Parkinson’s disease

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32 Parkinson’s disease

D.J. Burn

Key points

• Parkinson’s disease is the second most common neurodegenerative disease, affecting 1% of the population over the age of 65.
• Parkinson’s disease is characterised by bradykinesia, rest tremor, rigidity and, later in the disease course, postural instability.
• Neuronal loss in the brainstem (substantia nigra) leads to a profound dopamine deficiency in the striatum. This provides the rationale for dopaminergic replacement therapies.
• Depression is common in Parkinson’s disease. It is the major determinant of quality of life and is often missed. The depression of Parkinson’s disease can be readily treated.
• Levodopa, coupled with a dopa-decarboxylase inhibitor, remains the most potent oral treatment for Parkinson’s disease. There is debate as to whether levodopa should be deferred in biologically young patients, in an attempt to delay the onset of motor complications.
• Several other drug treatments are available for the management of Parkinson’s disease. When given as adjunctive therapy to levodopa, the primary aim of these agents is to smooth out motor fluctuations.
• End-of-dose deterioration and the on–off phenomenon are motor complications synonymous with the use of levodopa, usually after a number of years. Despite advances in oral pharmacotherapy, the on–off phenomenon remains difficult to treat effectively.
• Surgical treatments of Parkinson’s disease, using deep brain stimulation, are effective in highly selected cases.
• Advanced Parkinson’s disease is difficult to manage, particularly dementia and neuropsychiatric problems. Reduction of dopaminergic therapy may be the best compromise. Rivastigmine may be useful for dementia associated with Parkinson’s disease.

Parkinson’s disease is the most common cause of Parkinsonism and is the second most common neurodegenerative disease, after Alzheimer’s disease. Although descriptions of the condition appeared before the nineteenth century, it was James Parkinson’s eloquent account in 1817 that fully documented the clinical features of the illness now bearing his name. The identification of dopamine deficiency in the brains of people with Parkinson’s disease and the subsequent introduction of replacement therapy with levodopa represent a considerable success story in the treatment of neurodegenerative illness in general. There remain, however, a number of significant management problems in Parkinson’s disease, particularly in the advanced stages of the condition.

Epidemiology

Parkinson’s disease affects 1% of the population over 65 years of age, rising to 2% over the age of 80. One in 20 patients is, however, diagnosed before their 40th year. It is estimated that 110,000 people have Parkinson’s disease in the UK. The condition is found worldwide, with variability in prevalence estimates most likely reflecting study methodology, rather than real differences. Most epidemiological studies have indicated a small male-to-female predominance.

Other causes of Parkinsonism include neurodegenerative conditions, multiple system atrophy and progressive supranuclear palsy. The prevalence for these conditions is approximately 5.0 per 100,000. Drug-induced Parkinsonism is a common form of so-called symptomatic Parkinsonism. It affects 10–15% of individuals exposed to dopamine receptor-blocking agents including neuroleptics and some labyrinthine sedatives.

Aetiology

Both genetic and environmental factors have been implicated as a cause of Parkinson’s disease. While opinions were initially polarised, it now seems probable that in the majority of cases there is an admixture of influences, with environmental factors precipitating the onset of Parkinson’s disease in a genetically susceptible individual.

Environmental factors became pre-eminent in the 1980s, when drug addicts attempting to manufacture pethidine accidently produced a toxin called MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine). Ingestion or inhalation of MPTP rapidly produced a severe Parkinsonian state, indistinguishable from advanced Parkinson’s disease. Notably, not all individuals exposed to MPTP developed Parkinsonism, either acutely or on subsequent follow-up, suggesting inter-individual susceptibility to the toxic effects. MPTP is a relatively simple compound and is quite similar to paraquat. The more recent demonstration that chronic systemic exposure to the pesticide rotenone can reproduce the clinical and pathological features of Parkinson’s disease in rats has generated considerable interest.

In a small number of patients, genetic factors are dominant. The discovery of a mutation in the gene coding for a synaptic protein called α-synuclein has provided tremendous impetus for further research. Such mutations have been described in fewer than 10 families worldwide. Nevertheless, because α-synuclein is a major component of the pathological hallmark of Parkinson’s disease, the Lewy body (see below), the challenge is to discover how a mutation in this protein in a tiny minority can relate to the formation of Lewy bodies in the vast majority. In recent years, eight genetic loci and a further four genes (parkin, DJ-1, PINK1 and LRRK-2) have been identified (Healy et al., 2004). The intriguing thing is that the protein products of these genes are involved in a cellular system called the ubiquitin-proteasome system, which plays a crucial role in removing and recycling abnormal or damaged proteins. Current thinking is that abnormalities in the way in which the cell handles mutated or abnormal proteins may ultimately lead to its death, through increased oxidative stress and/or reduced mitochondrial energy production. The Lewy body may actually represent a defence mechanism by the cell to ‘parcel up’ potentially damaging proteinaceous material (Olanow et al., 2004).

More recently, cell-to-cell transfer of α-synuclein has been demonstrated in vitro and also in engrafted stem cell tissue. This suggests that the pathology of Parkinson’s disease may be propagated between neurones and could have major implications for the spread of Lewy body pathology within the brain, as well as its treatment (Olanow and Prusiner, 2009) (Fig. 32.1).

image

Fig. 32.1 Summary of pathophysiological processes believed to be central to Parkinson’s disease.

Pathophysiology

The characteristic pathological features of Parkinson’s disease are neuronal loss in pigmented brainstem nuclei, together with the presence of eosinophilic inclusion bodies, called Lewy bodies, in surviving cells. The pars compacta of the substantia nigra in the midbrain is particularly affected. Dopaminergic neurones within this nucleus project to the striatum, which is, therefore, deprived of the neurotransmitter dopamine. In Parkinson’s disease, there is a loss of over 80% of nigral neurones before symptoms appear. The ‘Braak hypothesis’ has been proposed to account for spread of pathology within the Parkinsonian brain and suggests that α-synuclein may first accumulate in the lower brainstem and then gradually ascend rostrally to affect critical brain regions including the substantia nigra and ultimately the cerebral cortex (Braak et al., 2003).

Dopaminergic neurones are not the only cells to die within the brainstem, and a plethora of other nuclei and neurotransmitter systems are also involved. For example, cholinergic neurones within the pedunculopontine nucleus degenerate, providing potential clinicopathological correlates with postural instability, swallowing difficulty (dysphagia) and sleep disturbance (REM sleep behavioural disturbance). The involvement of this nucleus in Parkinson’s disease may explain why dopaminergic therapy is relatively ineffective in treating these particular clinical problems. Within the striatum, changes occur within γ-aminobutyric acid-containing neurones, as a consequence of nigrostriatal dopaminergic deficiency and also non-physiological dopaminergic replacement. These changes are thought to play a key role in mediating the development of involuntary movements (dyskinesias) which develop after a number of years of levodopa treatment. The loss of noradrenergic and serotonergic neurones within the locus coeruleus and the raphé nucleus, respectively, may provide a pathophysiological basis for depression, which is common in Parkinson’s disease.

Clinical features

Motor features

Bradykinesia is a sine qua non for Parkinsonism in general. If a person does not have slowness of movement, they cannot have either Parkinsonism or Parkinson’s disease. Rest tremor, extrapyramidal rigidity (so-called lead pipe and/or cog-wheel) and postural instability comprise the remaining classic tetrad of clinical features for Parkinson’s disease. Asymmetry of signs at disease onset is very common. The rest tremor is a rhythmic movement with a frequency of 4–6 Hz (cycles/s), typically noticed with the patient at rest. It is sometimes described as ‘pill-rolling’ in nature, from the movement of the thumb across the fingers. However, 15–20% of patients do not develop a tremor. Further, up to 60% of people with Parkinson’s disease may have a dominant postural tremor, worse with the arms held outstretched, which can cause diagnostic confusion with essential tremor (see below). Postural instability is a late feature of Parkinson’s disease and comprises an impairment of righting reflexes with a tendency to fall. There may be a flexed truncal posture and loss of arm swing when walking. There is reduced blink frequency and facial expression, which, together with rather reduced volume (hypophonic) and monotonous speech, may lead to significant difficulties in communication. Writing becomes small (micrographia) and barely legible.

Non-motor features

Autonomic dysfunction may occur in Parkinson’s disease. The patient may drool and have greasy skin (seborrhoea). Urogenital difficulties, with erectile dysfunction in males and urinary urgency in both sexes, are commonly encountered. Frank incontinence is, however, rare. Constipation is invariable and is multifactorial in origin. Falling blood pressure on standing (postural hypotension) may contribute to falls later in the disease course. Depression affects approximately 40% of people with Parkinson’s disease and is a major determinant of both carer stress and nursing home placement. It can be a very early feature, and may precede the onset, of Parkinson’s disease. Recent studies have demonstrated that depression, above any other factor, is the most significant determinant of quality of life in the person with Parkinson’s disease, yet it is generally underdiagnosed. The occurrence of dementia in Parkinson’s disease is related predominantly to the age of the patient. Longitudinal community-based studies indicate that dementia may ultimately develop in 80% of people with Parkinson’s disease. The cognitive impairment may be accompanied by hallucinations that are often visual, delusional misinterpretation, including paranoid ideation, and rapid fluctuations in attention.

Differential diagnosis

It is important to remember that, while Parkinson’s disease is a common form of Parkinsonism, there are numerous other degenerative and symptomatic causes. Further, ‘all that shakes is not Parkinson’s disease’. Table 32.1 gives a differential diagnosis for causes of Parkinsonism. These are separated into degenerative and symptomatic categories. The list is not exhaustive and excludes, for instance, rare Parkinsonian manifestations in uncommon diseases. A detailed description of these different causes of Parkinsonism is beyond the scope of this chapter, but a few points should be highlighted. Essential tremor is not included in Table 32.1, as this common condition does not cause bradykinesia. Nevertheless, it may be very difficult to differentiate from tremor-dominant Parkinson’s disease. A positive family history and good response to alcohol may provide vital clues towards the diagnosis of essential tremor, although in practice these are not always reliable.

Table 32.1 Differential diagnosis of Parkinsonism

Degenerative causes Symptomatic causes
Parkinson’s disease Dopamine receptor blocking agents

Several clinical and clinicopathological series have confirmed our fallibility in not making a correct diagnosis of Parkinson’s disease. If clinical criteria, such as those produced by the UK Parkinson’s Disease Brain Bank, are not applied, then the error rate (false-negative diagnosis) may be as high as 25–30%. These criteria are listed in Box 32.1. Degenerative conditions commonly masquerading as Parkinson’s disease include progressive supranuclear palsy, multiple system atrophy and Alzheimer’s disease.

Box 32.1 Clinical criteria for diagnosis of Parkinson’s disease

Step 1 Diagnosis of Parkinsonian syndrome

The patient has bradykinesia, plus one or more of the following:

(a) classic rest tremor
(b) muscular rigidity
(c) postural instability, without other explanation

Step 2 Exclusion criteria for Parkinson’s disease

(a) history of repeated strokes
(b) history of repeated head injury
(c) history of definite encephalitis
(d) oculogyric crises
(e) dopamine receptor blocking agent exposure at onset of symptoms
(f) more than one affected relative
(g) sustained remission
(h) strictly unilateral features after 3 years
(i) supranuclear gaze palsy
(j) cerebellar signs
(k) early severe autonomic involvement
(l) early severe dementia
(m) extensor plantar
(n) cerebral tumour or hydrocephalus on CT
(o) negative response to large doses of levodopa
(p) MPTP exposure

Step 3 Supportive prospective positive criteria for Parkinson’s disease (three or more required for diagnosis of definite Parkinson’s disease)

(a) unilateral onset
(b) rest tremor present
(c) progressive disorder
(d) progressive persistent asymmetry
(e) an excellent (>70%) response to levodopa
(f) a sustained (>5 years) response to levodopa
(g) severe levodopa-induced dyskinesias
(h) clinical course >10 years

CT, computed tomography.

Drug-Induced Parkinsonism

Perhaps the most important differential diagnosis to consider when a patient presents with Parkinsonism is whether their symptoms and signs may be drug induced. This is because drug-induced Parkinsonism is potentially reversible upon cessation of the offending agent. Reports linking drug-induced Parkinsonism with the neuroleptic chlorpromazine were first published in the 1950s. Since then, numerous other agents have been associated with drug-induced Parkinsonism. Many of these are widely recognised, although others are not (Box 32.2). Compound antidepressants were a problem in the past because they contained neuroleptic drugs. For example, fluphenazine was found with nortriptyline in Motival® (discontinued in the UK in 2006) and often overlooked as a potential culprit. Repeat prescription of vestibular sedatives and anti-emetics such as prochlorperazine and cinnarizine are other commonly encountered causes of drug-induced Parkinsonism. The pathogenesis of drug-induced Parkinsonism is unlikely to be only due to dopamine receptor blockade. If this were the case, the incidence and severity should correlate with the drug dosage and length of exposure, and this is not clearly observed. Sodium valproate is also now recognised to cause an encephalopathy dominated by Parkinsonism and cognitive impairment which is reversible upon drug cessation. Again, there is considerable idiosyncrasy in who develops this encephalopathy when exposed to valproate.

Box 32.2 Examples of non-neuroleptic drugs associated with drug-induced Parkinsonism

Sodium valproate
Tetrabenazine
Calcium channel blockers (e.g. cinnarizine)
Amiodarone
Lithiuma
Phenelzineb
Amphotericin Bc
5-Fluorouracilb
Vincristine–adriamycinb
Pethidineb

a Lithium causes postural tremor. Reports of Parkinsonism occurring with lithium have usually been in the context of prior exposure to neuroleptics.

b Only single case reports of drug-induced Parkinsonism with these drugs.

c One case report of drug-induced Parkinsonism in a child after bone marrow transplantation and a second in association with cytosine arabinoside therapy.

Drug-induced Parkinsonism is more common in the elderly and in women. The clinical features can be indistinguishable from Parkinson’s disease, although the signs in drug-induced Parkinsonism are more likely to be bilateral at the onset. Withdrawal of the offending agent will lead to improvement and resolution of symptoms and signs in approximately 80% of patients within 8 weeks of discontinuation. Drug-induced Parkinsonism may, however, take up to 18 months to fully resolve in some cases. Further, in other patients, the Parkinsonism may improve after stopping the drug, only to then deteriorate. In this situation, the drug may have unmasked previously latent Parkinson’s disease. This contention is supported by a study which noted an increased risk of Parkinson’s disease in subjects who had experienced a previous reversible episode of drug-induced Parkinsonism.

Investigations

The diagnosis of Parkinson’s disease is a clinical one and should be based, preferably, upon validated criteria. In young-onset or clinically atypical Parkinson’s disease, a number of investigations may be appropriate. These include copper studies and DNA testing to exclude Wilson’s disease and Huntington’s disease, respectively. Brain imaging by computed tomography (CT) or magnetic resonance imaging (MRI) may be necessary to exclude hydrocephalus, cerebrovascular disease or basal ganglia abnormalities suggestive of an underlying metabolic cause. When there is difficulty in distinguishing Parkinson’s disease from essential tremor, a form of functional imaging called FP-CIT SPECT (also known as DaTSCAN) may be useful, as this technique can sensitively identify loss of nigrostriatal dopaminergic terminals in the striatum (Fig. 32.2). Thus, in essential tremor, the SPECT scan is normal, whereas in Parkinson’s disease, reduced tracer uptake is seen (Jennings et al., 2004).

image

Fig. 32.2 A normal FP-CIT SPECT scan image, showing symmetric tracer uptake in both striata (mirror image commas). In Parkinson’s disease, the tail of the comma is lost at an early stage, with the most severe loss being contralateral to the side most affected clinically.

Differentiating Parkinson’s disease from multiple system atrophy and progressive supranuclear palsy is a not uncommon clinical problem and may be very difficult, particularly in the early disease stages. FP-CIT SPECT cannot differentiate Parkinson’s disease from these other forms of degenerative Parkinsonism. MRI brain scanning, anal sphincter electromyography, tilt table testing for orthostatic hypotension and eye movement recordings may all be of some help, although they are rarely diagnostic in their own right.

Treatment

General approach

When treatment becomes necessary, it is impossible to generalise about which drug should be commenced. All currently available drugs for Parkinson’s disease are symptomatic, as no agent has yet been shown, beyond reasonable doubt, to have disease-modifying or neuroprotective properties. There is no accepted algorithm for the treatment of Parkinson’s disease, although a clinical management guideline has been produced (NICE, 2006).

A number of factors, including patient preference, age, severity and type of disease (tremor-dominant versus bradykinesia-dominant) and co-morbidity, need to be taken into account. The efficacy and tolerability of levodopa in Parkinson’s disease was first described 1967, when the drug was started in low doses and gradually increased thereafter (Cotzias et al., 1967).

Unfortunately, despite dramatic initial benefits, the limitations of levodopa treatment were quickly realised and a phenomenon termed the ‘long-term levodopa syndrome’ was recognised. This syndrome comprises premature wearing off of the anti-Parkinsonian effects of levodopa, and response fluctuations. The wearing-off effect is the time before a patient is due their next dose of medication, during which they become increasingly bradykinetic. Response fluctuations can include dramatic swings between gross involuntary movements (dyskinesias) and a frozen, immobile state. The rapid and sudden switching between the dyskinetic state and profound akinesia is also termed the ‘on–off’ phenomenon. If this occurs rapidly and repeatedly, the term ‘yo-yo-ing’ is sometimes used. These problems emerge at a rate of approximately 10% per year, so that by 10 years into their illness all Parkinson’s disease patients can expect to experience such unpredictable responses. Notably, however, levodopa-induced dyskinesias and fluctuations develop earlier in younger Parkinson’s disease patients than in older patients. On–off episodes may be extremely disabling and remain a major therapeutic challenge in the management of Parkinson’s disease.

Current management trends have, therefore, shifted towards either later administration of levodopa, provided alternative treatments can give adequate symptomatic control, or the use of combination therapies, in an effort to reduce the cumulative dose of levodopa given. The benefit for such ‘levodopa-sparing’ strategies beyond 5 years into the illness remains a matter of debate.

Drug treatment

Levodopa preparations

Immediate-release levodopa

Irrespective of the debate regarding early or late levodopa therapy, there is no doubt that levodopa remains the most effective oral symptomatic treatment for Parkinson’s disease. It is administered with the peripheral dopa-decarboxylase inhibitors carbidopa or benserazide, where carbidopa plus levodopa is known as co-careldopa (Sinemet®) and benserazide plus levodopa is co-beneldopa (Madopar®). The decarboxylase inhibitor blocks the peripheral conversion of levodopa to dopamine and thereby allows a lower dose of levodopa to be administered. Levodopa readily crosses the blood–brain barrier and is converted by endogenous aromatic amino acid decarboxylase to dopamine and then stored in surviving nigrostriatal nerve terminals.

Immediate-release levodopa is usually commenced in a dose of 50 mg/day, increasing every 3–4 days until a dose of 50 mg three times daily is reached. The patient should be instructed in the early stage of the illness to take the drug with food to minimise nausea. Paradoxically, in more advanced Parkinson’s disease, it may be beneficial to take levodopa 30 min or so before food, as dietary protein can critically interfere with the absorption of the drug. If there is little or no response to 50 mg three times daily, the unit dose may be doubled to 100 mg. Should the patient’s levodopa dose escalate to 600 mg/day with no significant response, the diagnosis of Parkinson’s disease should be reviewed. Levodopa, commenced in the above way, is usually well tolerated. Nausea, vomiting and orthostatic hypotension are the most commonly encountered side effects. These adverse events may be circumvented by increasing the levodopa dose even more slowly, or co-prescribing domperidone 10 or 20 mg three times daily. Later in the illness, and in common with all anti-Parkinsonian drugs, levodopa may cause vivid dreams, nightmares or even a toxic confusional state.

Clinically relevant drug interactions with levodopa include hypertensive crises with monoamine oxidase type A inhibitors. Levodopa should, therefore, be avoided for at least 2 weeks after stopping the inhibitor. Levodopa can also enhance the hypotensive effects of antihypertensive agents and may antagonise the action of antipsychotics. The absorption of levodopa may be reduced by concomitant administration of oral iron preparations.

Controlled-release levodopa

Both Sinemet® and Madopar® are available as controlled-release (CR) preparations. The nomenclature for Sinemet CR® is confusing, as the drug is marketed as Sinemet CR® (carbidopa/levodopa 50/200) and also as Half Sinemet CR® (carbidopa/levodopa 25/100). Trying to prescribe Half Sinemet CR® unambiguously can be difficult. If the instruction is misinterpreted and a tablet of Sinemet CR® is halved, the slow-release mechanism is actually disrupted.

Levodopa in controlled release preparations has a bioavailability of 60–70%, which is less than the 90–100% obtained from immediate-release formulations. Controlled release preparations have a response duration of 2–4 h, compared with 1–3 h for immediate release.

Two large studies in early Parkinson’s disease over 5 years have not shown any benefit for controlled release use over immediate-release levodopa in terms of dyskinesias and response fluctuation frequency. However, controlled release preparations may be of help in simplifying drug regimens, in relieving nocturnal akinesia, and in co-prescribing with immediate-release levodopa during the day to relieve end-of-dose deterioration.

Two commonly encountered problems with controlled release preparations are, first, changing the patient from all immediate release to all controlled release levodopa. This is poorly tolerated, as controlled release levodopa has a longer latency than immediate-release levodopa to turn the patient ‘on’ (typically 60–90 vs. 30–50 min), and the patient’s perception is that the quality of their ‘on’ period is poorer. Second, controlled release preparations should not be prescribed more than four times a day, as the levodopa may accumulate, causing unpredictable motor fluctuations.

Co-careldopa intestinal gel

An intestinal gel preparation of levodopa and carbidopa (Duodopa®) is available that is administered directly into the small bowel (specifically, the jejunum) via a percutaneous route, using a portable electronic pump. Through continuous delivery in this way, motor fluctuations may be significantly reduced. Although effective, this treatment modality requires careful patient selection. The endoscopic insertion of a percutaneous jejunostomy carries a definite morbidity and mortality. The treatment is also very expensive while mechanical problems with tube detachment and blockage have been reported.

Dopamine agonists

In theory, dopamine agonists, which stimulate dopamine receptors both post- and presynaptically, would seem to be a very attractive therapeutic option in Parkinson’s disease, as they may bypass the degenerating nigrostriatal dopaminergic neurones. Unfortunately, experience to date with the oral agents available has usually shown them to be less potent than levodopa and less well tolerated. One drug in this class, apomorphine, is used in a parenteral form. It is particularly potent and is described in detail below.

Dopamine agonists differ in their affinity for a number of receptors, including the dopamine receptor family. It is not known whether these differences are clinically significant, but experience to date would suggest not. Cabergoline is an ergot dopamine agonist with a much longer plasma half-life of 63–68 h than other agents in this class. This means that once-daily dosing is possible. Ropinirole and pramipexole are non-ergot derivatives that originally had to be administered three times daily. Slow release preparations of ropinirole (XL) and pramipexole (PR) are now available for once-daily dosing. A transdermally administered non-ergot dopamine agonist, rotigotine, is also available as a 24-h adhesive patch.

Four double-blind, randomised and controlled studies of up to 5 years duration have compared the use of a dopamine agonist (cabergoline, ropinirole, pramipexole and pergolide) with levodopa in the treatment of early Parkinson’s disease. Although the studies differed in a number of ways, such as levodopa supplementation not being permitted in the pergolide study, the results produced a consistent message that use of dopamine agonists in early Parkinson’s disease is associated with a lower incidence of dyskinesias when compared with levodopa. Supplementary levodopa was, however, required in a significant number of patients in the cabergoline (65% of patients initially randomised to cabergoline), ropinirole (66% of patients initially randomised to ropinirole) and pramipexole (53% of patients initially randomised to pramipexole) studies, suggesting that only a subgroup of patients derive adequate benefit from agonist monotherapy alone. Follow-up studies suggest that the addition of levodopa is required in the vast majority of patients and that any initial benefits in terms of lower dyskinesia incidence on agonist alone may be lost when levodopa is then introduced.

There have been very few comparative studies performed between the dopamine agonists, so it is not possible to be definitive as to which drug should be recommended. In practice, it is often worth changing from one agonist to another if side effects are a problem, since there is variability in a given patient’s tolerance to the different drugs.

Dopamine agonist side effects

The principal side effect of the dopamine agonists are nausea and vomiting, postural hypotension, hallucinations and confusion, and exacerbation of dyskinesias. Ergot derivatives run the risk of causing pleuropulmonary fibrosis, which occurs in 2–6% of patients on long-term bromocriptine treatment. Annual monitoring with chest X-ray and erythrocyte sedimentation rate (ESR) has been suggested for patients taking ergot derivative agonists, although the utility and cost-effectiveness of this recommendation have not been established. More recently, concern has been expressed over the high frequency of cardiac valvulopathy, notably of the tricuspid valve, found in patients exposed to the ergot derivatives pergolide and cabergoline. Neither drug should be used as first-line agonists in Parkinson’s disease. If prescribed, regular echocardiographic monitoring should be undertaken. There is also an increased risk of toxicity when erythromycin is co-prescribed with a dopamine agonist.

Ropinirole and pramipexole were previously implicated in causing ‘sleep attacks’, with sudden onset of drowsiness, leading to driving accidents in some cases. The term ‘sleep attack’ is almost certainly a misnomer, however, as patients do have warning of impending sleepiness, although they may subsequently be amnesic for up to several minutes while in this state. Excessive sleepiness attributable to anti-Parkinsonian drugs is actually not a new phenomenon and is almost certainly a ‘class effect’ of all dopaminergic therapies. It is essential to advise patients taking all anti-Parkinsonian agents that they may be prone to excessive drowsiness. This may be compounded by the use of other sedative drugs and alcohol.

Dopamine agonists have also been associated with impulse control disorders (ICDs). These disorders include pathological gambling, hypersexuality and excessive shopping. The onset may relate to dopamine D2/3 receptor stimulation in predisposed individuals. The patient and their carer should be warned about these potential problems before the drug is prescribed and regularly screened for abnormal behaviours while taking the agonist.

Catechol-O-methyl transferase inhibitors

Inhibitors of the enzyme catechol-O-methyl transferase (COMT) represent a novel addition to the range of therapies available for Parkinson’s disease (Schrag, 2005). Use of the first agent in this class, tolcapone, was originally suspended in Europe because of fears over hepatotoxicity, although the drug became available again in 2005, accompanied by strict prescribing and monitoring guidelines. Entacapone is also available and studies have not shown derangement of liver function with this drug.

COMT itself is a ubiquitous enzyme, found in gut, liver, kidney and brain among other sites. In theory, COMT inhibition may occur both centrally, where the degradation of dopamine to homovanillic acid is inhibited, and peripherally, where conversion of levodopa to the inert 3-O-methyldopa is inhibited, to benefit the patient with Parkinson’s disease. In practice, both tolcapone and entacapone act primarily as peripheral COMT inhibitors.

Placebo-controlled studies in patients with fluctuating Parkinson’s disease have confirmed the efficacy of entacapone in decreasing ‘off’ time and permitting a concomitant reduction in levodopa dose. A 20% reduction in ‘off’ time is reported, translating into nearly 1.5 h less immobility per day. This reduction tends to occur towards the end of the day, a time when many Parkinson’s disease patients are at their worst in terms of motor function. A comparison of entacapone and tolcapone suggested that tolcapone may be the more potent COMT inhibitor, achieving up to an extra 1.5 h of ‘on’ time per day.

When entacapone is prescribed, a 200 mg dose is used with each dose of levodopa administered, up to a frequency of 10 doses/day. Because of increased dyskinesias, an overall reduction of 10–30% in the daily dose of levodopa may be anticipated. Entacapone can be employed with any other anti-Parkinsonian drug, although caution may be needed with apomorphine. More recently, entacapone has been marketed as a compound tablet with levodopa and carbidopa (Stalevo®). Although each tablet contains 200 mg of the COMT inhibitor, there are six different doses of levodopa available (50, 75, 100, 125, 150 and 200 mg), to provide flexibility. The compound tablet may help adherence by significantly reducing the total daily number of tablets a patient needs to take.

Tolcapone is prescribed as a fixed 100 mg three times a day regimen, increasing if necessary to 200 mg three times a day. It may only be used after the patient has tried and failed entacapone and where provision for 2-weekly monitoring of liver function tests for the first 12 months, reducing in frequency thereafter, is available. Again, a concomitant reduction in levodopa may be necessary to offset an increase in dyskinesias.

The optimal way to use COMT inhibition is unknown. A patient experiencing end-of-dose deterioration, or generally underdosed, would seem to be the ideal candidate. However, there are few comparative studies of COMT inhibitors versus dopamine agonists available to provide guidance as to which class of drug is best to use, and when. The STRIDE-PD study (Stocchi et al., 2010) assessed the potential benefit of combined treatment with levodopa and entacapone in de novo Parkinson’s disease patients to address whether this combined treatment was associated with a lower incidence of dyskinesias. Unfortunately, the opposite was actually found, with a higher incidence of dyskinesias in patients randomised to levodopa and entacapone compared with levodopa alone.

Other than exacerbation of dyskinesias, COMT inhibitors may also cause diarrhoea, abdominal pain and dryness of the mouth. Urine discolouration is reported in approximately 8% of patients taking entacapone.

It is best to avoid non-selective monoamine oxidase inhibitors or a daily dose of selegiline in excess of 10 mg when using entacapone. In addition, the co-prescribing of venlafaxine and other noradrenaline (norepinephrine) reuptake inhibitors is best avoided. Entacapone may potentiate the action of apomorphine. Patients taking iron preparations should be advised to separate this medication and entacapone by at least 2 h.

Monoamine oxidase type B inhibitors

The propargylamines selegiline and rasagiline are inhibitors of monoamine oxidase type B. Inhibition of this enzyme slows the breakdown of dopamine in the striatum. These agents effectively have a ‘levodopa-sparing’ effect and may delay the onset of, or reduce existing, motor complications. Both drugs may also have an antiapoptotic effect (apoptosis is a form of programmed cell death thought to be important in several neurodegenerative conditions, including Parkinson’s disease). Whether or not the drugs have a neuroprotective effect by this or some other means remains controversial. A recent study suggested that 1 mg of rasagiline may have a disease-modifying benefit in early Parkinson’s disease, although this study was difficult to interpret since the same effect was not seen with the 2 mg dose (Olanow et al., 2009). Further, the magnitude of effect was very modest and of uncertain clinical relevance. The findings, therefore, need to be interpreted with caution but do offer some cause for optimism.

A single daily dose of 5 or 10 mg of selegiline is prescribed. Higher doses are associated with only minimal additional inhibition of monoamine oxidase. Selegiline may also be administered as a lyophilised freeze-dried buccal preparation. The dose of rasagiline is 1 mg daily.

Both selegiline and rasagiline may be used as de novo or adjunctive treatments in Parkinson’s disease, although trial data for the latter indication are strongest for rasagiline and buccal selegiline.

Following publication of a study (Lees, 1995) which showed excess mortality in a group of patients taking selegiline, it was suggested that the drug was best avoided in patients with falls, confusion and postural hypotension. A subsequent meta-analysis, including nine trials of selegiline, did not, however, identify any excess mortality in patients taking selegiline (Ives et al., 2004). Selegiline can cause hallucinations and confusion, particularly in moderate-to-advanced disease. The withdrawal of selegiline may then be associated with significant deterioration in motor function. Unlike selegiline, rasagiline is not metabolised to amfetamine-like products, so neuropsychiatric side effects are less frequent. Selegiline should not be co-prescribed with selective serotonin reuptake inhibitors, as a serotonin syndrome, including hypertension and neuropsychiatric features, has been reported in a small minority of cases. Caution is also required for rasagiline when co-prescribing with a selective serotonin reuptake inhibitor.

Amantadine

Amantadine was introduced as an anti-Parkinsonian treatment in the late 1960s. It has a number of possible modes of action, including facilitation of presynaptic dopamine release, blocking dopamine reuptake, an anticholinergic effect, and also as a N-methyl-d-aspartate (NMDA) receptor antagonist. Initially employed in the early stages of treatment, where its effects are mild and relatively short-lived, interest has focused more recently upon the use of amantadine as an antidyskinetic agent in advanced disease (Blanchet et al., 2003).

Daily doses of 100–300 mg amantadine may be used. Some recommend even higher doses for improved antidyskinetic effect, although side effects become much more frequent at higher doses. These side effects include a toxic confusional state, peripheral oedema and livedo reticularis (a persistent patchy reddish-blue mottling of the legs, and occasionally the arms). There may be significant rebound worsening of Parkinsonism when amantadine is withdrawn. The mechanism for this is unknown.

Anticholinergic drugs

The availability of anticholinergic drugs such as trihexyphenidyl and orphenadrine predated the introduction of levodopa by nearly 90 years. Anticholinergic drugs have a moderate effect in reducing tremor but do not have any significant benefit upon bradykinesia.

The use of anticholinergic agents has declined because of troublesome side effects, including constipation, urinary retention, cognitive impairment and toxic confusional states. In selected younger patients, an anticholinergic drug may still be helpful but close monitoring is advised. Postmortem studies have suggested that long-term anticholinergic use may have adverse disease-modifying effects in Parkinson’s disease, by increasing cortical levels of Alzheimer-type pathology (Perry et al., 2003).

Tricyclic antidepressants have anticholinergic properties, normally regarded as a disadvantage in the treatment of depression. These drugs are generally longer acting than other anticholinergic agents and may have a potential benefit in Parkinson’s disease, both for their anticholinergic effects and also their effect in inhibiting monoamine reuptake at adrenergic nerve endings. A low dose of a tricyclic antidepressant, for example, amitriptyline 10–25 mg, at night is sometimes useful in alleviating nocturnal akinesia, improving sleep and improving performance early in the morning.

Apomorphine

Apomorphine is a specialised, but almost certainly underused, drug in the treatment of Parkinson’s disease. It is the most potent dopamine agonist available and is administered either by bolus subcutaneous injection or by continuous subcutaneous infusion. The drug is acidic and is generally difficult to administer in a stable form which does not lead to irritation of skin or mucosal surfaces. Alternative methods of administration, including transdermal and intranasal routes and the use of an implantable copolymer-based apomorphine matrix, are being evaluated.

The drug produces a reliable ‘on’ effect with short latency of action. A single bolus lasts for up to 60 min, depending upon the dose given. Continuous subcutaneous apomorphine may significantly improve dyskinesias in advanced Parkinson’s disease, as well as lessening akinesia and rigidity. This may allow oral anti-Parkinsonian medications to be reduced.

Apomorphine causes profound nausea, vomiting and orthostatic hypotension. These problems are counteracted by pre-dosing for 2–3 days with domperidone 20 mg three times daily. Neuropsychiatric disturbance, probably at a lower frequency than with oral agonists, and skin reactions, including nodule formation, are other potential side effects. Apomorphine, in conjunction with levodopa, may cause a Coomb’s positive haemolytic anaemia, which is reversible. It is recommended that patients be screened before beginning treatment and at 6-monthly intervals thereafter.

Surgical treatment

There has been renewed interest in the use of neurosurgical techniques for the treatment of Parkinson’s disease (Walter and Vitek, 2004). This has resulted not only from recognition of the shortcomings of medical treatment currently available but also from an improved understanding of basal ganglia circuitry and better neuroimaging methods. Table 32.2. summarises techniques currently being employed and evaluated. The functional effects of lesioning (-otomy) and the use of deep brain stimulation are similar, in that the high frequency used in stimulation is believed to act by blocking, or ‘jamming’ neurones. Deep brain stimulation has the advantage of being reversible but is costly, and programming the stimulator may be very time consuming.

Table 32.2 Summary of anatomical targets for surgical treatment of Parkinson’s disease

image

The subthalamic nucleus target is the current target of choice in most centres and the number of published patient-years experience with this surgical approach has increased rapidly over the past decade. Several randomised controlled studies have confirmed the benefits that may be gained from deep brain stimulation of the subthalamic nucleus, in terms of impairment, activities of daily living, and quality of life. Careful case selection is essential for all forms of surgical intervention for Parkinson’s disease: older and less biologically fit patients, those with active cognitive and/or neuropsychiatric problems, and patients with a suboptimal levodopa response are generally regarded as poor surgical candidates.

Surgery may also play a role in neurorestorative treatments. Such approaches include stem cell and fetal cell transplantation, and also gene transfer using viral vectors. To date, there have been conflicting results regarding the efficacy of fetal cell transplants. These differences may well reflect transplantation technique, the nature of the tissue being implanted, whether immunosuppression is prescribed, and how patients are selected and assessed. Despite the negative results from two double-blind studies of embryonic cell implantation, researchers continue to explore the potential benefits from this approach.

Patient care

Common therapeutic solutions to problems encountered in the management of people with Parkinson’s disease are presented in Table 32.3. After diagnosis, the provision of an explanation of the condition, education and support are essential. The Parkinson’s Disease Society (www.parkinsons.org.uk) produces an excellent range of literature to help the newly diagnosed patient come to terms with the condition. In accordance with advice given by the Society itself, patients who drive are advised to inform their insurance company and also the Driver and Vehicle Licensing Agency.

Table 32.3 Common therapeutic solutions in the management of Parkinson’s disease

Problem Cause Possible Solution
Early-onset dyskinesias in young Parkinson’s disease patient Exposure to levodopa?
Biological factors?		 Delay introduction of levodopa, or use lowest possible dose, or use alternative agent (e.g. agonist, MAOB inhibitor)
One dose of levodopa does not last until the next (wearing off) Advanced disease (pre- and post-synaptic changes) More frequent, smaller doses of levodopa, COMT inhibitor, dopamine agonist or MAOB-inhibitor
Pain and immobility during the night Evening dose of levodopa not lasting long enough Use slow release levodopa preparation or dopamine agonist
Freezing episodes and/or unpredictable motor fluctuations Advanced disease (pre- and post-synaptic changes) Apomorphine, duodopa or surgeryPhysiotherapy helpful for freezing
Mismatch between patient’s symptoms and signs Underlying depression? Consider antidepressant
Confusion and hallucinations with preserved cognition Toxic (drug-related) psychosis Exclude intercurrent infection or other medical problem
Review and reduce anti-Parkinsonian therapy Consider atypical anti-psychotic agent
Confusion and hallucinations with impaired cognition Underlying brain pathology, and cholinergic deficit Reduce anti-Parkinsonian therapy
Cholinesterase inhibitor

A doctor will record impairments in the clinic, while the patient is more concerned with their disability and handicap. Thus, a patient can be noted to have seemingly marked impairment and yet may not complain about significant disability. The converse may also be true. Not all patients, therefore, require immediate treatment. Further, concomitant depression may distort the patient’s perception of their disability, leading to inappropriate prescribing of anti-Parkinsonian therapy. In this situation, the use of an antidepressant may be more helpful. There is no good evidence base for which antidepressant should be used, and both the tricyclic agents and selective serotonin reuptake inhibitors have their advocates.

Accurate adherence with the timing of therapy may be particularly important in patients who are beginning to develop long-term treatment complications. It can be helpful for patients to keep diary cards when they begin to experience problems with either bradykinesia or dyskinesia, so that these symptoms can be related to drug and food intake. Careful changes in timing of drug therapy or meals may initially be sufficient to reduce variation in performance. Some patients experience troublesome early morning bradykinesia. It may then be beneficial to prescribe an initial dose of a rapidly acting agent, such as dispersible oral co-beneldopa, to take on first wakening so that the patient can then get up and dress. A combination of levodopa with dopamine agonists, which are more slow acting, may be useful in the patient with motor fluctuations. A combination of levodopa and a COMT inhibitor may be more appropriate in a patient with end-of-dose deterioration.

Other factors that need to be considered in patients with Parkinson’s disease are the benefits of adequate sleep and rest at night, which may be made more difficult if they have urinary frequency or problems with nocturnal bradykinesia. Judicious use of hypnotic therapy may be appropriate, while a tricyclic antidepressant may offer the dual benefit of sedation with anti-cholinergic effect. Low friction sheets to assist turning in bed and encouragement of mobility through physiotherapy may also be helpful. The treatment of the patient with severe disease remains one of the greatest challenges in the management of Parkinson’s disease. On–off fluctuations may be refractory to oral dopaminergic therapies. Sudden freezing episodes compound failing postural stability, leading to increasing falls and injuries. In select patients, the use of apomorphine, either as bolus injection (via a ‘Penject’ device) or as a continuous subcutaneous infusion, may be helpful.

The presence of reduced dexterity in virtually all people with Parkinson’s disease means that thought needs to be given to the way in which medication is dispensed and stored. If the patient is taking a complex regimen of drugs or has early cognitive problems, the use of pre-packaged therapies may improve adherence.

Patients’ relatives also need emotional and social support through what can be a very demanding period. The loss of physical mobility, together with a personality change, can be very difficult for relatives to cope with. The involvement of occupational therapists, social workers and specialists in palliative care in this situation is important.

Psychosis and dementia

When cognitive impairment is problematic, the use of conventional antipsychotic medication is inappropriate because such drugs can precipitate a catastrophic worsening of Parkinsonism. Behavioural disturbances require discussion with carers and, if possible, with the patient him- or herself. A graded withdrawal of anti-Parkinsonian drugs is often indicated, aiming to simplify the regimen to levodopa monotherapy. In rare cases, it may be necessary to reduce the dose or even completely withdraw levodopa therapy in order to control aggressive, sexually demanding or psychotic features. When reduction in dopaminergic therapy is ineffective or not tolerated because of unacceptable immobility, an atypical antipsychotic drug may be considered. In practice, the choice narrows down to quetiapine or clozapine, since risperidone and olanzepine are associated with worsening Parkinsonism, even in low doses. Further, both risperidone and olanzepine should not be used in cognitively impaired elderly people because of an increased risk of stroke. Clozapine is difficult to use for Parkinson’s disease-associated psychosis because of the need to register the patient with a blood-monitoring programme. When quetiapine is used, it should be commenced in a low dose of 25 or 50 mg at night and increased slowly. The sedative effects may be helpful in promoting sleep.

Cholinesterase inhibitors have shown promise in treating the neuropsychiatric features of Parkinson’s disease and may also have modest cognitive-enhancing benefits. Visual hallucinations, delusions, apathy and depression seem to be particularly responsive to these agents. These effects have been demonstrated for rivastigmine in dementia associated with Parkinson’s disease in a large, multicentre, double-blind, placebo-controlled study (Emre et al., 2004). A randomised controlled trial of memantine in dementia associated with Parkinson’s disease (and also patients with the closely related dementia with Lewy bodies) showed a modest benefit for memantine in the primary end-point, the Clinician’s Global Impression of Change (Aarsland et al., 2009).

Autonomic problems

Other complications that may need attention include disorders of gut motility, which present as constipation or difficulty with swallowing, disturbances of micturition, sometimes presenting as nocturia, and postural hypotension. Constipation can be managed in the usual way with bulking agents and, if necessary, stimulant laxatives and stool-softening agents. The management of postural hypotension includes assessment of the patient’s autonomic function in order to establish whether this is primarily drug related or associated with autonomic neuropathy. If the patient is dizzy on standing, simple measures such as advice on rising slowly may be adequate. The use of elastic stockings, to reduce pooling of the blood in the lower limbs, is sometimes helpful. Pharmacological approaches include the use of fludrocortisone or occasionally midodrine (a selective α1-adrenergic agonist). It is also important to consider other therapies the patient is receiving that might contribute to such symptoms, for example, diuretics, and to stop these if possible.

Case studies

Case 32.1

A 48-year-old man, Mr V, has a 2-year history of Parkinson’s disease. He is still working in an office. His wife confides in the Parkinson’s Disease Nurse Specialist that she is concerned about his gambling. Whilst never a problem before his diagnosis, he is now spending huge sums of money on on-line casinos. They are getting into financial difficulties on account of this habit. She is upset and desperate for help.

Questions

1. What might be responsible for this gentleman’s behaviour?
2. What would be the most appropriate management?

Answers

1. The most likely cause of Mr V’s pathological gambling (so-called because of the adverse effect this is having on his family and life in general) relates to his medication. He was, in fact, taking the dopamine agonist pramipexole, as well as rasagiline to control his Parkinsonian symptoms. Dopamine agonists have been associated with impulse control disorders.
2. Mr V’s dopamine agonist should be withdrawn as quickly as possible, via down-titration of the dose over a few weeks. This will, of course, worsen his motor symptoms. In Mr V’s case, he required the use of co-careldopa to regain adequate control of his Parkinsonism, but off the agonist his gambling habit ceased completely. His wife was delighted. Had the patient and his wife been warned of this possible problem prior to starting the agonist the situation may not have got to such a near-disastrous social level. It is, therefore, essential to warn all patients starting dopamine agonists about the risk of impulse control disorders and to document this in writing in the medical records.

Case 32.2

A 70-year-old man, Mr W, was diagnosed as having mild Parkinson’s disease 6 months ago. This did not require any treatment. He has no past medical history of note. He returns to clinic and it is clear that both his impairment and disability have worsened.

Questions

1. What initial treatment options should be considered for Mr W?
2. What considerations should be given to the initial drug choice?

Answers

1. There is no evidence to suggest that Mr W is depressed; a masked depression should always be considered when there is a ‘mismatch’ between impairment and reported disability. This was not the case here. A number of first-line anti-Parkinsonian drugs might, therefore, be considered, including immediate-release levodopa preparations, dopamine agonists and monoamine oxidase type B inhibitors.
2. Co-morbid illness or a life-shortening problem, such as cancer, usually mean that levodopa would be first choice, simply because it is most potent, with a good risk:benefit ratio. If the patient is biologically fit, then either a dopamine agonist or a monoamine oxidase type B inhibitor might be appropriate, so long as the disability is not too severe and there are no other contraindications. Dopamine agonists and selegiline, in particular, have the potential to cause or exacerbate neuropsychiatric problems and the patient and their family should be warned of such side effects. In particular, the patient and their family should be informed of the risk of impulse control disorders, generally associated with dopamine agonists, and this warning recorded in the medical records. By using these ‘levodopa-sparing’ agents, the onset of dyskinesias may be delayed by several years.

Case 32.3

A 59-year-old gentleman, Mr X, has had Parkinson’s disease for 8 years. This was initially treated with selegiline and ropinirole. Due to progressive functional disability and his wish to keep working, levodopa was introduced 5 years previously. He is now experiencing severe motor fluctuations during the day, with periods of marked dyskinesia and also increasingly unpredictable ‘off’ periods, during which he is stiff, immobile and anxious. Unsuccessful attempts to smooth out these fluctuations have been made by manipulating his levodopa unit dose and frequency, the use of entacapone, and changing his dopamine agonist.

Questions

1. What therapeutic options could be considered in Mr X’s case?
2. What factors would influence the choice of treatment?

Answers

1. A relatively simple option that has not yet been considered is amantadine. This agent may have useful antidyskinetic effects in advanced Parkinson’s disease. It is usually administered as 100 mg daily initially, increasing gradually to two or three times daily. The dose of levodopa therapy is left unchanged, to avoid worsening ‘off’ periods. Neuropsychiatric problems and/or a livedinous rash may complicate the use of amantadine, although younger patients are often able to tolerate the drug better. An alternative approach which may well be required is the use of continuous subcutaneous apomorphine with or without amantadine, as this may have a significant antidyskinetic effect and also effectively manage freezing episodes. Duodopa® therapy, administered via a percutaneous jejunostomy, may also be a consideration. Finally, deep brain stimulation of the subthalamic nucleus may be appropriate for Mr X.
2. Patient choice, after being given the relevant options, is clearly important, as the treatments involved are potentially invasive and associated with morbidity. A previous history of neuropsychiatric problems, active psychosis or severe depression, or cognitive impairment would be relative contraindications to surgery. Severe needle phobia or the lack of an appropriately experienced and committed local nurse specialist would compromise the effective administration of apomorphine.

Case 32.4

A 63-year-old lady, Mrs Y, is referred by a colleague because of suspected Parkinson’s disease. There is also evidence of some cognitive decline in the past 12 months. She has a background history of epilepsy which was quiescent until three years ago. At that stage, she presented to the neurology department, and her anticonvulsant regimen adjusted to good effect. Examination confirms a mini-mental state examination (MMSE) score of 22/30, symmetric bradykinesia and some rigidity.

Questions

1. Which question might give additional diagnostic help in this lady’s history?
2. What would be the best management?

Answers

1. Given this lady’s history of epilepsy, and the subsequent evolution of Parkinsonism and cognitive decline, one would be suspicious of the change in her anticonvulsant medication. A drug history confirmed that she had been switched from phenytoin to sodium valproate, raising the possibility of a ‘valproate encephalopathy’.
2. Discontinuation of the valproate is definitely worth attempting and converting to an alternative anticonvulsant. If there is doubt over the diagnosis, an FP-CIT SPECT scan can be helpful; in Parkinson’s disease, the scan is abnormal, whereas in drug-induced Parkinsonism, because the problem is caused by postsynaptic blockade of dopamine receptors, tracer uptake will be normal. In this case, Mrs Y’s Parkinsonism resolved completely and on repeat testing 6 months later her MMSE had risen to 29/30. She was taking lamotrigine to control her seizures at review.

Case 32.5

Mr Z has an 8-year history of Parkinson’s disease. He is 77 years old. His motor symptoms are well controlled on a combination of one tablet of co-careldopa (25/100), three times a day and selegiline 10 mg daily. His wife comes to clinic with him and reports that he has recently been confused at night. Further, he has been hallucinating, seeing his long-dead mother at the bottom of the bed.

Question

What should be done?

Answer

The problem here is to what extent the features of Mr Z’s psychosis relates to his drugs or to the underlying disease process. Dementia associated with Parkinson’s disease is more common in the older patient with long-standing disease.

An MMSE to assess cognitive function in more detail would be appropriate (although note that this scale is relatively insensitive in detecting dementia associated with Parkinson’s disease). Intercurrent infection and metabolic derangements, for example, hypothyroidism, should also be excluded.

Selegiline is best avoided in cases like this and should be discontinued. This may lead to an improvement in Mr Z’s psychotic features, without any other action being necessary. The use of a typical antipsychotic agent for Mr Z is absolutely contraindicated, as it will only serve to worsen his Parkinson’s disease. If cognitive function is well preserved and discontinuing selegiline fails to improve the situation, then a low dose of the atypical antipsychotic quetiapine could be considered. If there is evidence of dementia, a cholinesterase inhibitor would be a better therapeutic choice.

References

Aarsland D., Ballard C., Walker Z., et al. Memantine in patients with Parkinson’s disease dementia or dementia with Lewy bodies: a double-blind, placebo-controlled, multicentre trial. Lancet Neurol. 2009;8:613-618.

Blanchet P.J., Verhagen-Metman L., Chase T.N. Renaissance of amantadine in the treatment of Parkinson’s disease. Adv. Neurol.. 2003;91:251-257.

Braak H., Del Tredici K., Rüb U., et al. Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiol. Aging. 2003;24:197-211.

Cotzias G.C., Van Woert M.H., Schiffer L.M. Aromatic amino acids and modification of parkinsonism. N. Engl. J. Med.. 1967;276:374-379.

Emre M., Aarsland D., Albanese A., et al. Rivastigmine for dementia associated with Parkinson’s disease. N. Engl. J. Med.. 2004;351:2509-2518.

Healy D.G., Abou-Sleiman P.M., Wood N.W. PINK, PANK or PARK. A clinician’s guide to familial parkinsonism. Lancet Neurology. 2004;3:652-662.

Ives N., Stowe R.L., Marro J., et al. Monoamine oxidase type B inhibitors in early Parkinson’s disease: meta-analysis of 17 randomised trials involving 3525 patients. Br. Med. J. 2004;329:593-596.

Jennings D.L., Seibyl J.P., Oakes D., et al. (123I)beta-CIT and single-photon emission computed tomographic imaging vs. clinical evaluation in Parkinsonian syndrome: unmasking an early diagnosis. Arch. Neurol. 2004;61:1224-1229.

Lees A.J., on behalf of the Parkinson’s Disease Research Group of the United Kingdom. Comparison of therapeutic effects and mortality data of levodopa and levodopa combined with selegiline in patients with early, mild Parkinson’s disease. Br. Med. J.. 1995;311:1602-1607.

National Institute for Health and Clinical Excellence. Parkinson’s disease: diagnosis and management in primary and secondary care. Clinical Guideline 35. London: NICE, 2006. Available at: http://www.nice.org.uk/page.aspx?o=CG035

Olanow C.W., Perl D.P., DeMartino G.N., et al. Lewy-body formation is an aggresome-related disorder: a hypothesis. Lancet Neurol. 2004;3:496-503.

Olanow C., Rascol O., Hauser R., et althe ADAGIO Study Investigators. A double-blind, delayed-start trial of rasagiline in Parkinson’s disease. N. Engl. J. Med.. 2009;361:1268-1278.

Olanow C.W., Prusiner S.B. Is Parkinson’s disease a prion disorder? Proc. Natl. Acad. Sci.. 2009;106:12571-12572.

Perry E.K., Kilford L., Lees A.J., et al. Increased Alzheimer pathology in Parkinson’s disease related to antimuscarinic drugs. Ann. Neurol.. 2003;54:235-238.

Schrag A. Entacapone in the treatment of Parkinson’s disease. Lancet Neurol. 2005;4:366-370.

Stocchi F., Rascol O., Kieburtz K., et al. Initiating levodopa/carbidopa therapy with and without entacapone in early Parkinson disease: the STRIDE-PD study. Ann. Neurol. 2010;68:18-27.

Walter B.L., Vitek J.L. Surgical treatment for Parkinson’s disease. Lancet Neurol.. 2004;3:719-728.

Further reading

Chaudhuri K.R., Healy D.G., Schapira A.V.H. Non-motor symptoms of Parkinson’s disease: diagnosis and management. Lancet Neurol. 2006;5:235-245.

Clarke C.E. Parkinson’s disease. Br. Med. J. 2007;335:441-445.

Hauser R.A. Levodopa: past, present and future. Eur. J. Neurol. 2009;62:1-8.

Lees A.J., Hardy J., Revesz T. Parkinson’s disease. Lancet. 2009;373:2055-2066.

Olanow C.W., Stern M.B., Sethi K. The scientific and clinical basis for the treatment of Parkinson’s disease. Neurology. 2009;72(21 Suppl 4):S1-136.

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