Parkinson’s disease

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).

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Jun 18, 2016 | Posted by in PHARMACY | Comments Off on Parkinson’s disease

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