parkinson's disease · parkinson's disease cdmarsden parkinsonism is a clinical syndrome...

62ournal ofNeurology, Neurosurgery, and Psychiatry 1994;57:672-681

NEUROLOGICAL MANAGEMENT

Parkinson's disease

C D Marsden

Parkinsonism is a clinical syndrome domi-nated by a disorder of movement consistingof tremor, rigidity, elements of bradykinesia(slowness of movement), hypokinesia(reduced movement) and akinesia (loss ofmovement), and postural abnormalities.Parkinson's disease consists of the clinicalsyndrome of parkinsonism associated with adistinctive pathology consisting of degenera-tion of pigmented brain stem nuclei, includ-ing the dopaminergic substantia nigra parscompacta, with the presence of Lewy bodiesin remaining nerve cells.

Parkinson's disease is a common and dis-abling illness affecting some 1 in 1000 of thepopulation. Symptoms usually appear afterthe age of 50 years, but the young are notexempt. Prevalence in those over the age of50 rises exponentially. A community-basedsurvey in Aberdeen' revealed age-specificprevalence rates per 100 000 of the popula-tion of 47 between the ages of 40-49 years,78 between 50-59, 254 between 60-69, and832 between 70-79. Men and women areaffected, and the disease occurs worldwide,although perhaps less frequently in China andAfrica than in Western countries.The Office of Health Economics2 calcu-

lated that there were probably between60 000-80 000 people suffering fromParkinson's disease in the United Kingdom.Harris3 estimated that there were 22 000 peo-ple disabled by Parkinson's disease living inthe community, 22% of which were severelyhandicapped, 48&3% were appreciably handi-capped, and 29-7% of which had a minorhandicap. The Office of Health Economics2estimated that there were 15 000 patientswith Parkinson's disease in hospital or resi-dential care, 22 000 handicapped in the com-munity and more than 30 000 in thecommunity but not handicapped.The Association of British Neurologists4

estimated that within a population of 250 000people there would be 400 patients withParkinson's disease, ofwhom 342 would havesignificant disability (see Wade and Langton-Hewer, 1987).5The cause of Parkinson's disease in

unknown. There may be a genetic predisposi-tion rendering individuals more vulnerable totoxic substances. Some surveys have hintedthat exposure to a rural environment includ-ing well water or pesticides may be of signifi-

cance, but no common environmental toxinhas been identified.The practical management of Parkinson's

disease follows a series of steps in the individ-ual's life history of their illness. For the pur-pose of this review, I will follow the patientfrom the time of their initial symptoms,through diagnosis and early management,into the complications of long term treatmentand the problems of increasing disability.

Early symptomsThe characteristic tremor of Parkinson's dis-ease affects about 70% of patients. Many pre-sent with much vaguer symptoms. Sensationsof numbness or pain without demonstrablesensory loss often are described. Muscles maybe referred to as painful and tender and limbsmay be said to be weak or stiff. Difficultywith handwriting, or inability to undertakerepetitive sequential tasks such as cleaningthe teeth, winding a watch, doing up buttonsor manipulating spoons may be the sole com-plaint for many months. Fatigue is a commoncomplaint, as is depression and a vague sen-sation that the patient has slowed down andlife has become weary. Unexplained weightloss may be prominent.

Against this background, a number ofalternative diagnoses are often entertained tobegin with. Everything may be attributed to adepressive illness. Aches and pains may beinterpreted as due to rheumatism. Fatigueand weight loss may suggest a more sinistercause. The initial tendency for the symptomsto begin on one side of the body may be mis-interpreted as a hemiparesis.

DiagnosisEventually, the characteristic features ofparkinsonism are recognised, and the ques-tion then becomes whether this is due toParkinson's disease or some other condition.The diagnosis is clinical for there is no testspecific for Parkinson's disease. Even themost experienced neurologist may have diffi-culty in making the diagnosis at this stage ofthe illness.

In two recent series of patients diagnosedas having Parkinson's disease in life whocame to autopsy,67 the pathological diagnosiswas of some other condition in approximately

UniversityDepartment ofClinical Neurology,Institute ofNeurology,The National Hospitalfor Neurology andNeurosurgery, QueenSquare, London,WClN 3BG, UKC D MarsdenCorrespondence to:Professor Marsden

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a quarter of cases. The commonest alterna-tive diagnoses were Steele-Richardson-Olszewski disease (progressive supranuclearpalsy) and multiple system atrophy (Shy-Drager syndrome with autonomic failure,striatonigral degeneration, and olivoponto-cerebellar degeneration in various combina-tions). In the early stages of these conditionsthe eye movement disorder characteristic ofprogressive supranuclear palsy may not beapparent, and the symptoms and signs ofautonomic failure and cerebellar deficit typi-cal of multiple system atrophy may not beevident. PET imaging using '8F-dopa andother ligands can discriminate typicalParkinson's disease from other parkinsoniansyndromes in about 80% of cases, but is notspecific or widely available.8Hughes et al,7 on the basis of the autopsy

findings in 100 cases diagnosed as havingParkinson's disease in life, recommended thefollowing clinical criteria to improve the suc-cess rate for diagnosing Parkinson's disease.There needs to be bradykinesia plus one ofthe following: a classic rest tremor, unilateralonset, progressive persistent asymmetry, anexcellent response to levodopa (>70%), levo-dopa induced dyskinesias, and continuedresponse to levodopa for at least five years.Parkinson's disease would be excluded ifthere were no response to levodopa, morethan one affected relative, early dementia,early postural imbalance and falls, early auto-nomic findings, a significant abnormality ofeye movement, and cerebellar or pyramidalsigns.A further series of 100 cases of pathologi-

cally proven Parkinson's disease9 found thattremor was present at the onset in 69%, andin the course of the disease in 75% of cases.Only 77% of patients had a "good" or "excel-lent" initial levodopa response. Accordingly,failure to respond to an apomorphine or lev-odopa challenge test (using single injectionsof apomorphine or a single dose of Sinemetor Madopar) does not exclude the diagnosisof Parkinson's disease; nor does it completelyexclude a subsequent positive response tolonger term oral levodopa therapy.Conversely, some patients with Steele-Richardson-Olszewski disease or multiple sys-tem atrophy may show a response tolevodopa initially.

Initial treatmentHaving made the diagnosis of Parkinson'sdisease, important decisions have to be madeabout subsequent management. Thesedepend upon an open and frank discussion ofprognosis, options for treatment and manage-ment, and the personal philosophy of thepatient and their carer. These initial discus-sions will set the framework for a lifetime ofliving with Parkinson's disease.Many patients seek as much information as

they can find about their illness. TheParkinson's Disease Society provides a largerange of excellent educational information.Patients need to know that Parkinson's dis-

ease cannot be cured, but that it can be effec-tively relieved by symptomatic treatment. Lifeexpectancy is now near to normal, and themain issue is the maintenance of the bestquality of life. Patients will also be reassuredto know that there is only a small risk of pass-ing the illness to their children. They needadvice on diet, the need for exercise and sen-sible home exercise programmes,'0 and theywill seek reassurance on the effect of lifestyleon their illness and their illness on lifestyle.Moderate alcohol intake does not affectParkinson's disease adversely, and there areno major bars to recreational activities.Discussion of the effect of the illness on sex-ual activity may be reassuring and specificproblems associated with hygiene, childbirth,and hormone replacement therapy requirediscussion with women patients. The issue ofdriving should be raised and appropriateassessment undertaken. Most patients willnot have major problems with speech, handfunction, and walking at this stage, but thosewho do will benefit from contact with speechtherapists, physiotherapists, and occupationaltherapists. Contact with Social Services maybe required to sort out problems of housing,adaptation of the home, and financial difficul-ties.As far as drug treatment is concerned, it

should be pointed out that there are two cate-gories of drug treatment to be considered: (a)treatment designed to slow the rate of pro-gression of the disease (neuroprotection); and(b) symptomatic treatment.

NEUROPROTECTIONNothing is known to halt Parkinson's disease,but in recent years there have been sugges-tions that the administration of selegiline(Deprenyl), an irreversible monoamine oxi-dase B inhibitor, may have an effect on thenatural history of the illness. The rationale forthe use of selegiline in early Parkinson's dis-ease was that inhibition of monoamine oxi-dase B might prevent damage caused bydopamine metabolism resulting in oxidativestress, and also that selegiline had been foundto prevent the capacity for 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)to cause experimental parkinsonism in subhu-man primates. These concepts lay behind themajor DATATOP study in North Americawhich investigated the effects of selegline andvitamin E treatment in de novo patients withParkinson's disease."1 12The major result of this study was that

early selegiline treatment delayed the need forlevodopa significantly (but vitamin E had noeffect, either alone or in combination withselegiline). Selegiline itself was found tohave a modest symptomatic antiparkinsonianaction, so it proved impossible to decide defi-nitely whether its effect in delaying the needfor levodopa treatment was due to this symp-tomatic action or whether there was an addi-tional true neuroprotective action.Whether one should use selegiline at the

time of diagnosis or not depends upon one'sphilosophy of levodopa treatment for

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Parkinson's disease. Levodopa and otherantiparkinsonian drugs offer only sympto-matic relief, so it is crucial here to distinguishbetween the impairments typical ofParkinson's disease (tremor, rigidity, akinesia,and postural deficits), the disabilities theycause and the handicaps that result. Levodopaand other symptomatic antiparkinsoniandrugs are employed to relieve disability andhandicap.

If the strategy in an individual is to delaylevodopa treatment for as long as possible(see below), then the early administration ofselegiline at the time of diagnosis is a rationalpolicy.

SYMPTOMATIC TREATMENTThere has been controversy over which drugsto use and when to use them! Much of thisdebate has turned on the issue of whether lev-odopa should be given early or late inParkinson's disease. In fact, although thepublished work on this topic may seempolarised, in practice there is much less dis-cord.

Levodopa is the most reliable and effectivesymptomatic treatment for Parkinson's dis-ease. Most patients with true idiopathic Lewybody Parkinson's disease will respond to levo-dopa treatment. Indeed, failure to respondsuggests (but does not prove) an alternativediagnosis.7 In contrast, directly actingdopamine agonists such as bromocriptine andpergolide only benefit about a third to a halfof patients when given alone.'3 The problemwith levodopa is that a large portion ofpatients will develop complications of treat-ment after some years.'4 These complicationsrepresent a complex interaction between thelong term effects of the drug and the progres-sion of the disease itself. Fluctuations anddyskinesias are a major problem in those withdisease of younger onset, while the emer-gence of cognitive and psychiatric problemsalong with imbalance and speech difficultytend to occur in the more elderly patient.The objective of symptomatic drug treatmentin Parkinson's disease is to keep the patientfunctioning independently for as long as pos-sible. Life expectancy in Parkinson's diseaseis now near to normal.'5-'7

Taking all these facts together, the criticalissue in the management of Parkinson's dis-ease becomes the need to individualise treat-ment. Decisions will be based upon firstly,the patient's age. The younger patient withParkinson's disease, facing a long life with theillness, may opt to delay levodopa treatmentuntil it is absolutely necessary. The elderlypatient, with a limited life span, may opt forearly levodopa treatment to get its benefits assoon as possible. Secondly, the patient's dis-ability and handicap must be considered. Inthe early stages of Parkinson's disease,although impairment is evident, there may belittle disability or handicap. At this stage,symptomatic treatment may not be requiredat all. Thirdly, the patient's expectations inthe light of their social and occupationaldemands will affect decisions. An elderly,

retired individual may tolerate a level ofimpairment that would be insufferable to ayoung, active patient.

All these factors have to be taken intoaccount in a final decision as to the use ofsymptomatic drug treatment at various stagesof Parkinson's disease. The patient requirescounselling on the options available, and theshort and long term outlook faced. In the endanalysis, patients will decide on the basis oftheir own individual philosophy, responsibili-ties and requirements.

Symptomatic treatment when disabilityand handicap occurThere comes a time when Parkinson's diseaseprogresses to the point that symptomatictreatment needs to be initiated. The mostcommon problems that patients and clini-cians consider important for the decision tobegin symptomatic agents are threat toemployment; threat to ability to handledomestic, financial, or social affairs; threat tothe ability to handle activities of daily living;and worsening gait and balance.

At this stage, disability and handicaps stillmay be mild and some might opt to use ananticholinergic drug or amantadine to provideinitial symptomatic relief. Both drugs canimprove function by about 20%, which ismuch less than the benefit obtained with lev-odopa or a dopamine agonist. This may besufficient, however, to maintain indepen-dence initially. Anticholinergics and amanta-dine tend to produce unacceptable adverseeffects, particularly in the elderly, where theymay contribute to forgetfulness, memory dif-ficulties, hallucinations, and even psychoses.Nevertheless, anticholinergics and amanta-dine may give valuable relief early in the ill-ness, thereby avoiding the need fordopaminergic drugs. Anticholinergic drugsalso may be helpful to suppress tremor resis-tant to other medications.

Eventually the time comes when strongersymptomatic treatement is required. Thequestion then is whether to begin with lev-odopa or a directly acting dopamine agonistsuch as bromocriptine or pergolide. The aimsnow are to provide adequate symptomaticrelief of disability and handicap, and to adopta strategy least likely to lead to long termcomplications.

STRATEGIES TO DELAY OR PREVENT LONGTERM COMPLICATIONSThe dilemma in the choice between levodopaversus a dopamine agonist is due to the factsthat (a) levodopa is more or less guaranteedto work, but has a high incidence of longterm complications. (b) Bromocriptine andpergolide are less likely to be effective whengiven alone but, in those who can obtain ade-quate benefit, there is a lesser risk of the longterm development of fluctuations and dyski-nesias.

Using dopamine agonists as monotherapywill provide adequate symptomatic relief inonly a minority of patients (ranging from

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30%18 to around 50% 13920). In the study bythe Parkinson's Disease Research Group inthe United Kingdom,2' of 263 patientsentered into treatment with bromocriptinealone (mean dose 36 mg/day; range 7-5-120mg/day) 181 withdrew, mainly due to lack ofresponse (41 cases), deterioration despitetreatment (30 cases), or adverse reactions (69cases). The early use of dopamine agonistmonotherapy, however, reduces the likeli-hood of developing complications such asfluctuations and dyskinesias in those whogain adequate relief.'92022 Furthermore, delay-ing the initiation of levodopa delays the timewhen such complications occur.2'-26

Again, the decision whether to use adopamine agonist or levodopa often isdecided according to individual circum-stances. The patient in whom disability andhandicap has reached a stage which urgentlythreatens independence or employment mayopt for immediate levodopa treatment as thebest guarantee of relief. Those in whom thepressure is less may opt for a dopamine ago-nist first as the best insurance again long termproblems. The younger patient may wish todelay levodopa for as long as possible. Theelderly patient may opt for early levodopatreatment because long term side effects areof less concern, and the neuropsychiatric sideeffects of directly acting dopamine agonistsare more of a hazard.

If the decision is for levodopa, the nextproblem is whether to use standard Sinemetor Madopar, or the delayed release forms ofSinemet CR or Madopar CR. There are theo-retical reasons in favour of Sinemet CR orMadopar CR.2728 The large swings in lev-odopa plasma levels produced by standardSinemet or Madopar may be deleterious andcontribute to long term complications.Starting treatment with more stable bloodlevels produced by Sinemet CR or MadoparCR may decrease long term complications,and this theory is under clinical trial at thepresent time.A few experience nausea and vomiting

when levodopa is introduced, even when tak-ing the drug after food. Usually this can beprevented by prefacing each dose with dom-peridone 10-20 mg an hour beforehand.One strategy that has been advocated as a

compromise is to employ a low dose of lev-odopa combined with a dopamine agonist.Rinne and colleagues'9 29 30 have advocatedthis as a means of reducing to some extentthe long term complications of fluctuationsand dyskinesias. Although an attractiveoption, the evidence that combined treatmentdoes indeed reduce long term side effects hascome under recent criticism." 32

Strategies for treating complications oflong term levodopa treatmentWith long term treatment with levodopa(defined as greater than five years) only about25% of patients continue to have a good,smooth response.4"33 Most patients developeither troublesome fluctuations, troublesome

dyskinesias, toxicity at therapeutic or sub-therapeutic dosages, or total or substantialloss of efficacy. There are three common pat-terns of late failure of chronic levodopa treat-ment: (a) the emergence of increasinglysevere fluctuations and dyskinesias, which areparticularly prevalent in younger patients; (b)the appearance of increasingly severe cogni-tive impairment and psychosis; often with (c)postural instability and falls, gait difficulties,and speech problems, which are particularlyprevalent in the more elderly.

FLUCTUATIONSThe initial benefits of levodopa treatment aresustained. Most patients experience generalimprovement throughout the day with littleresponse to each individual dose. With thepassage of time, however, an increasing pro-portion of patients begin to experience fluctu-ations of their response.'s'6 Most patients willdevelop fluctuations within about five yearsafter starting levodopa therapy. Initially thesetake the form of the "wearing-off effect" or"end-of-dose deterioration", which is definedas fluctuations in motor disability related tothe timing of levodopa intake. With the pas-sage of time and modification of treatment,such motor fluctuations become increasinglyabrupt and random, culminating in the "on-off effect", which is defined as sudden unpre-dictable fluctuations in motor disabilityunrelated to the timing of levodopa intake.The main risk factors for fluctuations

appear to be the duration of treatment25 26 anddosage.'7 As indicated above, using low dosesof levodopa seems to delay the onset of thisproblem,37 as does delaying the introductionof levodopa.2' Fluctuations appear to be morecommon and occur sooner in patients whodevelop Parkinson's disease at a youngerage.38 39

Fluctuations in motor disability are oftenaccompanied by a variety of other disabling,variable symptoms.40 The associated dyskine-sias are discussed below. During off periods,many patients complain bitterly of pain andother sensory complaints,4142 akathisia,4'respiratory distress,44 depressive moodswings,45A7 sweating and other autonomicsymptoms,48 hallucinations,45 anxiety andpanic attacks,4549 sometimes with screaming,50and slowing and impairment of thoughtprocesses.5' 52

In the fully developed "on-off" state, theswings in motor function and other symp-toms may become highly unpredictable andrapid ("sudden offs"). Some doses of lev-odopa may fail to have any effect at all ("dosefailures"), or there may be a considerabledelay before the patient switches on("delayed-on"). Furthermore, many patientsdescribe diurnal variation in their responsive-ness to levodopa, getting most benefit in themorning particularly after the first dose of theday, but less and less response as the day goeson with bad periods in the afternoon andevening.Many mechanisms contribute to the emer-

gence of fluctuations during long term lev-

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odopa therapy.53-55 There appears to be nosignificant change in the peripheral pharma-cokinetic handling of levodopa during longterm treatment.56 There is, however, a short-ening of therapeutic benefit after each dose.55In addition, the character of the pharmacody-namic response to levodopa changes duringlong term treatment. When treatment is com-menced, the degree of improvement bears amore or less linear relationship to dose andplasma levodopa level. In those who developthe "wearing-off" and particularly the "on-off" effect, however, this classic dose-response relationship changes into a sigmoidcurve. Patients switch "on" at a critical levelof plasma levodopa, below which they are"off" and above which they are more or lessfully "on".57 Increasing the dose of levodopanow does not improve the quality of the "on"period, but prolongs its duration. Theabsolute threshold for turning a patient withParkinson's disease "on" with levodopa doesnot change during chronic treatment, but thiscritical threshold appears.The emergence of a critical threshold has

important implications for management. Thenatural response to the appearance of the"wearing off" effect is to reduce individuallevodopa doses and increase their frequency.This strategy, however, although initiallyeffective, often fails quite quickly. Thesmaller doses may produce peak plasma levelsbelow threshold, so that the patient does notturn fully "on", or remains just at thresholdso that they oscillate between "on" and "off".In addition, the smaller dose and lowerplasma levels mean a reduced duration ofresponse, even if threshold is reached.Now, with plasma (and brain) levodopa

levels hovering around threshold, peripheralpharmacokinetic factors assume greaterimportance. Delayed gastric emptying,58 orlarge protein meals competing for absorptionor brain entry of levodopa,53 may drop brainlevodopa levels to or below threshold, andreduce the duration of response even if itoccurs.

In patients who have developed the "wear-ing-off" effect, and to a less predictable extentin those with the true "on-off" effect, main-taining a continuous supply of dopamine or adopamine agonist to the brain, such as byintravenous535960 or intestinal6l62 infusion oflevodopa can overcome such fluctuations.The same can be achieved by a constant sub-cutaneous infusion of the dopamine agonistapomorphine.63

Against this background, the followingstrategies are employed to try and overcomethe emergence of fluctuations during chroniclevodopa therapy.

Selegiline can be mildly effective in treating"wearing-off" problems.6465 The addition ofslow-release Sinemet CR or Madopar CR, tomaintain more constant blood levels of levo-dopa, also may help particularly in the earlystages of the emergence of this problem.6672Many patients will also require supplementalstandard Sinemet or Madopar as well asSinemet CR or Madopar CR to obtain an

adequate response. It often takes over anhour for the delayed release medications tobecome effective, and patients frequently findthat these formulations do not give a suffi-cient "kick-start" to switch them "on". espe-cially with the first dose of the day. Theaddition of directly acting dopamine agonists,such as bromocriptine or pergolide,7374 whichhave a longer biological half-life than lev-odopa, can also be used in combination withstandard Sinemet or Madopar, and SinemetCR or Madopar CR. There is some evidencethat pergolide is more effective and better tol-erated than bromocriptine.75

Attention to gastric and dietary factors alsobecomes important. Dissolving levodopa inliquid before ingestion may help,76 as may theuse of the dispersible Madopar preparations,which act more quickly. Occasional patientsmay benefit from drugs enhancing gastricemptying or antacids.77 78 Taking levodopabefore rather than after meals also may pro-duce a more reliable and rapid effect.58Reduction in dietary protein also may be ofbenefit.79

Despite these strategies, many patientsevolve into the situation of sudden andunpredictable "off" periods. In these circum-stances, subcutaneous apomorphine injec-tions may be used to rescue patients from"off" periods, or apomorphine may beemployed as a continuous subcutaneous infu-sion.63 80

DYSKINESIASAs motor fluctuations begin to develop dur-ing chronic levodopa therapy, a variety ofdyskinesias appear.81 82 These are convention-ally divided according to the time of theirappearance after individual doses into: (a)those occurring at the peak of benefit-"peakdose dyskinesias"; (b) those occurring asmobility improves and/or as it wanes-"diphasic dyskinesias"; (c) those occurring in"off periods" or in the early morning-"offperiod dyskinesias". Peak dose dyskinesiasare commonly choreic, ballistic, or stereo-typed; less commonly they are dystonic; theytend to be more unsightly than disabling.Diphasic dyskinesias are similar in type topeak dose of dyskinesias, although dystonia isoften more prominent and tends to be moresevere and disabling. "Off period" dyskinesiastend to be dystonic, painful, and distressing.The pattern of dyskinesias, both in their char-acter and timing, varies considerably frompatient to patient, but is fairly consistent ineach individual.The mechanisms responsible for the

appearance of dyskinesias are complex andnot fully understood.8384 Whereas the thresh-old for motor benefit from levodopa does notappear to change during chronic therapy, thatfor the production of dyskinesias decreasesdramatically. Indeed, in those who havedeveloped the typical "wearing-off" and "on-off" effect, the threshold for dyskinesias issimilar to that required for motor benefit.83Diphasic dyskinesias85 appear when theplasma level of levodopa is rising or falling

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but not during the peak. Thus, patientsdescribe a flurry of dyskinesias as the initialevidence of a levodopa effect; such dyskine-sias may settle during the period of maximummobility, only to reappear as the patient turns"off". Off period dyskinesias, especially thepainful cramps and dystonias, may be evidentfirst thing in the morning as well as during"off' periods during the day. Although theyoccur when mobility is as its worst, they dis-appear if levodopa is entirely withdrawn for a

period of time.Management of dyskinesias is difficult.

Often reducing the dose of levodopa mayimprove the dyskinesias, but at the expense ofintolerable worsening of mobility. When peakdose dyskinesias are causing disability, how-ever, reducing each individual dose may

resolve the problem. Alternatively, substitut-ing an increasing dose of a dopamine agonistsuch as bromocriptine or pergolide while low-ering the dose of levodopa can help.

Diphasic dyskinesias are even more diffi-cult to manage. As they occur with intermedi-ate plasma levels of levodopa, it would seem

rational to increase levodopa intake.86 Usuallythis eventually produces much more severe

dyskinesias and other adverse effects.Lowering the dose is equally unsatisfactorybecause increasing parkinsonism ensues. Thebest strategy probably is to add increasingdoses of an agonist such as pergolide whilereducing levodopa intake.

"Off period" painful dystonia can be very

disabling. The best way of preventing suchdyskinesias is to try and overcome "off" peri-ods by the strategies described above.Sometimes the addition of baclofen, an anti-cholinergic, or lithium is of benefit.

FREEZING, POSTURAL IMBALANCE, GAITPROBLEMS AND SPEECH DIFFICULTIESWhile chronic levodopa treatment continuesto help some problems of Parkinson's disease,albeit for shorter and shorter periods of timeand increasingly unreliably, other disabilitiesbegin to emerge which are less responsive.

As "wearing-off" emerges, freezingepisodes often appear during "off" periods.These particularly affect gait. Patients beginto experience start hesitation, and freezing on

the turn or when passing through enclosedspaces.87 Accompanying such freezingepisodes is increasing instability of gait.Postural reflexes become impaired. Patientsbecome increasingly unsteady, and no longercorrect when imbalanced. Not only do theyfail to take appropriate action to prevent a

fall, but they also lose rescue reactions and so

cannot protect themselves if they fall. A com-mon problem arises from sudden unexpectedfreezing when walking. The feet get glued tothe ground, momentum carries the patientforward, they cannot correct this imbalancebut fall and injure themselves. Unexpectedfalls with injury thus become a major prob-lem, particularly in "off" periods.88

Speech also may be compromised, withincreasing hypophonic dysfluency, hesita-tions, and even freezing during speech.8990Swallowing too may be disturbed.9'

Levodopa and dopamine agonists, duringlong term treatment, seem less capable ofrelieving these impairments of posture, gait,and speech.88929' Reasons for the emergenceof these difficulties during long term levodopatreatment may relate to progressivepathology23 and the effects of ageing.93 In par-ticular, degeneration of neurons in thosenuclei in brainstem centres controlling pos-ture, locomotion, and speech may beinvolved.

Unfortunately, there is no effective way ofmanaging these problems with medication,other than by attempting to control themwith optimum levodopa and dopamine ago-nist replacement therapy. Once locomotorand speech problems begin to intrude, how-ever, considerable help can be obtained fromthe physiotherapist, the speech therapist, andthe occupational therapist.

Physiotherapy designed to improve gaitpatterns, and to educate the patient to min-imise risks of falls is of benefit. Teachingstrategies to ease getting out of the bed or achair, to initiate walking and to manage turnsis helpful. Walking aids are a problem topatients with Parkinson's disease. They tendto carry, rather than use a stick or frame; awheeled rollator is often of more benefit.Other valuable aids include elevating chairs,house lifts, automatic controlled beds, bed-hoists, strategically placed rails, toilet aids,bath seats and showers, and feeding utensils.Unfortunately, about a half of patients andtheir carers need aids and equipment to assistdaily living.94 Close and regular contact withthe occupational therapist and physiothera-pist is essential to assess the need for appro-priate assistance, which often requires a visitto the patient's home, and to select the mostuseful aids for the individual patient.95Liaison between the occupational therapist,physiotherapist, and social services is crucialto ensure the provision of such assistance,and the designated social worker can provideinvaluable advice and practical help in finan-cial matters. The Parkinson's Disease Societyalso provides considerable help in all theseareas. It is the responsibility of the specialistand general practitioner, in liaison, to ensurethat patients are referred early rather thanlate, and repeatedly, to the appropriate pro-fessionals.

Speech and feeding problems also may bea major cause of disability and handicap atthis stage,9194 and the advice of the speechtherapist now may be invaluable.9&98Assessment of speech deficits, formal speechtherapy and education, and the provision ofappropriate communication aids may berequired. Advice on dietary and swallowingstrategies may be necessary and helpful.99Drooling of saliva, due to failure to swallow,is sometimes a major problem. An anticholin-ergic drug may help to dry the mouth.

It is also appropriate to consider the prob-lems of the bladder and the bowels at thispoint, for at this stage of the illness theseoften cause considerable disability anddistress.

Urinary frequency (especially at night) and



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urgency due to detrusor instability are a com-mon part of Parkinson's disease,100 and can beimproved with levodopa treatment. In elderlymen there is the common added problem ofthe enlarged prostate. Frequently, it is diffi-cult to know whether the prostate or theParkinson's disease is responsible for urinaryproblems in men with Parkinson's disease.Referral to an expert uroneurologist may beessential, and careful investigation is oftenrequired to distinguish outflow obstructionfrom the bladder dysfunction inherent toParkinson's disease. Careful selection of thosesuitable for prostatic resection is essential ifincontinence is to be avoided. An anticholin-ergic may help urgency and frequency, butcan precipitate urinary retention (and glau-coma), and can make constipation worse.

Constipation is a very common problem inParkinson's disease,99 10' caused by many fac-tors including reduced mobility, anticholiner-gic drugs, dietary imbalance, and autonomicdysfunction. A high fibre diet with fruit,drinking more water, and bulk laxatives areuseful.

Postural hypotension and syncope some-times may be a problem in true Parkinson'sdisease, due partly to pathology in the auto-nomic nervous system and also to the effectsof drug treatment. Head-up tilt of the bed atnight, elastic stockings, and fludrocortisonemay be required.

COGNITIVE AND NEUROPSYCHIATRICPROBLEMSMost patients with Parkinson's disease, earlyin their illness, have subtle changes on neu-ropsychological testing suggestive of frontallobe dysfunction.52 102 103 In the early stageshowever, these usually do not appear to causeobvious cognitive disability. With the passageof time, however, they may develop into amore disabling syndrome of abulia. Abuliarefers to apathy, slowness of thought(bradyphrenia),'04 and blunting of drive andresponse to external stimuli. Such a syn-drome may progress further with increasingimpairments of memory to form a focaldementia of frontal lobe type. Around20-30% of patients may go onto develop amore multifocal, pervasive dementia affectingmany or all areas of cognitive function.'05 Aparticular characteristic of this syndrome,which predominantly affects the elderlypatient with Parkinson's disease, is a fluctuat-ing, confusional state often with visual, andeven auditory, hallucinations.'06 Such patientsmay have good days where cognitive functionappears relatively preserved interspersed withperiods of mental confusion, impairment ofattention, and hallucinations.

There are many reasons for cognitiveimpairment in Parkinson's disease.5' Drugtreatment may be responsible, particularlyanticholinergic agents in the elderly.'07Undoubtedly some may develop the coinci-dental pathology of Alzheimer's disease whichis common in the elderly. Some of the fea-tures of frontal lobe dysfunction may beattributed to increasing dopaminergic inacti-vation of frontocaudate cognitive systems. As

the disease advances, not only is there greaterinvolvement of nigrocaudate dopaminergicpathways, but also it is likely that dopaminer-gic innervation of the frontal cortex itself isimpaired. Another factor which has emergedin recent years is the realisation that Lewybody pathology in the cerebral cortex is muchmore widespread than was hitherto envis-aged. The advent of ubiquitin immunostain-ing for Lewy bodies has shown that theseinclusions are present in cortical neurons tosome extent in virtually every patient withParkinson's disease. In many of those withsevere cognitive impairment there is wide-spread cortical Lewy body pathology. DiffuseLewy body disease previously was thought tobe a rare condition, but it is now suggestedthat it may be a common cause of the con-fused dementia in the elderly patient withParkinson's disease.'06 108-110

Along with cognitive impairment, a num-ber of neuropsychiatric problems also mayemerge associated with chronic disease.Isolated visual pseudo-hallucinations are notinfrequent. Patients may see human or ani-mal "familiars", which may or may not bethreatening. Such hallucinations, which againare more common in the elderly patient, andparticularly at night, may be due in part todrug intake. Reducing dopaminergic drugsoften leads to their disappearance. Somepatients, however, go on to develop a frankconfusional state and may even become psy-chotic.The appearance of disabling cognitive

impairment or of a confusional state in apatient with Parkinson's disease shouldprompt a search for some intercurrent illness,including chest and urinary infections andmetabolic disturbances. In many cases drugtreatment is likely to be the cause. All anti-cholinergic drugs should be withdrawn,including amantadine. If the confusion doesnot clear, the dose of dopaminergic drugsneeds to be reduced. Unfortunately, however,while the confusional state may clear as drugsare withdrawn, mobility may deteriorate.Often, as drugs are manipulated, a state isreached in which the -patient is either mobilebut confused and hallucinating, or mentallyclear but immobile. The balance between theextremes may be brittle and it is very difficultto achieve a satisfactory compromise. In thissituation, a limited drug holiday, withdrawingdopaminergic drugs for one day each week,sometimes helps to dispel the psychotoxicity,allowing a reasonable dose of drugs to main-tain mobility on other days. Prolonged drugholidays have been abandoned, for thepatient may deteriorate to a severe state ofimmobility, with risks of pneumonia or deepvein thrombosis. Indeed, dopaminergic drugwithdrawal may precipitate a state of intenserigidity, mental confusion, and unexplainedpyrexia akin to the neuroleptic malignantsyndrome.

If drug manipulation fails, it may be neces-sary to use the atypical neuroleptic clozapineto control the neuropsychiatric complications.Clozapine, which acts predominantly throughD-4 dopamine receptors, has much less



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propensity to cause extrapyramidal sideeffects and to worsen mobility in Parkinson'sdisease. It is not devoid of this risk, but some-times it can be employed successfully to con-trol neuropsychiatric complications whilemaintaining an adequate dose of dopaminereplacement therapy to maintain mobil-ity."'"-'13 There are, however, practical diffi-culties to the use of clozapine because of itstendency to produce agranulocytosis in a sig-nificant proportion of patients (perhaps1-2%). This requires frequent and regularmonitoring of blood counts and withdrawalof clozapine at the slightest hint of toxicity.An alternative strategy is to employ a smalldose of a conventional neuroleptic, such asthioridazine at night.

Finally, mood changes are a major compo-nent of Parkinson's disease. Around twothirds of patients are significantlydepressed."4115 In part this is a natural reac-tion to the disabilities imposed by their illnessbut that may not be the only reason fordepression in Parkinson's disease. It has beenargued that pathology in serotonergic sys-tems, and perhaps also in noradrenergic sys-tems, known to occur in Parkinson's disease,may also contribute to depression. A noctur-nal dose of tricyclic antidepressant such asimipramine or amitriptyline may be required.A sedative antidepressant with anticholinergicproperties may also aid sleep and reduce noc-turnal urinary frequency. Although a popularantidepressant drug, fluoxetine may increaseparkinsonian disability."16 Occasionally, elec-troconvulsive therapy (ECT) may be requiredto treat severe depression in Parkinson's dis-ease. Not only does ECT relieve the depres-sion, but the parkinsonism also can improvetemporarily.

Anxiety and panic attacks also can be a dis-abling feature of Parkinson's disease, espe-cially during "off' periods. A benzodiazepinesuch as diazepam or a beta-blocker such aspropranolol may help such patients.

Role of neurosurgery in Parkinson'sdiseaseBefore the introduction of levodopa treat-ment around 1970, stereotaxic surgery waswidely employed to treat Parkinson's dis-ease."17 The preferred target in most centreswas the ventrolateral nucleus of the thalamus,in particular, the nucleus ventralis inter-medius. A unilateral thalamotomy could suc-cessfully reduce or abolish contralateraltremor and rigidity in most patients, with anacceptably small (5-10%) risk of hemiparesisor hemiplegia. Bilateral thalamotomy, how-ever, carried a higher (20% or so) risk ofsevere speech disturbance and other compli-cations. Thalamotomy did not usuallyimprove the various manifestations of akine-sia, which often progressed to cause increas-ing disability.

Levodopa, for the first time, relieved akine-sia, so the use of thalamotomy rapidlydeclined. It was reserved for the occasionalpatient with mainly unilateral drug resistantdisabling tremor. 118119As the long term complications of levodopa

treatment emerged, and persisted in many

despite every attempt at drug manipulation,stereotaxic surgery has begun to undergo arenaissance, in three forms.'20

Laitinen and colleagues'2' had continuedLeksell's practice of posteroventral pallido-tomy, and recently published evidence thatthis operation not only could improve tremorand rigidity, but also akinesia, gait, andspeech. Furthermore, this lesion could reduceor abolish some disabling levodopa induceddyskinesias. The role of posteroventral palli-dotomy is being re-evaluated in many centres.

Benabid et al,'22 following the observationthat suppression of tremor by electrical stim-ulation was a useful method of localising thetarget site for traditional thalamotomy, har-nessed the technology of continuous electricalthalamic stimulation for suppression oftremor. The advantages of this methodinclude a lower incidence of complications,and the opportunity for safe bilateral implan-tation. Furthermore, continuous thalamicstimulation also may suppress some levodopainduced dyskinesias. Again, this technique isunder clinical trial worldwide.

Finally, much has been written about braingrafting for Parkinson's disease. Initialenthuiastic reports on the use of adrenalautografts into the striatum have been subse-quently tempered by the realisation that themethod was not very successful and carriedhigh risks.'23 Adrenal grafting, in its originalform, has been discarded. The use of fetalsubstantia nigra grafts into striatum, usingstereotaxic methods, however, holds greaterpromise. Such grafts have been shown byPET to survive and to exert some beneficialeffects for years."24-"27 The method remainsexperimental at this stage, until the manypractical problems surrounding it have beenresolved.'28

Standards of care and auditDespite the large number of patients withParkinson's disease in the community, thecomplications of its treatment, and the dis-ability it produces, there has been little formalinvestigation of audit in this condition.The Association of British Neurologists'29

noted that Parkinson's disease was the 12thcommonest condition referred to neurologistsin the United Kingdom. They recommendedthat all such patients should be referred to aneurologist (unless geriatric referral was mostappropriate), and that they should have CTof the brain (although many would not con-sider CT or MRI of the brain to be necessary,unless there is another positive indication).A Working Group of the Royal College of

Physicians"30 provided a series of recom-mendations for the management of avariety of neurological conditions, includingParkinson's disease. These could provide thestandards against which quality of care maybe audited. The working party of theAssociation of British Neurologists4 docu-ment on neurological rehabilitation in theUnited Kingdom also provides a set of gen-eral standards of care for those with neurolog-ical disability, which also can form the basisof audit of management of disability in thosewith Parkinson's disease.



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