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The Royal Free Hospital NHS Trust, Hampstead, London NW3 2QG, UK Introduction: Parkinson’s disease (PD) is one of the most commonneurodegenerative disorders.
Sources of data: Literature search using Medline with keywords Parkinson’sdisease supplemented with previously published papers known to the author.
Areas of agreement: There have been significant recent advances in theunderstanding of the pathogenesis of the disease. There has also been a greaterrealization that the disorder may be associated with significant non-motordisturbances in addition to the more commonly recognized motor Areas of controversy: Although there is growing circumstantial evidence, it remains to be proven whether any of the current treatments for PD have aneuroprotective effect.
Areas timely for developing research: Although there is no cure, there areseveral management options for the early treatment of PD. As the disease progresses, further treatment options are available; however, the managementof late-stage motor complications and non-motor symptoms remains particularlychallenging and will benefit from further clinical research.
Keywords: Parkinson’s disease/motor complications/non-motor complications Parkinson’s disease (PD) is a common neurodegenerative disorder—asynucleinopathy—with a prevalence of 160/100 000 in Western Europerising to 4% of the population over 80.1 With an ageing population, the management of PD is likely to prove an increasingly important and challenging aspect of medical practice for neurologists and general physicians. Our understanding of the pathogenesis of the disease has been advanced in the last decade with the identification of several gene mutations which may shed light on the mechanisms of pathogenesis in British Medical Bulletin 2008; 86: 109–127 & The Author 2008. Published by Oxford University Press.
All rights reserved. For permissions, please e-mail: [email protected] The diagnosis of PD remains essentially a clinical one, and it is important to recognize the early features together with symptoms andsigns suggesting other causes of parkinsonism.
There has also been a rapid expansion in the treatment options both in the early and in the later stages of the illness together with a greaterawareness of non-motor complications. Guidelines for the diagnosisand management of patients with PD have been published from theNational Institute for Health and Clinical Excellence (NICE) in theUK.2 The pathological hallmark of PD is cell loss within the substantia nigraparticularly affecting the ventral component of the pars compacta. Bythe time of death, this region of the brain has lost 50– 70% of its neur- ones compared with the same region in unaffected individuals. The ear-liest documented pathological changes in PD3 have been observed inthe medulla oblongata/pontine tegmentum and olfactory bulb. In these early stages—Braak stages 1 and 2—patients are pre-symptomatic. Asthe disease advances—Braak stages 3 and 4—the substantia nigra,areas of the midbrain and basal forebrain become involved. Finally, thepathological changes appear in the neocortex.
This pathological staging is based on the distribution of lewy bodies.
Lewy bodies are the pathological hallmark of PD. They area-synuclein-immunoreactive inclusions made up of a number of neuro-filament proteins together with proteins responsible for proteolysis.
These include ubiquitin, a heat shock protein which plays an importantrole in targeting other proteins for breakdown. Mutations in thea-synuclein gene are responsible for some familial forms of PD inwhich lewy bodies are also seen. Mutations in the parkin proteinproduce a parkinsonian syndrome without lewy bodies in juvenilecases suggesting that the parkin protein plays an important role in thedevelopment of the lewy body. It has been shown that parkin facilitatesthe binding of ubiquitin (ubiquination) to other proteins such as thea-synuclein interacting protein synphilin-1 leading to the formation oflewy bodies.4 Lewy bodies are found in PD and Dementia with lewybodies (DLB), but are not a pathological hallmark of any other neuro-degenerative disease.
The identification of single gene defects in PD has focused interest on the ubiquitin-proteasome system (UPS) as one potential candidate inthe development of cell death.5 The UPS is important for intracellularproteolysis and a large number of intracellular processes that maintainthe viability of cells. It does this by removing unwanted proteins that are no longer required by the cell. Failure of the UPS leads to theabnormal aggregation of proteins including a-synuclein which are amajor component of lewy bodies. One of the first sites for LB depo-sition in early PD is the olfactory bulb. It is, therefore, of interest that adisturbance in smell and taste is often one of the earliest clinical fea-tures in PD raising the possibility that LB formation may be integralfor the activation of pathways leading to neuronal dysfunction anddeath.
The link between UPS and neurodegeneration has been strengthened by the discovery of mutations in genes which code for severalubiquitin-proteasome pathway proteins in PD.
Although PD is usually a sporadic disease, there are a growing number of single gene mutations which have been identified. At the time ofwriting, 11 genes have been mapped by genetic linkage with six genesidentified: a-synuclein (SNCA), ubiquitin C-terminal hydrolase like 1 (UCH-L1), parkin (PRKN), LRRK 2, PINK 1 and DJ-1 genes. Thesesingle gene defects with the notable exception of LRRK 2 are respon-sible for only a small number of patients with PD, though more impor-tantly their identification and the proteins that they encode for are providing significant insight into the disease mechanisms that may beresponsible for PD and other neurodegenerative diseases. A pointmutation of the SNCA gene leads to the early onset of PD in affectedmembers in an autosomal dominant pattern. Of interest, duplication ortriplication of the SNCA gene in affected members leads to PD symp-toms developing at a later age in the fourth or fifth decades raising thepossibility that overexpression of SNCA may be a factor in sporadicdisease.
The LRRK 2 gene (PARK8) is the most common cause of familial or the so-called ‘sporadic’ PD to date.8 The frequency of LRRK2mutations in patients with a family history of PD is 5 –7%. The hetero-zygous mutation, 2877510 g ! A, produces a glycine to serine aminoacid substitution at codon 2019 (Gly2019 ser). This LRRK2 G2019Smutation is the most commonly described, accounting for the majorityof familial cases and up to 1.6% of cases of idiopathic PD, though theprevalence seems to be very variable. The LRRK2 gene encodes for aprotein named dardarin (derived from the basque word for tremor; theoriginal families described came from Spain and England). Lewybodies have been identified in some LRRK 2 cases. Many of theLRRK2 patients reported have typical features of PD with onset inmiddle or late onset. Symptoms at onset may be typical of idiopathic PD characterized by unilateral bradykinesia and rigidity, with tremorpresent in some but not all patients.
A number of single gene mutations, e.g. parkin and DJ-1 with an autosomal recessive pattern of inheritance, may have a clinical patternof earlier age of onset, a more benign course with good response tolevodopa and the presence of dystonia. However, it is not possible toidentify parkin positive young onset PD patients from parkin negativepatients on clinical features alone.
There has been a great deal of research into mitochondrial genetics and function in PD. Abnormalities in Complex 1 of the oxidative phos-phorylation enzyme pathway is the most consistent finding, havingbeen detected in PD brains, blood platelets and skeletal muscle,although defects in other complexes have also been reported.9 It appears that the cells of the pars compacta are particularly suscep- tible to oxidative damage. Mitochondrial DNA studies have as yetfailed to identify a convincing gene mutation to explain the oxidative phosphorylation defects in PD. However, it seems likely that a mito-chondrial defect may play a role in the pathways leading to cell dys-function and death. The PINK1 gene codes for a mitochondrial complex and has been shown to be responsible for an autosomal reces-sive form of PD, though is not a major risk factor for sporadic disease.
Identifying environmental factors that predispose to the developmentof PD has proved elusive. Living in a rural environment appears toconfer an increased risk of PD, and perhaps causally linked to thissome but not all epidemiological studies have shown a correlationbetween exposure to pesticide use and wood preservatives.10 The onlyconsistent environmental factor is a strong negative correlationbetween cigarette smoking and the development of the disease. It isalso possible that mitochondrial dysfunction in PD is triggered by oneor more environmental toxins.
The characteristic features of PD are bradykinesia, rigidity and resttremor. These may not all be present. Postural instability may be afeature, though early postural instability backwards particularly with ahistory of falls is more suggestive of progressive supranuclear palsy(PSP). The clinical findings are usually asymmetrical in PD. The clinicaldiagnosis may often appear straightforward, though it is worth noting that post-mortem studies have shown an alternative diagnosis in up toa quarter of patients with PD diagnosed by general neurologists.11 Ofnote, there is substantially less diagnostic error in patients diagnosed inexpert movement disorder clinics12 which strengthens the argument forearly referral of patients to specialists expert in movement disorders.
A number of clinical criteria have been established. Table 1 outlines an abbreviated form of the UK Parkinson’s Disease Society Brain Bankclinical diagnostic criteria.
There are a number of other clinical signs that are worth highlight- ing. A change of handwriting with micrographia is often an earlyfeature as is reduced facial expression. A loss of arm swing on one sideis also an early and useful diagnostic feature. A glabellar tap does notseem to be particularly sensitive or specific.
A reduced sense of smell is, however, worth asking about since this may be one of the first symptoms in early PD.13 As the diseasebecomes more advanced, hypophonia, drooling of saliva (from reduced swallowing) and impairment of postural reflexes may develop.
Table 1 PD– UK PDS Brain Bank diagnostic criteria.
Step 1: Diagnosis of a parkinsonian syndromeBradykinesia (slowness of initiation of voluntary movement with progressive reduction in speed andamplitude of repetitive actions) and at least one of the following: (i) muscular rigidity, (ii) 4– 6 Hz resttremor and (iii) postural instability not caused by primary visual, vestibular, cerebellar or proprioceptive dysfunctionStep 2: Exclusion criteria for PD(i) History of repeated strokes with stepwise progression of parkinsonian features Neuroleptic treatment at the onset of symptoms Strictly unilateral features after 3 years Early severe dementia with disturbances of memory, language and praxis Presence of cerebral tumour or communicating hydrocephalus on CT scan Negative response to large doses of levodopa (if malabsorption excluded) Step 3: Supportive criteria for PD (three or more required for diagnosis of definite PD)(i) Persistent asymmetry affecting side of onset most Excellent response (70 – 100%) to levodopa Non-motor complications of the disease often become more trouble-some as the disease progresses. It is helpful to enquire about symptomsof depression which occurs in 40% of PD patients. The commonerconditions that may present with parkinsonian features and are oftenconfused with PD are listed in Table 2. The diagnosis of essentialtremor should be considered when a patient presents with a Table 2 Differentiating commoner causes of parkinsonism.
rigidity, frontal andpyramidal signs, poor treatment, controlof risk factors (e.g.,diabetes,hypertension,increasedcholesterol) dyspraxia, corticalsensory loss,myoclonus, dystonia,alien limbphenomenon,absence of responseto levodopa symmetrical limb tremor, worse with posture and is suppressed byalcohol. Head or voice tremor may also be present. In this condition,there may be an autosomal dominant inheritance, suppression of thetremor with alcohol and there should be no evidence of rigidity or bra-dykinesia on examination. Adult onset dystonia may also present withasymmetrical rest tremor and may explain some patients previouslylabelled as ‘benign tremulous PD’ who have scans with no evidence ofdopaminergic defecit.14 Although the diagnosis of PD is a clinical one, there are certain situ- ations where investigations can prove useful. Conventional brainimaging with MRI or CT is usually not required unless an alternativediagnosis is suspected such as normal pressure hydrocephalus or vascu-lar parkinsonism.
Single photon emission computerized tomography (SPECT) imaging using a dopamine transporter (DAT) can be helpful in differentiatingPD from a number of conditions, including essential tremor and dys- tonic tremor, neuroleptic-induced parkinsonism and psychogenic par-kinsonism all of which demonstrate normal DAT scans. Uptake withinthe basal ganglia is reduced in PD, the parkinsonian syndromes and After establishing a clinical diagnosis, it is vital to take time to explainthe condition and its implications to the patient and relatives. It maytake for some patients time to come to terms with and accept the diag-nosis. Linking patients with PD nurse specialists and PD charitableorganizations, if available locally, can be extremely helpful.
The timing when to start drug treatment in PD, particularly in the very early stages of the illness, when there may be little functionaldeficit can be difficult. The decision which should be made with fullinvolvement of the patient is determined by the degree of physicalimpairment balanced against the complications that can be related todrug treatment. Of increasing importance is the issue of whether earlytreatment confers the potential for neuroprotection. This remains unre-solved, despite a large number of in vitro, in vivo and human studiesmany of the latter using PET or SPECT imaging as surrogate markersof nigrostriatal dopaminergic function.16 At present, therefore, there are no proven neuroprotective therapies with only symptomatic treatments available.
If the patient and clinician feel treatment is required, what therapy should be commenced? This decision will be based on the age of thepatient, the likelihood of proper compliance, the presence of cognitive impairment, additional medical conditions and the wishes of thepatient. Treatment in the initial stage is to alleviate symptoms allowingthe individual to be fully independent and to carry out their normaldaily activities. It is vital that treatment is well tolerated. For thisreason, monotherapy is usually desirable. If patients can remain ontreatment with minimal side effects, with a satisfactory reduction ofsymptoms and a feeling of well-being that allows them to live indepen-dently and productively, then the introduction of treatment has clearlybeen worthwhile.
In patients with minimal or no disability, early treatment may still be initiated. One study has shown that self-reported health status using aParkinson’s Disease Questionnaire (PDQ)-39 at initial consultation andfor up to 18 months was worse in untreated PD patients,17 though thevalidity of the rating scale in this patient group has been questioned.18 Should treatment begin with levodopa, a dopaagonist or MAO-B inhibitor? For 40 years, levodopa, combined with a peripheral decarboxylaseinhibitor, has been regarded as the gold standard for the treatment of PD. It still remains in many respects the most efficacious drug treat-ment. However, the benefits achieved often come at a price. Long-termlevodopa Levodopa-induced dyskinesias develop at an average rate of 10% perannum after commencing levodopa, although this figure is higher inyounger onset patients. Motor fluctuations are most strongly related todisease duration and dose of levodopa exposure, whereas dyskinesiasare predominantly due to duration of levodopa treatment.19 The devel-opment of drug-induced dyskinesias in PD seems to be associated withintermittent stimulation of dopamine receptors. Levodopa has a shorthalf-life of 60 –90 min, and pulsatile levodopa supply to a denervatedstriatum seems to be an important aetiological factor. In addition, themore severe the nigral neuronal loss is at the introduction of levodopa,the sooner adverse features are seen. A controversial issue has beenwhether levodopa could have a neurotoxic effect. The ELLDOPAstudy20,21 tried to address this in a large, randomized placebo-controlled clinical study of patients with early PD who had not pre-viously received symptomatic treatment. The goal of the study was toascertain whether levodopa treatment affected the rate of disease pro-gression. At the end of a 2-week washout period, the UPDRS scores ofpatients treated with all three doses of levodopa were better than those of the placebo group in a dose-responsive pattern. Although this mayhint at a neuroprotective effect, it is possible that the 2-week washoutperiod was insufficient. However, the treated groups did show adose-dependent tendency towards motor complications includingdyskinesias. In addition to clinical outcomes, a sub-group of patientsunderwent ß-CIT SPECT imaging which was used as a marker forintact nigrostriatal dopaminergic neurones. This showed a largerdecrease in striatal DAT binding in a dose –response pattern. This mayinfer that levodopa actually hasten the progression of PD, though it isequally conceivable that the changes in uptake reflected a pharmaco-logical effect of levodopa on DAT activity. The issue regarding neuro-protection or neurotoxicity with levodopa remains unclear. However,given the risk of motor complications over time, which are dose depen-dent, using small doses of levodopa, tailored to the patient’s needs arepreferable.
There are six orally acting dopamine agonists available in the UK. Fourare ergot derivatives: bromocriptine, pergolide, cabergoline and lisur-ide; and two non-ergot drugs: ropinirole and pramipexole. Rotigotineis a non-ergot agonist available by transdermal patch. These drugs all work by stimulation of the post-synaptic dopamine receptors. Thedopamine agonists were initially licensed for use in conjunction withlevodopa in patients with advanced PD. Their introduction as first-lineagents came about as a result of their efficacy in improving motorsymptoms in addition to their ability to delay the introduction of levo-dopa and the subsequent development of levodopa complications.
Monotherapy trials have been undertaken comparing dopamine ago-nists with levodopa. The first such trial using bromocriptine in the1980s showed a delay in the onset of dyskinesias with bromocriptinemonotherapy compared with levodopa therapy, but no effect withregards to the onset of motor fluctuations.22 Trials of the more recentlyintroduced dopamine agonists showed a significant reduction in thedevelopment of motor complications in patients initiated on agonistmonotherapy compared with levodopa.23 – 25 However, in the publishedtrials of ropinirole and pramipexole monotherapy, patients treated withlevodopa showed improved UPDRS scores ( parts II and III) comparedwith those on dopamine agonists, although during the trials, patientand physician assessments for the two arms were comparable. Qualityof life (QoL) outcome measures over the 4 years of the CALM-PDstudy24 were the same for the levodopa and pramipexole groups. Theside effect profile of the dopamine agonists is similar to levodopa, but confusion and hallucinations are more frequent than with levodopatherapy alone.
The dilemma of first line treatment in PD is therefore this: dopamine agonists produce fewer motor complications and the same QoL scores,but the price for this is a higher incidence of side effects and reducedefficacy as determined by the UPDRS. There has been a general beliefthat the potential for side effects with dopa agonist monotherapy ismuch greater in elderly patients, but studies with the newer agonists donot bear this out and these drugs can be well tolerated in patients over75 years. However, as suggested above, additional caution is requiredin using agonists in the elderly.
The decision on which dopamine agonist to initiate is often an empirical one. There have been few head-to-head comparative studiesbetween the agonists. Cabergoline is an ergot derivative with a highaffinity for the D2 and D3 receptors. However, there have beenincreasing reports of non-inflammatory fibrotic degeneration of cardiac valves with the ergot agonists,26,27 specifically cabergoline and pergo-lide, and for this reason, they are no longer recommended as first-linetreatments. Regular monitoring including ESR, chest X-ray and 6-monthly echocardiography are recommended for those continuing onergot-derived agonists.
Commonly used non-ergot-derived dopamine agonists include ropi- nirole, pramipexole and rotigotine. An uncommon, but important, side effect most frequently reported to date with pramipexole is anincreased risk of pathological gambling.28,29 MAO-B inhibitors were widely used following the DATATOP study30for their proven efficacy in symptom improvement and presumed ‘neu-roprotective’ effect. However, a subsequent study by The UnitedKingdom Parkinson’s Disease Research Trial Group31 following over700 patients with mild early PD appeared to show a significantincrease in mortality in patients treated with selegiline and levodopacompared with levodopa alone or bromocriptine alone. This findingwas not replicated in further studies which indeed suggested the oppo-site, a possible reduction in mortality.32 A more recent meta-analysis of17 randomized trials involving a total of 3525 patients came to theconclusion that MAO-B inhibitors reduce disability, the need for levo-dopa and the incidence of motor fluctuations, without substantial sideeffects or increased mortality.33 Many of these studies have been ofshort duration and have not compared selegiline with initial treatmentwith a dopamine agonist. However, MAO-B inhibitors do have a potential role as first-line monotherapy in PD patients. Studies usingrasagiline, a novel MAO-B inhibitor, have demonstrated efficacy inearly and advanced disease. The TEMPO wash-in trial34 gave resultscompatible with a disease modifying effect, although like the dopamineagonist studies cited above, additional work needs to be done toconfirm a neuroprotective effect.
The treatment of late motor complications of PD After some years of stable, sustained response to levodopa therapy,most patients with PD experience fluctuations in motor performance,the effect of a single levodopa dose becoming progressively shorter(wearing-off phenomenon). Also, periods of immobility unrelated totimes of levodopa supply occur in most advanced cases (on–offphenomenon). Levodopa-induced dyskinesias occur with increasing duration of therapy, and more than 50% of patients will begin todevelop motor fluctuations and dyskinesias between 5 and 10 yearsafter commencing levodopa with 20 –30% developing dyskinesias after ,2 years. In younger patients, the situation is worse, with almost allpatients under the age of 40 developing motor complications after 6years levodopa-induced dyskinesias remains unsatisfactory. Simply reducing the daily dose frequently renders patients rigid and immobile.
Furthermore, choreic-dystonic involuntary movements appear as a concomitant of motor response to levodopa in most patients sufferingfrom motor fluctuations. Dyskinesias are usually present duringperiods of maximum motor response ( peak-dose dyskinesias) or duringthe entire ON phase (square wave dyskinesia), but a diphasic pattern,with dyskinesias present at the beginning and end of motor response,also exists. Peak-dose dyskinesias are related to high-plasma concen-trations of levodopa and can be managed by fractionating levodopadoses. Amantidine has also been shown to reduce peak-dose dyskine-sias. Long-acting dopamine agonists such as rotigotine may also behelpful by providing continuous dopaminergic stimulation. Biphasicdyskinesias occur when plasma levodopa levels are rising or falling.
They often affect the lower extremities to a greater extent. They may bedifficult to control, but may respond to higher levodopa doses or afast-acting agonist such as subcutaneous apomprphine injection.
Off-period dystonia also affects the lower limbs preferentially and isassociated with periods of inadequate mobility. This may respond to adispersible levodopa preparation or subcutaneous apomorphine injec-tion. The pathophysiology of motor complications during chronic levo-dopa therapy (levodopa long-term syndrome) is only partially understood. Currently, the consensus is that they reflect bothprogression of the underlying disease and the effects of intermittent,pulsatile levodopa supply to a denervated striatum.
A number of treatments have been used to reduce the severity and frequency of motor complications. The dopamine agonists have shownbeneficial effects in the reduction of ‘off’ time and a concomitantreduction in levodopa dose in the later stages of the disease. However,this has to be balanced against a possible increase in dyskinesias. Otherside effects which are commoner include somnolence and hallucina-tions. It does seem that the more recent agonists such as pramipexoleand ropinirole have benefit over bromocriptine by reducing ‘off’time.35,36 Amantadine, an NMDA receptor antagonist, was originally devel- oped as an anti-viral agent. By chance it was discovered to haveadditional properties including efficacy in PD. There is evidence thatamantadine can reduce the frequency of motor complications including freezing, ‘off’ periods and dyskinesias,37,38 although the evidence forefficacy was felt to be insufficient in a Cochrane review.39 There is,particularly in the elderly, a relatively high incidence of side effects which include confusion, hallucinations, ankle swelling and livedoreticularis.
Parenteral administration of a dopamine agonist in the form of sub- cutaneous apomorphine40 may be a useful adjunct to treatment by reducing ‘off’ time without increasing the tendency towards dyskinesiasor confusion. Similarly, duodenal levodopa infusion therapy has beenshown to reduce ‘off’ time, to improve motor function and improveQoL with no increase in dyskinesias in patients with advanced PD.41 Entacapone is a peripheral catechol-O-methyltransferase COMTinhibitor that complements the action of amino acid de-carboxylase(AADC) inhibitors. Assuming that the volume of distribution remainsunchanged, the addition of entacapone increases the plasma half-life oflevodopa by 45% after each dose. Similarly, tolcapone produces adose-dependent increase in levodopa half-life, even though it is givenindependently of the levodopa dose regime. When entacapone or tolca-pone are added to levodopa/AADC-inhibitor therapy, they inhibitCOMT—one of the enzymes responsible for the metabolism of dopa-mine—resulting in greater and more sustained plasma and centralnervous system levels of dopamine than with levodopa/carbidopaalone, producing a prolonged duration of antiparkinsonian action andsubsequent improvements in motor function. COMT inhibition, concentrations, so that levels remain within the therapeutic range andbenefit from each dose of levodopa will be prolonged. Tolcapone wasoriginally withdrawn because of reports of hepato-toxicity, but hasrecently been re-introduced for restricted use under strict monitoringguidelines. This is not the case with entacapone which is also availableas a combined triple medication (with levodopa and an AADCinhibitor) to improve compliance.
The introduction of a COMT inhibitor can be a safe and effective way of smoothing out fluctuations in motor response. COMT inhibi-tors reduce ‘off’ periods, prolong the ‘on’ time and allow a reductionof the levodopa dose.42 They do not, however, have a levodopa sparingeffect.
Entacapone and tolcapone are potent, specific and reversible COMT inhibitors that offer significant benefits, particularly in managingmotor fluctuations in patients with late-stage Parkinson’s disease, when wearing off is an important factor. They are also likely to have anincreasing role in the earlier stages of the illness. A study is currentlyunderway to determine whether the introduction of levodopa and enta- capone together reduces the development of dyskinesias compared withlevodopa alone.
The use of surgery in PD dates back over 50 years. In the early 1950s,patients particularly those with severe tremor would on occasion bereferred for ablative surgery usually to the contralateral thalamus. Withthe introduction of levodopa, surgical treatment fell from vogue. It issomewhat ironic that the widespread recognition of levodopa-inducedcomplications prompted surgeons and clinicians to revisit the area ofsurgical intervention. Initially, this concentrated on lesion surgeryusually in the form of pallidotomy which was shown to be successfulparticularly for levodopa-induced dyskinesias.
A further development came with the introduction of stimulators.
This involved high-frequency deep brain stimulation (DBS) of discretebrain areas producing functional and reversible inhibition of the targetsite. A number of areas within the basal ganglia can be targeted. Theprocedure most commonly carried to reduce bradykinesia, tremor andrigidity and which also reduces drug-related motor complications isbilateral subthalamic stimulation. This can produce very dramaticbenefit. The operation is technically difficult, but in experienced handsthe risk of adverse events is low. However, the infrastructure andsupport team required to assess, carry out and monitor patients limits the availability of this form of treatment. Furthermore, there is concernabout the increased incidence of psychiatric side effects, particularlydepression following DBS. Patients with cognitive impairment or sig-nificant depression are, therefore, not suitable for this form of treat-ment. In terms of patients most suitable for treatment,46 STN DBStends to be performed in patients under the age of 75 without signifi-cant systemic co-morbiditiy and in the absence of obvious structuralabnormality on MR imaging. Patients should be levodopa-responsivewho are disabled while ‘off’ and independent while ‘on’ with medi-cation. Most patients will have had disease duration of at least 5 yearsto allow for other causes of atypical parkinsonism to become evident.
Age seems to be less critical in Vim DBS performed for disabling tremor. Recent studies have suggested that DBS of the pedunculopon-tine nucleus may be beneficial in improving axial stability. Assessmentof a patient for DBS requires assessment by an experienced multi-disciplinary team.46 With the progression of the disease, there are a number of non-motorcomplications in PD that are often seen. In many cases, these are notdirectly related to involvement of dopaminergic pathways and may therefore develop even in patients where motor symptoms are wellcontrolled.
Sleep disorders are frequent in PD. This includes both disturbed noc-turnal sleep and excessive daytime somnolence.Nocturnal sleep disturb-ance occurs in 60– 98% of patients and correlates with disease severityand levodopa intake. Although the underlying pathology of PD may bein part responsible, it is important to also exclude associated disorderssuch as medication-related sleep disturbance including off-dystonia,depression, obstructive sleep apnoea, REM sleep behavioural disturb-ance (RBD), periodic limb movements of sleep and restless leg syn-drome (RLS). RBD is a parasomnia characterized by the loss of normalskeletal muscle atonia during REM sleep with prominent motoractivity accompanying dreaming and is increasingly recognized inpatients with neurodegenerative disease, particularly the synucleinopa-thies. There is evidence that its development can predict cognitiveimpairment in PD patients without dementia.47 If troublesome, it mayrespond to a small amount of clonazepam at night.
Daytime sleep events are also more common in PD. In the most extreme form, this can constitute sudden irresistible attacks of sleepattacks without warning.48,49 These episodes have been reported inpatients on levodopa monotherapy alone, but are more frequent withthe use of dopamine agonists, particularly ropinirole and pramipexole.
Patients need to be counselled to stop driving and to avoid operatingmachinery if these develop. These settle spontaneously as the offendingdrug is withdrawn.
Cognitive involvement in PD seems to be common. Many patients withPD develop dementia, typically 10 years or more after the onset ofmotor symptoms. The frequency of overt dementia varies from study tostudy depending on definition, methods of cognitive assessment and population differences, but is of the order of 40% for all PD patients.
More subtle cognitive disturbance particularly of executive function isextremely common even in early PD.
Dementia in PD may be related to a number of pathologies.
However, it seems to be the development of cortical lewy bodies and/or Alzheimer pathology which are most relevant. The cholinesteraseinhibitors rivastigmine, donepezil and galantamine have been shown in open studies to have a modest benefit in cognitive function and in theamelioration of hallucinations and psychosis in patients withPD-related dementia, although robust evidence-based data are strongestat this time for rivastigmine50 and to a lesser extent donepezil.51 Dementia with lewy bodies or Parkinson’s disease with dementia? There has been controversy over the differentiation of Parkinson’sdisease with dementia (PDD) and DLB. DLB is diagnosed when demen-tia occurs before or concurrently with parkinsonism. An arbitrary cutoffis often used—the 1 year rule—where a diagnosis of PDD is made ifextrapyramidal motor symptoms are present for 12 months or morebefore the onset of dementia and DLB if the onset of dementia precedesor occurs within 1 year of parkinsonism. Revised criteria for the clinicaldiagnosis of DLB have been published.52 These rely on the presence of adementing process with additional core features of fluctuating cognitionand variation in attention and alertness, recurrent visual hallucinationsand parkinsonian features. Parkinsonian signs have been correlated withthe severity of dementia in DLB. There are several features that may helpdistinguish DLB from PD: myoclonus, absence of rest tremor and poor response to levodopa and severe neuroleptic sensitivity. Both DLB andPDD are characterized pathologically by the presence of lewy bodies,though in PDD patients there is greater neuronal loss within the substan-tia nigra whereas in DLB patients there is greater cortical beta-amyloiddeposition. In DLB, the dementia produces marked defecit invisuo-spatial and executive function with prominent visual hallucina-tions levodopa-responsive. It is important to remember in both patient groupsthat dopaminergic drugs can substantially exacerbate confusion andvisual hallucinations in both conditions. Both conditions respond tocholinesterase inhibitors. For a recent update on the distinction betweenPDD and DLB, please refer to the review by McKeith.53 Depression is the most common mood disturbance in PD occurringwith a prevalence of up to 50%54 and occurring at any stage of theillness. Patients should be screened for underlying metabolic disturb- ances such as hypothyroidism which can be easily confused with adepressive illness. Mood fluctuations are commoner in more advanceddisease and have a stronger correlation with motor fluctuations.55 Depression, when diagnosed, can be treated with cognitive beha- vioural therapy and antidepressants including tricyclics and shortacting serotonin uptake inhibitors (SSRIs). There is evidence that pra-mipexole has a significant antidepressant action.56 Psychosis can occur in up to 30% of PD patients.57 It often presentswith hallucinations which are usually visual together with delusionsand agitation or sometimes aggression. Patients may become paranoidparticularly towards partners or other family members. Psychosis ispossibly mediated by loss of dopaminergic neurones particularly in thenigro-mesolimbic projections. It is often a feature in the developmentof PDD or DLB.
Most of the older antipsychotic agents tend to substantially worsen motor symptoms and should be avoided. The newer ‘atypical’antipsychotic agents such as quetiapine and clozapine are better toler-ated and often effective. Clozapine requires close monitoring of thewhite cell count because of a 1% incidence of agranulocytosis.
Acetylcholinesterase inhibitors may also be beneficial in reducinghallucinations and delusions in PD patients.
PD is a common neurodegenerative illness. A combination of geneticand environmental factors is likely to be important in producing abnor-mal protein aggregation within select groups of neurones, leading tocell dysfunction and then death. The diagnosis remains a clinical one,and there should be a high index of suspicion to exclude other causesof parkinsonism. A large number of agents together with surgical inter-ventions are now available to treat early and late complications of PD.
Increasing attention is being given to the diagnosis and treatment ofnon-motor complications in PD. Future developments in PD are likelyto focus on the concept of disease modifying drugs which offerneuroprotection.
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