DaTSCAN also appears to have a close correlation with the progression of Parkinson’s disease. However, DaTSCAN does not differentiate between Parkinson’s disease and other parkinsonian syndromes.

PET scan

Using ¹⁸F-labelled dopa the PET scan has similar properties and better resolution but is currently available as a research tool only. More recently, transcranial ultrasonography has been used to reveal characteristic hyperechogenicity of the SN in patients with early Parkinson’s disease, possibly suggestive of excessive iron deposition in the SN. However, this technique needs to be validated in large-scale studies before widespread use can be advocated.

CT or MRI

Scans are usually not needed for diagnosis, but a brain scan should be performed if parkinsonism is purely unilateral or otherwise atypical, or if additional signs (pyramidal) are present. CT or MRI may also be used to rule out a space-occupying lesion, vascular disease, and normal-pressure hydrocephalus. MRI brain scan is preferrable to a CT brain scan.

Bullet list 2  The nonmotor symptom complex

Management of Parkinson's disease

When to initiate treatment remains a key question and increasingly the modern school of thought would suggest that it may be best to start treatment at diagnosis. The decision to treat may be dictated by the following clinical issues:

• ◆ Involvement of the dominant hand relative to the nondominant hand and the effect on employment/occupation
• ◆ The particular subtype of Parkinson’s disease (bradykinesia-dominant disease may require earlier treatment than tremor-dominant disease) 

Bullet list 3  Diagnosis of parkinsonism (Parkinson’s Brain Bank criteria)

• Essential features

  • ◆ Bradykinesia and two of the following:
    • • Tremor (resting) and/or
    • • Rigidity (cogwheel or lead pipe)
    • • Postural imbalance, fixed, stooped posture
    • • Gait difficulty (shuffling, short-step gait (with or without festination)

  Additional features

  • ◆ Hypomimia (‘masked’ face)
  • ◆ Freezing episodes (sudden onset failure of movement)
  • ◆ Seborrhoea of the scalp
  • ◆ Mental and cognitive disturbance

   

• ◆ The individual sentiments of patients and carers (offer informed choice)
• ◆ Presence of nonmotor symptoms such as pain, depression, or sleep problems

Table 2  Comparison of parkinsonian tremor and essential tremor

 

Feature	Parkinsonian tremor	Essential tremor
Age at onset	Usually >50 years	>10 years
Occurrence	Incidence increases with each decade of age	Incidence remains the same with each decade of age
Family history	Rare	Common
Site	Usually hands, also legs and jaw; head uncommon	Hands, head (a no–no or yes–yes motion), vocal
Characteristics	At rest; supination/pronation action reduces; mental concentration increases	Postural; flexion/extension action increases; mental concentration diminishes
Frequency (Hz)	4–7	8–12
Lead-pipe rigidity	Yes	No
Cogwheel rigidity	Yes	Rare
Alcohol	No effect	Often improves
Treatment	Dopaminergics	β-Blockers, primidone

As initiating treatment, the NICE (National Institute of Health and Clinical Excellence (UK)) guidelines recommend levodopa, dopamine agonists, or monoamine oxidase-B inhibitors. Levodopa is a precursor to dopamine, converted to dopamine by dopa decarboxylation, and restores the dopamine lost due to degeneration of striatonigral cells. The addition of a peripheral decarboxylase inhibitor that does not cross the blood–brain barrier, such as carbidopa or benserazide, inhibits dopa decarboxylase in the rest of the body and reduces side effects. The bioavailability of levodopa has been enhanced further by the emergence of drugs such as tolcapone and entacapone that inhibit catechol-O-methyl transferase (COMT), which also breaks down dopamine.

Evidence suggests that levodopa therapy should be started at the minimal effective dose (usually 50–100 mg/day), in combination with a decarboxylase inhibitor given three to four times daily. Doses at or above 600 mg/day may be associated with a dyskinesia rate as high as 17% at 1 year. Side effects, such as light-headedness or nausea, may be relieved by taking the medication with food or by increasing the dose of decarboxylase inhibitor or taking domperidone, which does not cross the blood–brain barrier and hence does not cause central dopamine antagonism. Controlled-release preparations of levodopa, with addition of a COMT inhibitor (entacapone) to the traditional combination of levodopa and a decarboxylase inhibitor (carbidopa), are now licensed for the treatment of later stage Parkinson’s disease.

In advanced Parkinson’s disease refractory to other forms of conventional therapies, intraduodenal/-jejunal infusion of levodopa (Duodopa) forms an alternative route of administration. Studies have shown that Duodopa is effective in controlling motor fluctuations in advanced Parkinson’s disease and reduces dyskinesias.

Dopamine agonists

Dopamine agonists stimulate dopamine receptors directly and so bypass the degenerating presynaptic nigrostriatal neurons. Five types of dopamine receptors (D₁–D₅) have been identified so far; these are broadly divided into: D₁-like and D₂-like receptors. In the 1980s and 1990s ergot dopamine agonists such as bromocriptine, pergolide, and more recently cabergoline, were fashionable, whereas nonergot agonists were preferentially recommended owing to the risk of cardiac valvular fibrosis with ergot dopamine agonists. Ropinirole and pramipexole remain the two main oral nonergot dopamine agonists although recently rotigotine, a transdermal nonergot dopamine agonist patch, has been released, which is effective when given once a day and utilizes the concept of continuous dopaminergic stimulation (CDS). Both ropinorole and pramipexole are also now available as once a day therapy which leads to improved concordance with therapy in PD (Fig. 24.7.2.4). Side effects of dopamine agonists include nausea, vomiting, postural hypotension, and hallucinations/psychosis in susceptible individuals or at high doses. More specifically somnolence or sudden onset of sleep has been linked to nonergot dopamine agonists, but studies have revealed that somnolence can occur with progression of Parkinson’s disease and other dopaminergic drugs as well. Patients therefore need to be warned about driving when starting on these drugs. More recently, behavioural problems such as compulsive gambling, hypersexuality, and a complex medley of impulsive behaviour has been linked to use of dopaminergic drugs, particularly dopamine agonists. The exact prevalence is unknown but can be up to 7% in susceptible individuals.

Apomorphine is a powerful nonergot dopamine agonist that is administered subcutaneously by an infusion pump in advanced cases of Parkinson’s disease when oral therapy is no longer useful. Skin nodules and nausea are the main side effects. Subcutaneous apomorphine is indicated when oral or skin patch therapy is unable to control motor fluctuations.

Monoamine oxidase-B inhibitors

Selegiline 10 mg once daily or 5 mg twice daily orally (or 1.25 mg once daily by buccal administration) is a selective, irreversible blocker of intra- and extraneuronal monoamine oxidase B (MAOB), and reduces metabolism of dopamine. Rasagiline is a new, second-generation, irreversible, selective MAOB inhibitor that is administered orally at a dosage of 0.5 to 1 mg once daily. A recent study (ADAGIO) suggest a potential disease modifying effect of rasagiline. The side effects of MAOB inhibition include hallucinations, sleep disorders, agitation, postural hypotension, and withdrawal problems.

Anticholinergics

Anticholinergics block the action of acetylcholine against dopamine within the basal ganglia. These drugs may occasionally be used as an adjunct to levodopa therapy, helping to control rest tremor and dystonia. However, they are not routinely recommended and should be used with great caution in older patients with parkinsonian syndromes because of the risk of inducing a confusional state and aggravating dementia.

Other drugs

Amantadine 100 to 400 mg daily is an antiviral agent with a moderate antiparkinsonian effect. It acts, in part, via increased dopamine synthesis and may also have an antidyskinetic action.

Patients who may require surgery

Surgery has gained popularity in selected patients when conventional pharmacological therapy has failed to control symptoms. It has a morbidity rate of approximately 2% due to strokes and infection, and a mortality rate of about 0.5%. The operation of choice is deep brain stimulation of the subthalamic nucleus (STN), which reverses the akinesia and controls dyskinesias. Patients with severe resistant unilateral tremor could have single-side thalamic stimulation of the ventral intermediate (VIM) nucleus. Other surgical approaches such as delivery of viral vectors to the striatum for gene therapy or neurotransplantation remain experimental options currently, although some such as adenosine-associated virus (AAV), a nonpathogenic virus, is being used in human trials for gene delivery.

Intrajejunal levodopa infusion

It is indicated for the treatment of advanced levodopa-responsive Parkinson’s disease with severe motor fluctuations and dyskinesia. This involves giving L-dopa through jejunum via peg. It proved beneficial for nonmotor symptoms and health related quality of life in Parkinson patients.

Other parkinsonian/extrapyramidal syndromes

There are a number of degenerative diseases that have a more complex clinical picture than Parkinson’s disease and a poorer response to therapy. It may be impossible to distinguish idiopathic Parkinson’s disease from other parkinsonian syndromes.

Drug-induced parkinsonism

This is one of the most common causes of secondary parkinsonism, and is often misdiagnosed as Parkinson’s disease because clinical features may be indistinguishable. It causes rigidity, bradykinesia, tremor, and gait disturbance, and may be asymmetrical. Although several medications are associated with secondary parkinsonism, dopamine-blocking agents (neuroleptics) such as prochlorperazine or chlorpromazine are the most common offending agents, and are often prescribed to older people for nonspecific complaints such as dizziness, and drug-induced parkinsonism may take up to 9 months to disappear. The incidence of drug-induced parkinsonism is estimated to be 15 to 40% in patients receiving neuroleptics, and its prevalence increases with age. Vestibular sedatives are also implicated. Commonly used antiemetics and anti dizziness pills needs to be monitored.

Treatment consists of withdrawal of the offending medication. If drug withdrawal is impractical, patients are given the lowest possible dose or are changed to a new atypical agent, such as clozapine or quetiapine. Occasionally emergence of parkinsonism may be permanent.

Progressive supranuclear palsy

Progressive supranuclear palsy (PSP or Steele–Richardson–Olszewski syndrome) presents with gait disturbance and falls (predominantly backwards) in over 50% of cases, and is a disease of later life. The pathological hallmark is tau protein-positive filamentous inclusions known as neurofibrillary tangles in the glia and neurons.

The clinical picture consists of supranuclear gaze palsy, particularly downgaze with extension and rigidity of the neck, a staring look due to lid retraction, and predominant truncal extensor rigidity. Varying degrees of bradykinesia, dysphagia, personality changes, and other behavioural disturbances, such as a subcortical frontal dementia, coexist. Subtype with levodopa responsiveness have been described.

Multiple-system atrophy

Multiple-system atrophy (MSA) consists of a variable combination of parkinsonism with autonomic, pyramidal, or cerebellar symptoms and signs. In the past, patients were categorized as having striatonigral type (SND) if there were dominant parkinsonian signs, olivopontocerebellar type (OPCA) if cerebellar signs predominated. These terms are no longer in use and, currently, SND and OPCA variants are called MSA-P and MSA-C, respectively. The pathological feature of MSA is the glial cytoplasmic inclusions.

The parkinsonian features of MSA include progressive bradykinesia, rigidity and postural instability, and signs that are usually bilateral. Useful clinical clues include disproportionate anterocollis, truncal dystonia (this may resemble the so-called ‘Pisa syndrome’), characteristic sighing, and the presence of cold, blue hands. Autonomic failure, particularly postural hypotension, occurs early in MSA and is more severe than in idiopathic Parkinson’s disease.

The response to levodopa is commonly incomplete and benefit usually declines within 1 to 2 years of treatment.

Dementia with Lewy bodies

In dementia with Lewy bodies (DLB), widespread areas of neocortex as well as the brainstem and diencephalic neurons have Lewy bodies. Parkinsonian DLB may be indistinguishable from Parkinson’s disease, but these patients have early onset dementia (progressive cognitive decline interfering with normal social and occupational function) and may have hallucinations, delusions, and even psychosis in the absence of dopaminergic therapy, usually within 2 years of disease onset.

Clinical criteria for diagnosis include fluctuations in cognition and attention, recurrent and persistent visual hallucinations, and parkinsonian motor signs. Repeated early falls and neuroleptic sensitivity can be seen. Rarely, patients develop supranuclear gaze palsy; this may lead to the condition being mistaken for PSP.

Corticobasal ganglionic degeneration

Corticobasal ganglionic degeneration, also known as corticodentatonigral degeneration with neuronal achromasia, typically presents in the sixth or seventh decade with slowly progressive, unilateral development of tremor, apraxia, and rigidity in an upper limb.

The condition is characterized by progressive gait disturbances, cortical sensory loss, and stimulus-sensitive myoclonus, which results in a jerky, useless hand. A jerky, useless lower extremity is uncommon, but may occur; it is known as the alien limb phenomenon and can occur in about 50% of patients. Gait disturbance consists of a slightly wide-based, apraxic gait rather than the typical festinating gait of Parkinson’s disease. Patients with corticobasal ganglionic degeneration do not benefit from levodopa, and the disease course is relentlessly progressive.

Dopa-responsive dystonia

Patients with young-onset parkinsonism manifest dystonia, which may respond to dopaminergic drugs. Those with hereditary dopa-responsive dystonia (Segawa’s disease) have an excellent and sustained response to low-dose levodopa. This disorder characteristically shows marked diurnal variation, and may start in childhood with an odd and unusual gait; diagnosis can be made by checking for mutation in the GTP-cyclohydrolase gene.

Wilson’s disease

Wilson’s disease should be considered in every case of young-onset parkinsonism, because it is treatable and the consequences of nonrecognition can be grievous. The most common neurological manifestations include:

• ◆ A combination of parkinsonism and ataxia, characteristic of neurological Wilson’s disease. Tremor typically involves the upper limbs and the head, and rarely the lower limbs; classically, the tremor is coarse, irregular, and present during action. Holding the arms forward and flexed horizontally may demonstrate the activity of the proximal muscles (wing-beating tremor).
• ◆ Kayser–Fleischer rings—rings of brownish-green pigmentation, due to copper deposition in the cornea, may be easy to recognize in patients with light-coloured irises, and are best appreciated with a careful slit-lamp examination performed by an ophthalmologist. The most useful diagnostic test results are a low serum ceruloplasmin level and a raised 24-h urinary copper excretion.
• ◆ Juvenile Huntington’s disease, which is an autosomal dominant neurodegenerative disorder that typically presents with chorea, difficulty with gait and cognitive problems.

Neuroacanthocytosis

Neuroacanthocytosis is a rare cause of parkinsonism and typically presents with a hyperkinetic movement disorder, including chorea, tic-like features, and polyneuropathy. Acanthocytes are revealed on a fresh blood smear.

Vascular disease is a rare cause of a straightforward parkinsonian syndrome with a variety of clinical presentations. Onset is either acute or subacute, and symptoms (usually bilateral) are those seen in classic Parkinson’s disease, including tremor, bradykinesia, rigidity and postural instability, and a gait disturbance with minimal upper-extremity symptoms (lower-body parkinsonism), or walking with small steps (marche à petits pas), which is characteristic of vascular disease.

Dystonia

Dystonia is a syndrome of sustained muscle contractions, which may be due to either derangement of the spinal cord or cortical mechanism or a dopaminergic dysfunction of basal ganglia. Dystonia is focal if a single area is involved, e.g. the face, oromandibular area, arm, or neck. Focal dystonias are very well treated with botulinum toxin injections.

It is multifocal if two or more noncontiguous body regions are involved, e.g. an arm and a leg with cranial muscle involvement or blepharospasm and leg dystonia. Finally, it is generalized if both legs and one other body region are involved or the whole body is involved.

Generalized idiopathic torsion dystonia

The mode of inheritance of this type of dystonia is autosomal dominant (DYT1 gene on chromosome 9). This type of dystonia typically occurs in childhood and in early adult life. Symptoms often start in one area of the body and spread to other areas, and may present with twisted postures, turning in of the foot or arm, etc. Sometimes joints can twist; dystonia usually produces torsion—hence the term ‘torsion dystonia’. Oral medications such as anticholinergic drugs, e.g. trihexyphenidyl, are often the mainstay of treatment for early onset generalized dystonia.

Tardive dyskinesia

Tardive dyskinesia is a chronic condition that is induced by long-term exposure to dopamine-blocking drugs. Major tranquillizers and antiemetics, such as metoclopramide, are the real culprits. These involuntary movements usually start with the face and mouth and cause grimacing, lip smacking, and tongue movements. They may also involve the rest of the body and produce involuntary gestures, tics, and writhing movements. Treatment for tardive dyskinesia is withdrawal of the drug responsible when possible and replacement with newer antipsychotics, e.g. quetiapine or quatrain fumarate. Clonazepam has proved to be useful. Recent studies showed that vitamins E and B₆ have a positive effect on these movement disorders.

Chorea and related disorders 

Chorea is an irregular, rapid, uncontrolled, involuntary, excessive movement that seems to move randomly from one part of the body to another, often similar to dancing or piano playing. When chorea is severe, the movements may cause motion of the arms or legs which results in throwing. The main pathology lies in the caudate nucleus. Athetosis is a slower writhing and twisting movement. Choreoathetosis is a movement of intermediate speed, between the quick, flitting movements of chorea and the slower, writhing movements of athetosis. Chorea is closely related to ballism, which is a high-amplitude displacement of the proximal muscles.

Huntington’s disease, for example, is dominantly inherited; it is caused by a mutation on chromosome 4—the Huntington gene—characterized by an expansion of CAG repeats. Huntington’s disease generally starts in mid-adult life, around the age of 35 years; the Westpal variant occurs in childhood. There is no effective treatment for Huntington’s disease. Tetrabenazine will reduce the involuntary movements.

Sydenham’s chorea is associated with rheumatic fever, and commonly occurs in childhood with spontaneous remission usually taking place within 3 to 6 months.

Other causes of chorea are neuroacanthocytosis and systemic lupus erythematosus; it also rarely occurs in pregnancy—known as chorea gravidarum.

Tics

Tics are sudden, repetitive, stereotyped, nonrhythmic, involuntary movements (motor tics) or sounds (phonic tics). Motor tics are movement-based tics affecting discrete muscle groups.

Phonic tics are involuntary sounds produced by moving air through the nose, mouth, or throat. The characteristic feature of all tics is the patient’s ability to suppress them for brief periods of 30 to 60 s.

Tics confined to a single muscle group often persist through life. When tics move around from one part of the body to another, they are termed ‘chronic multiple tic’, or Gilles de la Tourette’s disease. The pathological basis of tics is not known, but they generally respond to drugs that decrease dopaminergic transmission. Gilles de la Tourette’s syndrome can cause severe tics and noises that are socially disruptive, and in such cases a minimal but therapeutic dose of tetrabenazine, usually between 12.5 and 100 mg daily, may be helpful.

Other rare conditions

Other rare conditions to exclude are neuroacanthocytosis, neuroferrritinopathy (neuronal brain iron storage disorders), spinocerebellar atrophy.