ccjm movement disorders in the older patient

7/30/2019 CCJM Movement Disorders in the Older Patient

1/14

S3 8 C L E V EL A N D C L I N I C J O U R N A L O F M E D I C I N E V O L U M E 7 2 S U P P L E M E N T 3 O C T O B E R 2 0 0 5

ABSTRACT

Movement disorders are especially prevalent in the elderly,

and some are highly treatable. Because reduced agilityand slowing of gait are associated with numerous move-

ment disorders as well as wit h the no rmal aging process,

the differential diagnosis of movement disorders in theelderly can be challenging. M any of these disorders sharefeatures of parkinsonism hypokinesia, tremor, and mus-cular rigidity. This article review s common and less com-

mon movement disorders in the elderly from a primarycare perspective, w ith an emp hasis on the presenting fea-

tures and the differential d iagnosis. It also provides gener-al management recomm endations with advice for t ai lor-

ing treatment to elderly patients.

KEY POINTS

A num ber of m ovement disorders Parkinson disease

(PD), essential tremor, dementia w ith Lew y bodies, small-vessel ischemic disease, and restless legs syndrom e arecommo n in the elderly, w ith prevalences of more than 1%in this population.

M ost medications for treating movem ent disorders shouldbe titrated m ore slow ly in elderly patients than isrecomm ended by th e manuf acturers.

PD is defined by th e presence of tw o of three cardinalmotor signs tremor, r igidity, and bradykinesia in the

absence of other causes for parkinsonism.

Early mobility problems in PD are usually treated withlevodopa or dopamine agonists. Levodopa is more

effective, better tolerated, easier to t itrate, and less costly,but it may accelerate the onset of moto r fluctuations.

Dopamine agon ists should be avoided in elderly PD

patients wit h confusion or hallucinations, as they are moreapt t han levodopa to cause or exacerbate th ese problems.

Parkinsonism can have many causes other than PD,including certain medications, mult iple system atrop hy,

progressive supranuclear palsy, dementia w ith Lewybodies, and other neurologic condition s.

Movement disorders are especially preva-lent in the elderly, and both the largenumber of these disorders and their simi-larities can make differential diagnosis a

challen ge. Man y of th ese disorders share th e hallmarkfeatures of parkinsonismhypokinesia, tremor, andmuscular rigidity. Moreover, some of the symptoms ofmov emen t disorders can resemble th e slowing of gaitand reduced agility th at accompany th e n ormal agingprocess, in which the spine degenerates, jointsbecome more lax and deteriorate, and peripheral sen-sorineu ral receptors degenerate.

This article provides a concise review for primarycare physicians of key diagnostic features of commonmovement disorders in the elderly and less commoncond itions th at m imic th ese disorders. It also providesan overview of recommended treatment strategies.Specific treatment algorithms will not be presented;instead, recommen dation s are offered for tailoring toindividual elderly patients. With the principal excep-tion of most medications used to treat Parkinson dis-ease (PD), most of the recommendations include off-label uses for medications approved by the US Foodand Drug Administration for other indications. Most

M ovem ent disorders in t he older pat ient:Different ial diagnosis and general management

M A RK S. BAR ON , MD

From the Virginia Commonwealth University School of Medicineand t he Sout heast Parkinsons Disease Research, Education an dClinical Center (PADRECC), Hunter Holmes McGuire VAMedical Center, Richmond, VA.

Address: Mark S. Baron, MD , Director, Southeast Parkin sonsDisease Research, Education and Clinical Center, HunterHolmes McGuire VA Medical Center, 1201 Broad Rock Road,Richmond, VA 23249; [email protected].

Disclosure: Dr. Baron reported th at h e has no finan cial interests oraffiliations that pose a potential conflict of interest with this article.


2/14

of these recommen dation s are supported by good clin-ical studies and are widely followed by clinicians car-ing for these patient s.

Because of the prevalence of PD and th e complex-

ity of its treatment, emphasis will be given to this dis-order. Because other conditions in the elderly can bedifficult to distinguish from PD (Table 1) , the differ-en tial diagnosis of parkinsonism will also be a focus.

PARKIN SON DISEASE

PD is a primary degenerative disease characterized bythe loss of the neurotransmitter dopamine from thesubstantia nigra. It is increasingly common withadvancing age, with a prevalence approaching 1% byage 65 an d 2% at age 80.1,2

Patient s with PD can n ormally remain independent

and ambulatory (albeit slower) for a very long time. Ina large series of patien ts with path ologically con firmedparkinsonian disorders reported in 2000,3 no patientswith PD progressed from initial symptom onset tostage III on t he H oehn and Yahr S cale of disability (ie,gait un steadin ess or imbalance, with or with out falls)within 1 year of th e on set of mot or symptom s, where-as 72% of patients with atypical parkinsonism ( multi-ple system atrophy, progressive supranuclear palsy,dementia with Lewy bodies, or corticobasal degenera-tion) did. The m edian time to progression to H oehnand Yahr stage IV (severe disability, but still able towalk or stand unassisted) was approximately 14 years

for those with PD vs less than 5 years for those withatypical parkinsonism. The advent of new medica-tion s and surgical int ervention s promises even a betterprognosis for PD patient s in th e future.

DiagnosisAlthough consensus criteria are lacking, movementdisorder specialists often defin e PD by th e presence oftwo of the following th ree cardin al motor sign s in th eabsence of oth er apparent causes for parkinson ism:

Tremor R igidit y Bradykinesia .

Drug-induced parkinsonism due to the use ofdopamin e-blocking agent s (eg, neuroleptics, meto clo-pramide) should be especially excluded. Asymmetrictremor is the most common early sympom of PDencountered by primary care physicians and shouldalways raise the possibility of PD. However, theabsence of tremor sho uld no t exclude consideration ofthe possibility of PD. In fact, tremor is also the onlycardinal feature th at m ay never occur.

Stricter criteria for a diagnosis of PD require an

unequivocal response to a dopaminergic medication(at least 1,000 mg/day of levodopa), but this require-men t is limiting in th at man y patients with early symp-toms are not treated.4 Also, some patients with other

forms of parkinsonism may respond to medications, atleast in itially. Addition ally, rest t remor can be medica-tion-resistant, although such an occurrence shouldalways prompt review of the diagnosis. For patientswith features typical of PD who respond predictably toantiparkinsonian medications, imaging studies are gen-erally not necessary.

Postural instability is often considered a fourth car-dinal feature of parkinsonism but is not generally con-sidered in the diagnosis of PD because of its frequentpresence in oth er parkinsonian syndromes. Moreover,if a patien t exh ibits postural instability (ie, stage III onthe 5-stage Hoehn and Yahr Scale) within 1 year ofth e on set of mot or sympt oms or is wh eelchair-depen-dent (Hoehn and Yahr stage V) within 7 or 8 years ofdisease onset, an alternative diagnosis is almost cer-tain.5 On occasion, uncertainty about responsivenessto a do pamin ergic medication can be settled by gradu-ally withdrawing the medication. See Table 1 for asummary of differentiating features of parkinsoniancond itions in th e elderly, most o f which are describedin detail in the text below.

General treatm ent considerationsA number of medications across several drug classesare commonly used to treat PD (Table 2) . Theseinclude the mainstay therapy levodopa (the levorota-tory form of dopa, the precursor of dopamine) as wellas dopamine antagonists, catechol-O-methyltrans-ferase (C O MT ) inh ibitors, an d antich olinergic agent s.T h e focus here is on general pharmacologic treatmen tconsiderations, since neurology consultation is war-ranted with complicated drug regimens or advancedstages of PD an d since most patien ts with complicatedcourses of PD are co-managed by neurologists in addi-tion to their primary care physicians. It is also worthnoting that most drugs that affect the central nervoussystem (whether for PD or other movement disorders

discussed below) should be titrated more slowly in theelderly than is normally recommended by the manu-facturers (see titration recommen dation s in Table 2 ) .

Protective t herapyTo date, no medications have convincingly beenshown to d elay the p rogression of PD. Epidemiologicstudies suggest that caffeine,68 tobacco,9 and non-steroidal anti-inflammatory drugs10 may reduce therisk for PD, but it would be difficult to advocate theregular use of these agents.

C L E V EL A N D C L I N I C J O U R N A L O F M E D I C I N E V O L U M E 7 2 S U P P L E M E N T 3 O C T O B E R 2 0 0 5 S3 9

BA RO N


3/14

Treatment of mobility problems in PDLevodopa vs dopamine agonists. Because of experimen-ta l11 and clinical12 evidence suggesting that treatmentwith levodopa, but not with dopamine agonists, accel-erates the onset of motor fluctuations, dopamine ago-nists are commonly considered the preferred first-lineagents for treating early mobility problems. On the

oth er han d, levodopa is more effective, better tolerated,easier and quicker to titrate, and considerably lessexpensive. For older patients, these factors may favorthe choice to initiate therapy with levodopa, but this

decision should be based on th e patien ts overall healthand cognition and not solely on chronological age.Also, even though dopaminergic medicationinducedinvoluntary movements (dyskinesias) develop inapproximately 40% of treated PD patients, motor com-plication s are less prevalen t in patien ts who are elderly.13

Levodopa. Levodopa is given with carbidopa, aperipheral dopa decarboxylase inh ibitor, to reduce th esystemic breakdown of levodopa. Without carbidopa,nearly all patients would experience intolerable sideeffects, mainly nausea and vomiting. Regular car-bidopa/levodopa may be a good first choice in theelderly and is less expensive than sustained-releaseformulation s (see Table 2 for recomm end ed dosages).A lth ough pu lsatile exposure of dopam ine receptors tolevodopa is purported to accelerate motor fluctua-tions, a head-to-head study did not show any benefitof sustained-release vs regular carbidopa/levodopa intime to onset of motor fluctuations.14 The conve-nience of a sustained-release formulation should beweighed against the additional cost.

Options among dopamine agonists. Bromocriptinewas th e first dopam ine agonist approved in th e U n itedStates but has been shown to be relatively less effec-tive th an t he n ewer agents in th is class.1519 Pergolide,

like bromocriptine, is an ergot-derived dop amine ago-nist, but it has fallen into disfavor because of an asso-ciated risk for indu cing valvular and pulmon ary fibro-sis.20 If either of these agents is used, patients shouldundergo yearly echocardiogram studies and be moni-tored for pulmonary involvement.

Pramipexole and ropinirole are the newest dopa-mine agonists approved in th e U nited St ates. Both areadmin istered orally, and th ey have comparable efficacyand side-effect profiles (Table 2) . Although patientscan occasionally be switched between these agents inrespon se to side effects, there is little eviden ce th at th isoffers the potential for better clinical efficacy.

Compared with levodopa, dopamine agonists aremore likely to cause confusion an d h allucin ations andshould be avoided in patients already manifestingthese problems. A low threshold for eliminatingdopamine agonists is appropriate in elderly patients.Even adv anced disease can generally be man aged withlevodopa therapy alone without compromising con-trol of parkinsonian symptom s, althou gh con sultationwith a neurologist (preferably a movement disorderspecialist) is advised in such advanced cases. Because


M O V EM EN T D I SO RD ER S

TABLE 1Differential diagnosis of parkinsonism in the elderly

D iso rd e r D if f e re n t ia t in g cl in ica l f e at u re sParkinsondisease (PD)

Drug-inducedparkinsonism

Multiple systematrophy

Progressivesupranuclearpalsy

Dementia wit hLewy bodies

Small-vesselarteriopathy

Normal-pressurehydrocephalus

Usually presents wit h asymmetri cparkinsonian symptoms

Falling is rare early in course Pati ent is ambulatory for >10 yr from

onset Highly responsive to dopaminergic drugs

Most oft en due to neuroleptics ormetoclopramide

If parkinsonian symptoms are asymmet-ric, the offending drug is probablyunmasking or exacerbating underlying PD

Symmetric p resentat ion Autonomic dysfunction f requent (not

universal) Parkinsonism or cerebellar at axia may

predominate Cogni t ion i s preserved Medication-resistant Patient wheelchair-dependent wit hin 5 yr

Symmetric presentat ion Prominent midline involvement Falling from outset Vertical gaze palsy (not universal) Neuropsychiat ric features M edicat ion-resistant Patient wheelchair-dependent w ith in 5 yr

Clin ically resembles PD, but w it hprogressive and prominent dementiabeginning withi n 1 yr of onset of mot orfeatures

Variable medicati on response wit h poor

tolerance due to hallucinations

Usually histo ry of hypertension, of tenof transient ischmic attacks/strokes

Clinically: dementia, dif fuse hyperreflexia,Babinski signs, disproportionateinvolvement o f legs/gait and oftenrelatively preserved finger-tapping

Medication-resistant

Triad of gait at axia, dementi a, urinaryincontinence

MRI: vent ricular enlargement dispropor -tionate to cortical atrophy and small-vessel ischemic changes

Conf irmed by beneficial responseto large-volume tap (3050 mL)


4/14

dopamine agonists and, to a lesser extent, levodopahave been associated with sleep attacks, it is impera-tive th at patien ts be warned of this risk.21

U ncertain role for COMT inhibitors. In theory,th ere could be long-term ben efit from th e early use of

C O MT inhibitors (eg, entacapone), which block oneof the major enzymes that break down dopamine, butwithout supportive evidence, it is difficult to justifyth e additional cost of introducing a C O MT inhibitorat an early stage.

Treatment of tremorLevodopa, dopamine agonists, and anticholinergicmedicat ions can be h ighly effective for treatin g parkin-sonian tremor.22 Some patients require 1,000 mg ormore of levodopa daily for adequate control. Becauseanticholinergic medications (and the antiviral drugaman tadine) have a h igh propensity to cause confusion

in the elderly, they should be considered second-lineagents in m ost elderly persons. Eth opropazine may pro-duce relatively less confusion th an oth er ant icholiner-gic agents but is available in the United States onlyfrom select compounding pharmacies; its usual thera-peutic dose is 50 to 100 mg three times daily.

M edication adjustme nts in the w ake of reduceddopaminergic responseRegular medication adjustments are generally neededin response to the progressive degeneration of dopa-

mine-producing cells and to keep pace with PD pro-gression. These adjustments should balance concernsabout in troducing levodopa (an d pot entially accelerat-ing mot or fluctuations) against th e n eed to adequatelytreat parkinsonian symptoms. The key is to tailor

adjustmen ts to t he individual patient . For example, if apatient complains of doing poorly in the morning butnot during the rest of the day, only the first morningdose needs to be in creased. For un satisfactory respons-es due to inadequate dosing, increasing the levodopadose is likely to provide similar efficacy at significantlyless cost than adding a COMT inhibitor. A formula-tion combining carbidopa/levodopa with the COMTinhibitor entacapone is available, but it is significantlymore expen sive th an using carbidopa/levodopa alon e.

Wearing off and unpredictable medication responsesW ithin 3 to 5 years of starting levodopa t herapy, man ypatient s begin t o experience a decrease in t h e duration

of their respon se to individual doses of the drug. Th iswearing off has been attributed to reduced storagecapacity of ingested as well as endogenous dopaminein axon terminals in t h e striatum as a result of cont in-ued loss of dopamine-producing cells and associatedsecondary axonal degeneration .

End-of-dose wearing off is fundamentally differentfrom a lack of sufficient response to a given dose level.Although increasing individual doses can extend theeffective on period (ie, the period of greater mobili-


TABLE 2

Pharmacologic agents commonly used to treat Parkinson disease in the elderly

UsualTypical therapeut ic M axim um Com m on

Class M edicat ion start ing dose Tit rat ion* dose dose adverse effects

Dopamine Carbidopa/levodopa Nausea, vivid dreams,Regular-release 1 tablet ti d t id q5d 1 tablet t id As tol erated confusion, hall ucinat ions

(25/100 mg)Sustained-release 1 tablet bid bid q5d 1 tablet bid As tol erated

(50/200 mg)

Dopamine Pramipexole 0.125 mg bid 0.125 mg 0.5 mg t id 4.5 mg/day Nausea, somnolence,agonist q34d confusion, hallucinat ions,

Ropinirole 0.25 mg bid 0.25 mg 23 mg t id 24 mg/day pedal edema, orthostat icq34d hypotension

COMT Entacapone 100 mg bid Add two 100 mg wit h 200 mg with Exacerbat ion of dopamineinhibitor (t aken w it h 100-mg each levodopa each levodopa side ef fect s, including

levodopa) doses q5d dose dose dyskinesias

Anticholinergics Trihexyphenidyl 1 mg qd 1 mg q45d 2 mg t id As tolerated Dry mouth, confusion,Benzt ropine 1 mg qd 1 mg q45d 2 mg t id As tolerated blurred vision

Antiviral Amantadine 100 mg qd 100 mg/wk 100 mg 400 mg/day Pedal edema, confusionbid or tid

* Titr ation recommendations are tailored to t he elderly.

For drug classes with more than one medication listed, adverse effect listings are for the entire class.

Tolcapone is anot her commercially available COMT inhib ito r, but it is not common ly used because of it s associated risk of liver f ailure (see text ).Because bot h ent acapone and t olcapone typically increase peak levels of levodopa, levodopa doses may need to be low ered by 20% t o 30%.

COMT = catechol-O-methylt ransferase


5/14

ty and treatment response), problems of wearing offare generally best treated by reducing the intervalbetween levodopa doses. Because of the longer dura-tion of response to dopam ine agon ists relative to lev-

odopa, adding or increasing the dose of a dopamineagonist can be a useful approach to problems of wear-ing off. Also, patients may benefit from switching tosustained-release preparations of carbidopa/levodopaor adding entacapone.

A t th is stage of PD, entacapone can exten d th e ontime in respon se to an individual dose of levodopa byup to 30 minutes or more.23,24 Alternatively, anotherCOMT inhibitor, tolcapone, is available and appearsto h ave greater lon g-term ben efits th an en tacapon e onmot or sympt oms and in reducing off time.25 However,tolcapon e was reported to be associated with 3 death sfrom fulminant hepatic failure among 40,000 patient-treatment years10 to 100 times the anticipatedrate.26 Th e drug has not been withdrawn from the U Smarket, however, and no further tolcapone-relateddeaths have been reported since regular monitoringrequirements have been in place.26 Because of itsdemonstrated efficacy, tolcapone should be consideredfor treatment of patients with otherwise medication-resistant disease.

With further disease progression, many patientsexperience unpredictability of medication responsesan d sudden off periods. In a m inority of patient s, par-ticularly those with more advanced disease, competi-

tion between neutral amino acids from ingested pro-tein an d levodopa for transportation in to th e centraln ervous system via a saturable tran sporter system mayinfluence medication responsiveness. Such patientsmay need to limit ingestion of protein for at least 1hour before and after taking levodopa. Poor stomachmotility may also contribute to erratic responses bypreventing normal levodopa transport to the duode-num. Metoclopramide, often prescribed to treat gas-tric dysmotility, may aggravate parkinsonism.

Some patients at this stage benefit greatly from ashort rest period or nap. Rescue doses of regular car-bidopa/levodopa often can effectively treat poor on

responses or sudden off periods. A new orally disinte-grating levodopa formulation may offer selected pat ientsgreater convenience, ease of use, and rapid access tomedication, which may increase on time.27 Anotheroption is apomorphine, an injectable dopamine agonistrecently approved in the United States specifically forthe intermittent treatment of off episodes in patientswith advan ced PD. On set of respon se to apomorph ine istypically within 10 minutes, compared with 20 to 30minutes or longer for regular carbidopa/levodopa.

Besides th e need to inject apom orphin e, its use is com-plicated by the need to premedicate, at least initially,with an antinausea agent. Despite these limitations,intermittent subcutaneous apomorphine therapy is gen-

erally well tolerated and can reduce off time by up to50% or more in pat ients with advan ced disease.28

Drug-ind uced dyskinesiasDyskinesias are associated with on periods, and m ostpat ien ts prefer dyskinesias, regardless of th eir severity,to severe off periods of immobility. Nevertheless,dyskinesias can be quite d ebilitating an d m ay requirelimiting the dose of dopaminergic medications.

Amantadine can be used to treat dyskinesias, butits benefits normally last only for up to 8 months. 29

T h e neuroleptic clozapine can be effective in treatin gdopaminergic medicationinduced dyskinesias, but

its use is limited by t he risk of agranulocytosis and th eneed for weekly drawing of blood samples.Preliminary experience30 suggests that the atypicalneuroleptic quetiapine may also ameliorate dyskine-sias. Unlike the smaller doses of quetiapine used tocontrol h allucinations induced by dopamin ergic med-ications, doses of 200 mg or more (generally at bed-time) may be required and can generally be well tol-erated even in elderly patients.30,31 In response to th istreatment of dyskinesias, higher doses of dopaminer-gic medications may be tolerated.

Postural instab ility

W ith in 5 t o 10 years of diagnosis of PD, most patien tsencounter balance problems and some may experi-ence regular falls. This feature normally developsslowly, however, and if it is prominent early on, it is ared flag suggesting an alternative diagnosis.

Balance problems usually are not improved bydopaminergic medications. Patients with balanceproblems should be referred to a physical therapist,who can suggest useful means to avoid falls and rec-ommend such aids as a cane or walker. Such patientscan be instructed to recognize and temper potentiallyrisky situations, such as rushing to answer the tele-phone or carrying dinner plates.

Associated symptomsBesides problems related to motor function, mostpatients with PD experience additional bothersomesympt oms due to t h e disease itself or to its treatm en t.Even when these cause more problems than themotor symptoms, patients and their caregivers maynot always freely mention th em t o th e ph ysician.

Dementia. PD-related dementia does not regularlyprogress as aggressively as that associated with




6/14

A lzheimer disease (A D) or demen tia with Lewy bodies,so the presence of a rapidly progressive dementia shouldespecially raise consideration of anot her etiology. A t th esame t ime, PD-related demen tia event ually develops in

a high percentage of patients,32 albeit at a slower pace.Elimination of such medications as selegiline, amanta-dine, an ticholinergics, and dopamine agon ists can oftenresult in significant improvement in cognition, partic-ularly in patients experiencing hallucinations.Generally, these patients can benefit from reducing oreliminating dopamine agonists in favor of levodopa.

Depression. Depression is thought to be due moreoften to th e neurodegenerative process of PD t han toreactive depression, in part because th e depression inpatients with PD tends to be keenly responsive toantidepressant medications.33 A ssociated depression isoften more debilitating than the underlying parkin-sonism and must be treated (see separate article ondepression on page S52 of this supplement).

N ausea. Both levodopa an d dopamin e agon ists mayproduce significant nausea. Patients who experiencemilder nausea might benefit from taking t heir medica-tion with m eals. Dopamin e th at is converted from lev-odopa in the periphery by dopamine decarboxylase isthought to produce nausea by stimulating dopaminereceptors in the area postrema in the brainstem. Adaily dose of 75 mg of carbidopa (as provided by threedoses of carbidopa/levodopa 25/100 mg) is generallynecessary to adequately inhibit peripheral production

of dopamine. Occasionally, patients may require largeramounts. Supplemental carbidopa (one or two 25-mgtablets) can be taken with the first morning dose orwith each dose of carbidopa/levodopa.

Additional problems. Autonomic dysfunction iscommon in patients with PD an d should n ot in itselfbe presumed to signify a diagnosis of multiple systematrophy.34 Such features as impotence, bowel andbladder dysfunction, and orthostatic hypotension arerelatively frequent and should each be addressed. Amajority of patients with PD sleep poorly, and th is cancontribute to daytime somnolence. Speech problemscan be disablin g and may respon d well to an int en sive

voice treatment program.35

Surgical interventionDeep brain stimulation targeting the subthalamicnucleus or globus pallidus interna has become thestandard surgical method for treating patients withadvanced medically refractory PD symptoms.36 Deepbrain stimulation is particularly effective for treatingmot or fluctuations, includin g dyskinesias. St imulationof the globus pallidus interna directly ameliorates

dyskinesias, while stimulation of the subthalamicnucleus benefits patients primarily by enabling themto greatly reduce their dopaminergic medications.Patient s generally respon d well to deep brain stimula-

tion surgery, and advanced age should not necessarilybe a deterrent. However, because this surgery carries asignificant risk of worsening dementia, it should beavoided in th ose with significant demen tia.

M ULTIPLE SYSTEM ATROPHY

Multiple system atrophy (MSA) is a sporadic diseasewith an estimated prevalence of 2 to 4 per 100,000 pop-ulation.37,38 It is equally prevalent among men andwomen, occurs most often in the sixth decade of life,and is associated with a mean survival of 6 to 9 years,although some patients have lived with the disease for

15 years or more.3942

MSA was previously separated int ostriatonigral degeneration, olivopontocerebellar atro-phy, and Shy-Drager syndrome. However, because theseconditions have similar pathologic features, includingalpha-synucleinpositive glial cytoplasmic inclusions,43

they are now thought to represent a single disease. Theclinical features of MSA are outlined in Table 1 .

DiagnosisThe diagnosis of possible MSA requires one of threecriteria (either auto n omic failure/urinary dysfun ction ,parkinsonism, or cerebellar ataxia) plus two charac-teristic features from the other two clinical criteria

domains.44

A fourth clinical domain (corticospinaldysfun ction ) is included as a feature but is no t a defin-ing criterion. T h e diagnosis of probable MSA requiresthe criterion for autonomic failure/urinary dysfunc-tion plus poorly levodopa-responsive parkinsonism orcerebellar ataxia. The diagnosis of definite MSArequires pathologic confirmation.

Although study results differ, most patients withMS A show n ormal in tellectual fun ction with relative-ly mild memory and executive dysfunction.45 Unlikepatients with PD, patients with MSA and predomi-nantly parkinsonian features typically present withprominent midline and symmetric limb involvement.

In MSA, gait instability often develops rapidly, andmost patients are wheelchair-dependent within 3 to 5years. Unlike those with progressive supranuclearpalsy, patients with MSA do not normally experienceregular falls from t he outset. Patient s with promin entcerebellar features generally have additional featuresto suggest MSA but occasionally may present with apure cerebellar syndrome, including scanning dys-arthric speech, limb ataxia, and a wide-based ataxicgait. Autonomic involvement tends to be more severe


BA RO N


7/14

th an in P D. Erectile dysfun ction almost always accom-panies MSA in m ales. U rinary incontinen ce or reten-tion and orthostatic hypotension are also frequentsymptoms. The finding of hypodense signal in the

putamen on gradient echo sequences can help to dif-ferentiate MSA from PD 46 but is also commonly seenin progressive supranuclear palsy.47

TreatmentSome patient s with M SA show a limited, mostly tem-porary response to antiparkinsonian medications.Others, often erroneously diagnosed with PD, mayimprove considerably when weaned from high doses ofantiparkinsonian medications. A trial of at least 1,000mg/day of levodopa is recomm ended t o assess for pot en-tial efficacy, and dopam ine agonists may be tried as well,with care taken not to worsen preexisting h ypotension.

Treated patien ts often quickly show orofacial and cervi-cal dystonic dyskinesias, which strongly suggest a diag-nosis of MSA. Most investigators have suggested thatdeep brain stimulation h as no beneficial role in treatingMSA 48 and may even be detrimental.49 There are noestablished therapies for the cerebellar ataxic features.

Inspiratory stridor due to vocal cord dysfunction isa commo n feature in MSA and is associated with poorsurvival.50 C on tinu ous positive airway pressure can bewell tolerated by most MSA patients with nocturnalstridor and has been suggested to reduce the risk ofsudden death during sleep.51 Aspiration also common-ly leads to early death, and initiation of periodic swal-lowing evaluation s is in dicated in m ost pat ients with-in 5 years of disease onset.52 Early involvement ofphysical, occupational, and speech therapists is criticalto t he o verall well-being of th e patient . Because MS Ais a devastating illness, the patient and family requireemotional support and care planning.

PROGRESSIV E SUPRAN UCLEAR PALSY

Progressive supranuclear palsy (PSP) is a rapidly pro-gressive disease that is mainly sporadic, occurs morecommon ly in men,53 and h as an estimated prevalence of5 to 6 per 100,000 population.37,54 It manifests after age

45, peaks early in the seventh decade of life, and is asso-ciated with a median survival of approximately 6 years(range, 1 to 17 years).55,56 The pat ho logy includes promi-nent neuron al loss and aggregates of abnormal tau pro-tein in the substantia nigra, basal ganglia, and brain-stem. Its major clinical features are present ed in Table 1 .

DiagnosisA n umb er of criteria h ave been propo sed for th e diag-nosis of PSP, including the National Institute ofNeurological Disorders and the Society for Pro-

gressive Supranuclear Palsy (NINDSSPSP) crite-ria,57 which are summarized as follows:

Possible PSP : gradual progressivity of sympt omswith onset at age 40 or later and either vertical

supranuclear gaze palsy or both slowing of verticalsaccades and prom inen t po stural instability with fallsin t he first year of onset, plus no eviden ce of other d is-eases that could explain th ese features.

Probable PSP: vertical supranuclear gaze palsy,promin ent postural instability, and falls in t he first yearof onset, as well as the other features of possible PSP.

Definite PSP: a history of probable or possiblePSP and histopathologic evidence of typical PSP.

Criteria that support the diagnosis of PSP andexclude diseases often con fused with PSP are also pre-sented in the NINDSSPSP report.57 The criteria forprobable PSP are highly specific, making th em suitablefor therapeutic, analytic epidemiologic, and biologicstudies, but no t very sensitive. T he criteria for possiblePSP are substantially sensitive, making them suitablefor descriptive epidemiologic studies, but less specific.

Most patients with PSP begin to experience recur-rent falls from the outset. Other early symptomsinclude bradykinesia, dysarthria, dysphagia, and vari-ous visual complaints. Early on, most patients showsubtle gaze-initiation delays and square-wave jerks.Hallmark vertical and later horizontal gaze palsies areno t generally an early feature and may never developin some cases.58 W h ile elderly person s often show lim-

ited upward gaze, downward gaze palsies are highlysuggestive o f PSP. Most patien ts will event ually devel-op a frontal lobe syndrome characterized by apathyand executive dysfunction.54 Midbrain atrophy onmagnetic reson ance imaging (MR I) can be diagnostic.H owever, imaging is essent ial to rule out oth er poten -tially treatable disorders, including hydrocephalus.

TreatmentT he treatment approaches for PSP are similar to th osedescribed for MSA. Swallowing problems are espe-cially critical in these patients, and future decisionsregarding such issues as eventu al percutan eous endo-

scopic gastrostomy t ube p lacemen t are best addressedat an early stage, when patients generally still haveinsight. Botulinum toxin type A may be consideredfor the treatment of apraxia of eyelid-opening andblepharospasm.

DEM ENTIA WITH LEW Y BODIES

Dem ent ia with Lewy bodies (D LB) is believed to be asporadic disease, with an estimated prevalence of0.3% in th ose over age 65 an d as high as 5% in th ose




8/14

over age 85.59 Because these patients manifest AD-like dementia and often show parkinsonian features(Table 1) , DLB is frequen tly confused with th ese con -ditions. Furthermore, the pathology of DLB has fea-tures of PD and AD, being defined by widespreaddeposition of neocortical and brainstem Lewy bodiesand a variable degree of AD-type pathology. How-ever, early on in P D, dem ent ia is usually absent or rel-atively mild, and if hallucinations occur, they canalmost always be attributed to antiparkinsonian med-ications or to a concurrent illness. Moreover, themotor features in PD t end t o be more prominent th anin D LB. In A D, extrapyramidal features are gen erallyabsent or particularly subtle, especially early on.

DiagnosisConsensus guidelines for the clinical diagnosis of

DLB established the primary criterion as progressivecognitive impairmen t o f sufficient severity to disruptnormal functioning.60 Other central diagnostic fea-tures include th e following:

Fluctuating cognition, with prominent changesin att ent ion an d awareness early in th e course ofillness

Com plex and recurring visual hallucinations Parkinsonian features that should not precede

th e on set of dementia by more th an 1 year.In addition to the primary criterion, two of these

three features are required for a diagnosis of probableDLB and one for possible DLB. These criteria werereported to permit a very high diagnostic specificitybut a lower sensitivity.61 It h as been suggested, h owev-er, th at th e low sensitivity might be im proved by bet-ter means of identifying cognitive fluctuations.61

Episodes of staring into space, periods of disorganizedan d illogical speech, an d excessive daytime d rowsinesshave also been reported to occur more commonly inDLB than in AD,62 but these features require furthervalidation.

TreatmentThe role of cholinesterase inhibitors in DLB remainscontroversial. 63 Severe sensitivity reactions have been

described with most neuroleptics, including clozap-ine.64 H owever, n o similar reaction has been describedwith quetiapine, and this agent has generally beenwell tolerated by patien ts with DLB.65 T he u se of que-tiapine m ay be necessary to perm it patient s to tolerateeven low doses of levodopa. Although not adequatelyestablished, the effectiveness of levodopa in DLB isprobably less than in PD. Dopamine agonists should,as a rule, be avoided, because of their cognitive sideeffects.

SM ALL-VESSEL ISCHEM IC DISEASE

Small-vessel ischemic disease (SVID) is a common,though underrecognized, cause of gait disturbances

and demen tia in th e elderly

66,67

and has been etiologi-cally associated most closely with chronic hyperten-sion.68,69 W hen demen tia is associated with SV ID, thecondition is regularly referred to as Binswanger dis-ease.66 In SVID, small, penetrating arterioles withinth e white mat ter and basal gray matt er undergo promi-nent thickening of their media and vascular walls,with lipohyalinotic degeneration.70,71 These patholog-ic changes are distinctly different from larger-vesselatherosclerotic disease, which can be associated withmulti-infarct dementia, another form of vasculardementia. Its clinical features are outlined in Table 1 .

DiagnosisDiagnostic criteria for Binswanger disease have beenproposed72 but h ave not been validated. According toth ese criteria, the following m ust be present:

Demen tia Two of the following:

(1 ) A vascular risk facto r or eviden ce of sys-temic vascular disease

(2 ) Eviden ce o f focal ce rebrovascular disease(focal neurologic signs, including hyper-reflexia and Babinski signs)

(3) Evidence of subcortical dysfunction, suchas a parkinsonian, m agnet ic, or senile gait,73,74

gegenhalten (involuntary resistance to pas-sive limb movemen t), or incont inen ce due toa spastic b ladder

Bilateral leukoaraiosis on computed tomography(C T ) or bilateral multiple or diffuse white m atterlesions each measuring more than 2 mm 2 on MRI

A bsence of multiple or bilateral cortical lesionson CT or MRI

A bsence of severe dementia (eg, Mini-MentalState Examination score >10) .

Patients with SVID present with an insidious orstepwise progression and often have had one or morehem iparetic strokes. Th e associated dem ent ia is typi-

cal of other subcortical dementias and, at least earlyon, can usually be differentiated from AD by morepromin ent apath y, perseverative beh avior, executivedysfun ction (in cluding impairment in con ceptualiza-tion and manipulation of information), and relativelyretained insigh t an d mem ory retrieval.75 Most patientsevent ually develop urin ary incon tinen ce, which oftenleads to differential consideration of normal-pressureh ydroceph alus. Furthermore, confirmatory white mat-ter chan ges on T 2-weighted M RI for SVID can also be


BA RO N


9/14

seen with transependymal diffusion of cerebrospinalfluid (CSF) in cases of hydrocephalus and, to someexten t, may be seen witho ut a clinical correlate.

TreatmentTreatment of SVID is symptomatic, and preventionrequires control of potential risk factors, includinghypertension.67

NO RM AL-PRESSURE HYD ROCEPHALUS

Normal-pressure hydrocephalus (NPH) occurs pre-dominantly during the sixth and seventh decades oflife. Its clinical features are summarized in Table 1 .Subarachnoid hemorrhage, meningitis, and cranialtrauma are well-established predisposing causes,although it is a misconception that such conditions

cause NPH by blocking CSF absorption across thearachn oid villi. A lthough N PH is a rare condition, itis frequently entertained clinically or mentioned onbrain CT and MRI radiology reports in the elderlyand should never be overlooked, as it is potentiallytreatable with surgery. On the other hand, establish-ing the diagnosis can be challenging, and ventricu-loperitoneal shunting should be considered only withthe knowledge that rates of immediate and remotesurgical complications are high, estimated to bearound 38% for permanent neurologic deficits and6% for death .76 At the same time, in the appropriatepatient, surgery can produce dramatic resolution of

gait problems and can stabilize, though not improve,cognitive deficits.77

DiagnosisNPH is classically recognized as a triad of gait distur-bance, altered mentation, and sphincter distur-bance.78 The gait disturbance is an early and promi-n ent feature, while cognitive impairmen t may be sub-tle or even absent. The diagnosis is unlikely whendementia precedes the gait problem, is severe, or isthe predominant clinical feature. Urinary urgency isalmost always present early on, but incontinence istypically a later feature. The gait may be ataxic and

wide-based, may be characterized by difficulty in ini-tiation (magnet ic gait), or may appear parkinsonianwith short steps and shuffling. Cognitive deficits arech aracterized by apath y and m ent al slowness79 and areusually distinguishable from AD-type dementia butnot from other subcortical dementias.

Supportive radiologic imaging findings include bal-looning of the frontal horns of the lateral ventricles,normal-sized or occluded sylvian fissures and corticalsulci, and modest to n o white m atter lesions. MRI can

be used to define periventricular and white matterischemic disease and hippocampal atrophy. Milderischemic white matter disease should not necessarilypreclude surgical consideration an d may directly result

from NPH. In most cases it is worthwhile to obtainone or more diagnostic large-volume taps (30 to 50mL of CSF). However, although a positive resultappears to be h ighly predictive, th e predictive accura-cy of a negative tap may be low. 80 Other diagnosticmeth ods that h ave been advocated include assessmen tof the respon se to 3 t o 5 days of more contin uous CSFdrainage via an external lumbar drain 8183 and mea-suremen t of B waves on cont inuous int racranial pres-sure monitoring.84 Isotope cisternography is generallyconsidered to be u nreliable.76,77,85

ESSEN TIAL TREM OREssent ial tremor (ET) h as estimated prevalence rates of0.4% to 3.9% in the general population and 1.3% to5.1% in persons older than 60.86 It is thought to h ave anautosomal dominant mode of inheritance,8790 and sus-ceptibility genes h ave been localized to chrom osomes 2and 3.91,92 The path oph ysiologic basis for ET is no t wellun derstood but probably originates from abn ormal cere-bellar signaling, possibly involving the inferior olive.93,94

DiagnosisT h e diagnosis of ET requires on e of the followin g:

Bilateral postural or kinetic tremor of th e hands95

Isolated head tremor without evidence of dystonia.Th e exclusion criteria are (1) oth er abnormal neu-

rologic signs, (2) recent neurologic trauma precedingthe onset of tremor, (3) presence of known causes ofenhanced physiologic tremor (eg, drugs, anxiety,depression, hyperthyroidism), (4) history or presenceof psychogenic tremor, (5) sudden onset or stepwiseprogression, (6) primary orthostatic tremor (predom-inantly in the legs upon standing), (7) isolated posi-tion -specific or task-specific t remors (eg, occup ation -al tremors, primary writing tremor), and (8) isolatedtremor in the voice, tongue, chin, or legs. 96

ET commonly affects the hands or forearms, head,

and laryn x. Th e arms are involved b ilaterally, th oughoften asymmet rically. Rest trem or may be presen t bu tis not the predominant feature.88 Amelioration withalcohol and a positive family history are supportivehistorical information. Occasionally, cognitive andpersonality disturbances may occur, involving verbalfluency, mental set-shifting, disinhibition, emotionalblunting, and depression.97 Comparable impairmentsin executive functioning and personality have beendescribed after cerebellar lesions.98




10/14

TreatmentThe anticonvulsant primidone may be the most effec-tive agent for treating ET,99,100 but it is often poorly tol-erated. Beta-blockers are the preferred alternative but

may have cardiovascular side effects.101 A mong beta-blockers, although both propranolol and atenolol areoften effective, some studies suggest that propranololmay be therapeutically superior to atenolol. 102,103

Benzodiazepines, including alprazolam,104 and theanticonvulsant topiramate105,106 can also benefitpatients with ET. See Table 3 for recommendeddosages of medicat ion s for ET.

Deep brain stimulation of the ventral intermediatenucleus of the thalamus can provide good long-termbenefits in cases of severe, medically intractable ET,including good efficacy for head tremor with bilateralsurgery.107

TARDIVE DYSKINESIA

Tardive syndromes are characterized by abnormalinvolun tary movemen ts (most often ch oreiform or dys-tonic) or akathisia (a sensation of restlessness thatcauses often-uncontrollable movements) caused byexposure to a dopamine-receptorblocking agent with-in 6 m on th s of the on set of sympt oms and persistin g forat least 1 mon th after cessation of the offending drug.108

In mild cases, stopping the offending drug can fre-quent ly lead to remission, but th is condition often per-sists and can be disabling. Tardive dyskinesia (T D) his-

torically refers specifically to rapid, repetitive, stereo-typic movement s that mostly involve t he oral, buccal,and lingual areas, though this term is now often usedmore globally to describe various tardive syndromes.

Diagno sis and risk fa ctorsThe American Psychiatric Association has required 3mon th s of exposure to an offendin g drug for a diagno-sis of TD ,109 although TD has been reported occasion-ally in elderly persons after as little as 1 month ofexposure.110

Elderly patien ts, especially th ose with demen tia, areth e most susceptible population: th e risk for TD from

traditional neuroleptic drugs in the elderly is 25% to30%.110,111 The risk is substantially lower with second-generation (ie, atypical) neuroleptics, althoughrisperidone has been associated with an annual TDincidence of greater than 2% in elderly patients withdementia.112 A mon g neuroleptics, clozapine an d queti-apine have the lowest reported incidence of TD andhave been con vincingly shown to induce T D on ly inpatients who were exposed to additional neurolep-tics.108 Drug-induced parkinsonism, like TD, also

occurs much more often in the elderly. In contrast,younger people are primarily at risk for acute neu-roleptic-induced dystonia, while age does not appearto influence the development of tardive akathisia

(persistent motor restlessness). Higher doses ofantipsychotics and concurrent use of anticholinergicmedications are associated with a higher risk.

H unt ington disease is a rare condition th at shouldn ot be con fused clin ically with T D, as it usually startsin early adult life and is rapidly fatal.

TreatmentThe most important intervention for TD is preven-tive: agents that block th e dopamin e receptor, includ-ing metoclopramide, must be prescribed only afterestablishing m edical necessity. W hen possible, theoffending agent should be discontinued immediately

with t he h ope of facilitatin g a remission. Switch ing toan atypical neuroleptic may be considered in patientswith active psychosis or in wh om T D is brought on orworsened as a result of lowerin g th e incitin g agen t.113

Among potential treatments (Table 3) , the dopa-min e depleter reserpine h as been used an d can be effec-tive, but dose-dependen t depression often limits its use-fulness.114 Tetrabenazine, another monoamine depleter,but with additional dopamine-receptorblocking prop-erties, is expected to be approved soon for use in theUnited States and may offer a more favorable benefit-to-side effect profile compared with reserpine.115 A

number of other agents, such as vitamin E and ben zodi-azepines (including clonazepam), may have some effi-cacy in milder cases, although studies have reportedconflicting respon ses to t hese agents.108 A lthough anti-cholinergic medications may benefit patients withacute dystonic dyskinesias, they may worsen orofacialdyskinesias.108 Botulinum toxin injection s may be usefulfor isolated blepharospasm or torticollis. Based on limit-ed case reports, deep brain stimulation appears to beeffective for treating m edically intractable T D, in clud-ing its orofacial symptoms.116,117

RESTLESS LEGS SYND ROM E

Restless legs syndrome (RLS) is thought to have anautosomal dominan t pattern of inh eritance,118,119 withan estimated prevalence among adults of 10% to12%.120 The prevalence increases to around 19% inthose 80 years or older,121 and symptom s ten d to wors-en with age. RLS is defined by four obligatory criteria:

Urge to move the legs Worsening of symptoms with rest Relief with act ivi ty Intensification during the evening.


BA RO N


11/14

ManagementRLS can cause enormous anxiety and, along with th efrequent accompan iment of periodic limb movem entsof sleep, often leads to sleep deprivation. Offendingmedications, including selective serotonin reuptakeinhibitors, monoamine oxidase inhibitors, lithium,antihistamines, and neuroleptics, should be discon-

tinued. Morning fasting serum ferritin, vitamin B12 ,and folate levels should be measured, and iron sup-plementation should be instituted to achieve a fer-ritin level of less than 50 g/L (low-normal range).120

Patients should be counseled to avoid prolongedidleness and sleep deprivation . Milder cases can occa-sion ally be tem pered with a sedative to p romot e sleep.However, benzodiazepines should be provided toelderly patients only after weighing such associatedrisks as inducing falls, confusion, and disinhibition.

Clonazepam probably offers no therapeutic advan-tage, and sho rt-acting agent s may be preferable.

Among treatment options for RLS (Table 3) ,dopamine agonists can generally be considered first-line agents, even in the elderly, and symptoms oftencan be controlled with a single small dose in theevening at the anticipated onset of symptoms. The

use of levodopa introduces a high risk of augmenta-tion of RLS, as defined by symptom onset at least 2hours earlier than was previously the case.122 Symp-toms can be severe and continuous, involving theentire body. A lthough no controlled trials have beencon ducted, augmen tation appears to be mu ch less of aproblem with dopamine agonists,120 and gabapentinappears to most benefit the minority of patients withpainful sympt oms.123 O piates are also often effective,and addiction is rare in th is population. 124,125


TABLE 3

Pharmacologic t reatments for common nonparkinsonian movement disorders in t he elderly

Typical U sualstart ing therapeut ic M axim um Com m on

D isorder Class M edicat ion dose Tit rat ion dose dose ad verse ef fects

Essent ial Ant iepilept ics Primidone 50 mg at 50 mg/wk 50100 mg bid 250 mg/day Sedat ion,t remor bedt ime unsteadiness

Topiramat e 25 mg/day 25 mg/wk 50100 mg bid 400 mg/day Weight loss,psychomotorslowing

Bet a-blocker Propranolol 20 mg/day 20 mg/wk 120160 mg bid 320 mg/day Hypot ensionbradycardia,

Select ive At enolol 12.5 mg/day 12.5 mg/w k 50100 mg/day 100 mg/day depression,beta-blocker fat igue,

bronchospasm*

Tardive Dopamine Reserpine 0.125 mg/day 0.125 mg/wk 0.3752 mg/day 4.5 mg/day Depression,dyskinesia depleter sedat ion,

hypotension

Dopamine Tet rabenazine 25 mg/day 25 mg/w k 100200 mg/day 200 mg/day Dep ression ,depleter/ sedat ion,antagonist hypotension,

parkinsonism

Benzodiazepine Clonazepam 0.5 mg at 0.5 mg q34d 14 mg/day As t olerat ed Sedat ion,bedt ime dizziness

Vitamin Vitamin E 1,600 IU/day 1,600 IU/day 1,600 IU/day Diarrhea

Rest less Dopamine Pramipexole 0.125 mg 0.125 mg 0.250.5 mg 3 mg/day Nausea,legs agonists at bedt ime q34d at bedt ime vivid dreams,syndrome hallucinat ions,

Ropinirole 0.25 mg at 0.25 mg 12 mg at 9 mg/day confusion,bedt ime q34d bedt ime pedal edema

Dopamine Carbidopa/ 25/100 mg 25/100 mg 25/100 mg As needed Nausea,levodopa at bedt ime q34d at bedt ime vivid dreams,

augmentation

Narcot ic Methadone 2.5 mg/day 5 mg/wk 525 mg/day 40 mg/day Sedat ion,constipation

* Adverse effects apply t o bot h beta-blockers (propranolol and atenolol). Because dose-dependent depression and other adverse effects are common with high doses, reserpine should be cautiously titrated in the

elderly, with close monitoring for potential adverse effects. Doses can be increased above those shown here if depression does not occur.

Adverse eff ects apply to both dopamine agonists (pramipexole and ropinirole).

In view of the risk for augmentation (see text), carbidopa/levodopa should be used only as a last resort.


12/14


ADDITIONAL DIFFERENTIAL CONSIDERATIONSBesides those already discussed, a few additional con-ditions enter the differential diagnosis of movementdisorders in the elderly patient.

Corticobasal degeneration is a rare disorder thatusually presen ts after age 60 with mot or an d cognit ivedysfunction. The motor involvement is characterizedby highly asymmetric akinesia, rigidity, and apraxia,often with prominent dystonia and alien-limb phe-nomena. Although occasionally mistaken for PD,these clinical features should generally suggest thiscon dition an d, moreover, are generally not responsiveto dopaminergic therapy.

Cerebellar ataxia. In an elderly patient with cere-bellar ataxia, the history and work-up include suchcon siderations as alcoh olism, medication side effects,

cerebrovascular disease, hydrocephalus, neoplasm,and a paraneoplastic syndrome.

Primary cerebellar degeneration and spinocere-bellar ataxias usually present earlier in adult h ood.

Peripheral neuropathies and skeletomuscular dis-orders commonly contribute to gait disorders in theelderly but are generally readily identifiable on ph ysi-cal examination .

Degenerative spine disease and spinal metastasesare more common in the elderly and must always becon sidered in an y patient with a spastic gait or senso-ry ataxia.

De novo psychogenic movement disorders arecomparatively infrequent in the elderly populationand can be diagnosed only after exclusion of otherpoten tial etiologies.

BA RO N

REFERENCES

1. Mayeux R, D enaro J, Hemenegildo N , et al. A population-basedinvestigation of Parkinsons disease with and without demen tia.Arch Neurol 1992; 49:494497.

2. Strickland D, Bertoni JM. Parkinsons prevalence estimat ed by astate registry. M ov D isord 2004; 19:318323.

3. Muller J, Wenning GK, Jellinger K, McKee A, Poewe W, LitvanI. Progression of Ho ehn and Yahr stages in parkinsonian disorders: aclinicopath ologic study. N eurology 2000; 55:888891.

4. de Rijk MC, Rocca WA, Anderson DW, Melcon MO, BretelerMM, Maraganore DM. A population perspective on diagnostic cri-teria for Parkinsons disease. Neurology 1997; 48:12771281.

5. Muller J, Wenning GK, Jellinger K, McKee A, Poewe W, LitvanI. Progression of Hoeh n an d Yahr stages in Parkinsonian disorders: aclinicopath ologic study. N eurology 2000; 55:888891.

6. Morens DM, Grandinetti A, Reed D, White LR, Ross GW.Cigarette smoking and protection from Parkinsons disease: falseassociation or et iologic clue? Neurology 1995; 45:10411051.

7. Gorell JM, Rybicki BA, Johnson CC, Peterson EL. Smoking andParkinsons disease: a dose-response relationship. Neurology 1999;52:115119.

8. Tanner CM, Goldman SM, Aston DA, et al. Smoking andParkinsons disease in twins. N eurology 2002; 58:581588.

9. Ascherio A, Zhang SM, Hernan MA, et al. Prospective study ofcaffeine consumption and risk of Parkinsons disease in men andwomen. An n Neurol 2001; 50:5663.

10 . Chen H, Zhang SM, Hernan MA, et al. Nonsteroidal anti-inflam-matory drugs and the risk of Parkinson disease. Arch Neurol 2003;60:10591064.

11 . Pearce RKB, Banerji T, Jenner P, Marsden CD. De novo adminis-tration of ropinirole and bromocriptine induces less dyskinesia than L-dopa in t he M PTP-treated marmoset. Mov Disord 1998; 13:234241.

12 . Rascol O, Brooks DJ, Korczyn AD, De Deyn PP, Clarke CE, LangA E. A five-year study of the incidence of dyskinesia in pat ients withearly Parkinsons disease who were treated with ropinirole or levo-dopa. 056 Study G roup. N Engl J Med 2000; 342:14841491.

13 . Golbe LI. Young-onset Parkinsons disease: a clinical review.Neurology 1991; 41(2 pt 1):168173.

14 . Block G, Liss C, R eines S, Irr J, N ibbelink D. Comparison of imme-diate-release and con trolled-release carbidopa/levodopa in Parkinsonsdisease: a mult icenter 5-year study. Eur Neurol 1997; 37:2327.

15 . Lieberman AN , N eophytides A, Leibowitz M, et al. Comparativeefficacy of pergolide and bromocriptine in patients with advancedParkinsons disease. Adv Neurol 1983; 37:95108.

16 . Pezzoli G, Martignoni E, Pacchetti C, et al. Pergolide compared

with bromocriptin e in Parkinsons disease: a m ulticent er, crossover,cont rolled study. Mov Disord 1994; 9:431436.

17 . Guttman M. Double-blind comparison of pramipexole andbromocriptin e treatmen t with placebo in advan ced Parkinsons dis-ease. International Pramipexole-Bromocriptine Study Group.Neu rology 1997; 49:10601065.

18 . Korczyn A D, Brunt ER, Larsen JP, N agy Z, Poewe WH , Ruggieri S.A 3-year randomized trial of ropinirole and bromocriptin e in early Park-insons disease. The 053 St udy G roup. N eurology 1999; 53:364370.

19 . Mizuno Y, Yanagisawa N , Kuno S, et al, Japanese PramipexoleStudy Group. Random ized, double-blind study of pramipexole withplacebo and bromocriptine in advanced Parkinsons disease. MovDisord 2003; 18:11491156.

20 . Van Camp G, Flamez A, Cosyns B, et al. Treatment of Parkinsonsdisease with pergolide and relation to restrictive valvular heart dis-ease. Lancet 2004; 363:11791183.

21 . Paus S, Brecht HM, Kster J, Seeger G, Klockgether T, WllnerU . Sleep attacks, daytime sleepiness, and dopamine agonists inParkinsons disease. Mov Disord 2003; 18:659667.

22 . Marjama-Lyons J, Koller W. Tremor-predominant Parkinsons dis-ease. Approaches to treatment. Drugs Aging 2000; 16:273278.

23 . Rinne U K, Larsen JP, Siden A , Worm-Petersen J. Entacaponeenhances the response to levodopa in parkinsonian patients with motorfluctuation s. N omecomt Study Group. N eurology 1998; 51:13091314.

24 . Larsen JP, Worm-Petersen J, Siden A, Gordin A, Reinikainen K,Leinonen M, N OMESAFE Study Group. Th e tolerability and effi-cacy of entacapon e over 3 years in pat ients with Parkinsons disease.Eur J Neurol 2003; 10:137146.

25 . Factor SA, Molho ES, Feustel PJ, Brown DL, Evans SM. Long-termcomparative experience with tolcapone and en tacapone in advancedParkinsons disease. C lin Neuroph armacol 2001; 24:295299.

26 . Keating GM, Lyseng-Williamson KA. Tolcapone-related liver dys-function: implications for use in Parkinsons disease therapy. CNSDrugs 2005; 19:165184.

27 . N ausieda PA , Pfeiffer RF, Tagliati M, Kastenholz KV, DeR oche C ,Slevin JT. A multicenter, open-label, sequential study comparingpreferences for carbidopa-levodopa orally disintegrating tablets andconventional tablets in subjects with Parkinsons disease. Clin Ther2005; 27:5863.

28 . Factor SA. Literature review: intermittent subcutaneous apomorphineth erapy in Parkin sons disease. Neurology 2004; 62(suppl 4):S12S17.

29 . Tho mas A, Iacono D, Luciano AL, Armellino K, DiIorio A, O nofrjM. Duration of amantadine benefit on dyskinesia of severeParkinson s disease. J Neu rol N eurosurg Psychiat ry 2004; 75:141143.

30 . Baron MS, Dalton WB. Quetiapine as a treatment for dopaminer-gic-induced dyskinesias in Parkinsons disease. Mov Disord 2003;


13/14

18:12081209.31 . Jaskiw GE, Thyrum PT, Fuller MA, Arvanitis LA, Yeh C.

Pharmacokinetics of quetiapine in elderly patients with selectedpsychotic disorders. Clin Pharmacokinet 2004; 43:10251035.

32 . Aarsland D, Andersen K, Larsen JP, Lolk A. Prevalence and char-

acteristics of dementia in Parkinson disease: an 8-year prospectivestudy. Arch N eurol 2003; 60:387392.

33 . McDonald WM, Richard IH, DeLong MR. Prevalence, etiology,and treatm ent of depression in P arkinsons disease. Biol Psychiatry2003; 54:363375.

34 . Magalhaes M, Wenning GK, D aniel SE, Quinn N P. Autonomicdysfunction in pathologically confirmed multiple system atrophyand idiopathic P arkinsons diseasea retrospective com parison.Acta Neurol Scand 1995; 91:98102.

35 . Ramig LO, Sapir S, Countryman S, et al. Intensive voice treat-men t ( LSVT ) for patien ts with Parkinsons disease: a 2 year followup. J Neurol N eurosurg Psychiatry 2001; 71:493498.

36 . The Deep-Brain Stimulation for Parkinsons Disease Study Group.Deep-brain stimulation of the subthalamic nucleus or the pars internaof the globus pallidus in Parkinsons disease. N Engl J Med 2001;345:956963.

37 . Schrag A, Ben-Shlomo Y, Quinn N P. Prevalence of progressive

supranuclear palsy and multiple system atrophy: a cross-sectionalstudy. Lancet 1999; 354:17711775.

38 . Tison F, Yekhlef F, Chrysostome V, Sourgen C. Prevalence of mul-tiple system atrophy. Lancet 2000; 355:495496.

39 . Wenning GK, Ben-Shlomo Y, Magalhaes M, Daniel SE, QuinnN P. Clin ical features and n atural history of multiple system at rophy:an analysis of 100 cases. Brain 1994; 117:835845.

40 . Ben-Sh lomo Y, Wenning G, Tison F, Quinn N P. Survival ofpatients with pathologically proven multiple system atrophy: ameta-an alysis. Neurology 1997; 48:384393.

41 . Testa D, Monza D , Ferrarini M, S oliveri P, Girotti F, Filippini G.Comparison of natural histories of progressive supranuclear palsyand m ultiple system atroph y. Neurol Sci 2001 ; 22:247251.

42 . Watanabe H, Saito Y, Terao S, et al. Progression and prognosis inmultiple system atrophy: an analysis of 230 Japanese patient s. Brain2002; 125:10701083.

43 . Papp MI, Kahn JE, Lantos PL. Glial cytoplasmic inclusions in the

CNS of patients with multiple system atrophy (striatonigral degen-eration, olivopontocerebellar atrophy and Shy-Drager syndrome). JNeurol Sci 1989; 94:79100.

44 . Gilman S, Low PA, Quinn N , et al. Consensus statement on t hediagnosis of multiple system atrophy. J Neurol Sci 1999; 163:9498.

45 . Stocchi F, Brusa L. Cognition and emotion in different stages and sub-types of Parkinsons disease. J N eurol 2000; 247(suppl 2) :II114II121.

46 . Kraft E, Trenkwalder C, Auer DP. T 2*-weighted MRI differenti-ates mult iple system atroph y from Parkinsons disease. N eurology2002; 59:12651267.

47 . Seppi K, Schocke MFH, Esterhammer R, et al. Diffusion-weight-ed imaging discriminates progressive supranuclear palsy from PD,but not from the parkinson variant of multiple system atrophy.N eurology 2003; 60:922927.

48 . Chou KL, Forman MS, Trojanowski JQ, Hurtig HI, Baltuch GH.Subthalamic nucleus deep brain stimulation in a patient with levo-dopa-responsive multiple system atrophy. Case report. J Neurosurg

2004; 100:553556.49 . Tarsy D , A petauerova D, Ryan P, N orregaard T. Adv erse effects

of subthalamic nucleus DBS in a patient with multiple system atro-phy. Neurology 2003; 61:247249.

50 . Yamaguchi M, Arai K, Asahina M, Hattori T. Laryngeal stridor inmultiple system atrophy. Eur Neurol 2003; 49:154159.

51 . Iranzo A, Santamaria J, Tolosa E, et al. Long-term effect of CPA Pin the treatment of nocturnal stridor in multiple system atrophy.N eurology 2004; 63:930932.

52 . H igo R, Tayama N , Watanabe T, N itou T, U gawa Y. Video-fluoroscopic and manometric evaluation of swallowing function inpatients with multiple system atrophy. Ann Otol Rhinol Laryngol2003; 112:630636.

53 . Santacruz P, Uttl B , Litvan I, G rafman J. Progressive supranuclearpalsy: a survey of the disease course. Neurology 1998; 50:16371647.

54 . N ath U, Ben-Shlomo Y, Thomson RG , et al. Th e prevalence ofprogressive supranuclear palsy (Steele-Richardson-Olszewski syn-drome) in the UK. Brain 2001; 124:14381449.

55 . De Bruin VM, Lees AJ. Subcortical n eurofibrillary degeneration pre-senting as Steele-Richardson-O lszewski and oth er related syndromes: areview of 90 pathologically verified cases. Mov Disord 1994; 9:381389.

56 . Litvan I, Mangone CA, McKee A, et al. Natural history of pro-gressive supranuclear palsy (Steele-Richardson-Olszewski syn-drome) and clinical predictors of survival: a clinicopathologicalstudy. J N eurol N eurosurg Psychiatry 1996; 60:615620.

57 . Litvan I, Agid Y, Calne D, et al. Clinical research criteria for thediagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome): report of the NINDS-SPSP internationalworkshop. N eurology 1996; 47:19.

58 . Vidailhet M, R ivaud S, Gou ider-Khouja N , et al. Eye movementsin parkinsonian syndromes. Ann Neurol 1994; 35:420426.

59 . Mega MS, Masterman DL, Benson DF, et al. Dementia with Lewybodies: reliability and validity of clinical and pathologic criteria.Neu rology 1996; 47:14031409.

60 . Rahkonen T, Eloniemi-Sulkava U, Rissanen S, Vatanen A,

Viramo P, Su lkava R. Dementia with Lewy bodies according to theconsensus criteria in a general population aged 75 years or older. JNeu rol N eurosurg Psychiatry 2003; 74:720724.

61 . McKeith IG, Ballard CG, Perry RH, et al. Prospective validationof consensus criteria for th e diagnosis of dementia with Lewy bodies.Neu rology 2000; 54:10501058.

62 . Ferman TJ, Smith GE, Boeve BF, et al. DLB fluctuations: specificfeatures that reliably differentiate DLB from AD and normal aging.Neu rology 2004; 62:181187.

63 . Wild R, Pettit T, Burns A. Cholinesterase inhibitors for dementiawith Lewy bodies. Cochrane Database Syst Rev 2003:CD003672.

64 . Burke WJ, Pfeiffer RF, McComb RD. Neuroleptic sensitivity toclozapine in dementia with Lewy bodies. J Neuropsychiatry ClinNeu rosci 1998; 10:227229.

65 . Fernandez HH, Trieschmann ME, Burke MA, Friedman JH.Qu etiapine for psychosis in Parkin sons disease versus dement ia withLewy bodies. J C lin Psychiatry 2002; 63:513515.

66 . Caplan LR. Binswangers diseaserevisited. Neurology 1995;45:626633.

67 . Roman GC, Erkinjuntti T, Wallin A, Pantoni L, Chui H C. Subcor-tical ischaemic vascular dementia. Lancet Neurol 2002; 1:426436.

68 . Awad IA, Spetzler RF, Hodak JA, Awad CA, Carey R. Incidentalsubcortical lesions identified on magnetic resonance imaging in theelderly. I. Correlation with age and cerebrovascular risk factors.Stroke 1986; 17:10841089.

69 . van Swieten JC, Geyskes G G, D erix MMA, et al. Hypertension inthe elderly is associated with white matter lesions and cognitivedecline. Ann Neurol 1991; 30:825830.

70 . Blass JP, H oyer S, N itsch R. A translation of Otto Binswangersarticle, The delineation of the generalized progressive paralyses.1894. Arch Neurol 1991; 48:961972.

71 . DeR euck J, Crevits L, De Coster W, Sieben G, vander Eecken H .Pathogenesis of Binswanger chronic progressive subcorticalenceph alopathy. Neurology 1980; 30:920928.

72 . Bennett DA, Wilson RS, Gilley DW, Fox JH. Clinical diagnosis ofBinswangers disease. J Neurol Neurosurg Pyschiatry 1990; 53:961965.

73 . Caplan LR, Schoene WC. Clinical features of subcortical arte-riosclerotic enceph alopathy ( Binswanger disease). Neurology 1978;28:12061215.

74 . Thompson PD, Marsden CD. Gait disorder of subcortical arterio-sclerotic ence phalop ath y: Binswangers disease. Mov Disord 1987; 2:18.

75 . Traykov L, Baudic S, Raoux N , et al. Pattern s of memory impairmentand perseverative behavior discriminate early Alzheimers disease fromsubcortical vascular dementia. J Neurol Sci 2005; 229230:7579.

76 . Hebb AO, Cusimano MD. Idiopathic normal pressure hydro-cephalus: a systematic review of diagnosis and outcom e. Neu rosurgery2001; 49:11661184.




14/14


77 . Savolainen S, Hurskainen H, Paljrvi L, Alafuzoff I, Vapalahti M.Five-year outcom e of normal pressure hydrocephalus with or without ashunt : predictive value of the clin ical signs, neuropsychological evalu-ation and infusion test. A cta N eurochir (Wien) 2002; 144:515523.

78 . Adams RD, Fisher CM, Hakim S, Ojemann RG, Sweet WH.

Symptomatic occult hydrocephalus with normal cerebrospinal-fluidpressure: a treatable syndrome. N Engl J Med 1965; 273:117126.

79 . Thomsen AM, Brgesen SE, Bruhn P, Gjerris F. Prognosis ofdementia in normal-pressure hydrocephalus after a shunt operation.An n Neurol 1986; 20:304310.

80 . Malm J, Kristensen B, Karlsson T, Fagerlund M, Elfverson J,Ekstedt J. Th e predictive value of cerebrospinal fluid dynam ic testsin patients with the idiopathic adult hydrocephalus syndrome. ArchNeurol 1995; 52:783789.

81 . Di Lauro L, Mearini M, Bollati A. The predictive value of 5 daysCSF diversion for shunting in normal pressure hydrocephalus. JN eurol N eurosurg Psychiatry 1986; 49:842843.

82 . Haan J, Thomeer RTWM. Predictive value of temporary externallumbar drainage in normal pressure hydrocephalus. Neurosurgery1988; 22:388391.

83 . Chen IH, Huang CI, Liu HC, Chen KK. Effectiveness of shuntin gin patien ts with norm al pressure hydrocephalus predicted by tempo-

rary, controlled-resistance, continuous lumbar drainage: a pilotstudy. J N eurol N eurosurg Psychiatry 1994; 57:14301432.

84 . Symon L, Dorsch N WC. Use of long-term intracranial pressuremeasurement to assess hydrocephalic patien ts prior to shun t surgery.J Neurosurg 1975; 42:258273.

85 . Krauss JK, Halve B. Normal pressure hydrocephalus: survey oncontemporary diagnostic algorithms and therapeutic decision-mak-ing in clinical practice. Acta Neurochir (Wien) 2004; 146:379388.

86 . Louis ED, Ottman R, H auser WA. How common is the most com-mon adult movem ent disorder? Estimat es of the prevalence of essen-tial tremor throughout the world. Mov Disord 1998; 13:510.

87 . Rautakorpi I, Takala J, Marttila RJ, Sievers K, Rin ne U K. Essentialtremor in a Finnish population. A cta N eurol Scand 1982; 66:5867.

88 . Rajput A, Robinson CA, Rajput AH. Essential tremor course anddisability: a clinicopathologic study of 20 cases. Neurology 2004;62:932936.

89 . Tanner CM, Goldman SM, Lyons KE, et al. Essential tremor in

twins: an assessment of genetic vs environmental determinants ofetiology. N eurology 2001; 57:13891391.

90 . Lorenz D, Frederiksen H, Moises H, Kopper F, Deuschl G,Christensen K. High concordance for essential tremor in monozy-gotic twins of old age. Neurology 2004; 62:208211.

91 . H iggins JJ, Ph o LT, N ee LE. A gene (ETM) for essential tremormaps to chromosome 2p22p25. Mov Disord 1997; 12:859864.

92 . Gulcher JR, Jonsson P, Kong A, et al. Mappin g of a familial essentialtremor gene, FET1, to chromosome 3q13. Nat Genet 1997; 17:8487.

93 . Deuschl G, Wenzelburger R, Lffler K, Raethjen J, Stolze H.Essential tremor and cerebellar dysfunction: clinical and kinematicanalysis of intent ion t remor. Brain 2000; 123:15681580.

94 . Pinto AD, Lang AE, Chen R. The cerebellothalamocortical path-way in essential tremor. N eurology 2003; 60:19851987.

95 . Brennan KC, Jurewicz EC, Ford B, Pullman SL, Louis ED. Isessential trem or predominant ly a kinetic or a postural tremor? A clin-ical and electrophysiological study. Mov Disord 2002; 17:313316.

96 . Elble RJ. Diagnostic criteria for essential tremor and differentialdiagnosis. N eurology 2000; 54(11 suppl 4):S2S6.

97 . Lombardi WJ, Woolston DJ, Roberts JW, Gross RE. Cognitivedeficits in pat ient s with essent ial tremor. Neurology 2001; 57:785790.

98 . Schmahmann JD, Sherman JC. The cerebellar cognitive affectivesyndrom e. Brain 1998; 121:561579.

99 . Gorman WP, Cooper R , Po cock P, C ampbell MJ. A comparison ofprimidone, propranolol, and placebo in essential t remor, using quan-titative analysis. J Neurol Neurosurg Psychiatry 1986; 49:6468.

100. Koller WC, Royse VL. Efficacy of primidone in essential tremor.N eurology 1986; 36:121124.

101. Sullivan KL, Hauser RA, Zesiewicz TA. Essential tremor. Epi-demiology, diagnosis, and treatment. Neurologist 2004; 10:250258.

102. Jefferson D, Jenner P, Marsden CD. Beta-adrenoreceptor antagonistsin essential trem or. J N eurol N eurosurg Psychiatry 1979; 42:904909.

103. Leigh PN , Marsden CD, Twomey A, Jefferson D. Beta-adreno-

ceptor an tagonists and essent ial tremor. Lancet 1981; 1:1106.104. Huber SJ, Paulson GW. Efficacy of alprazolam for essential tremor.

Neu rology 1988; 38:241243.105. Connor GS. A double-blind placebo-controlled trial of topiramate

treatm ent for essential tremor. N eurology 2002; 59:132134.106. Gatto EM, Roca MCU , Raina G, Micheli F. Low doses of topira-

mate are effective in essential tremor: a report of three cases. ClinNeuropharmacol 2003; 26:294296.

107. Lyons KE, Pahwa R. Deep brain stimulation and essential tremor.J Clin N europhysiol 2004; 21:25.

108. Fernandez HH, Friedman JH. Classification and treatment of tar-dive syndromes. Neurologist 2003; 9:1627.

109. Baldessarini RJ, Cole JO, Davis JM, et al. Tardive dyskinesia: sum-mary of a Task Force Report of the American Psychiatric Association.Am J Psychiatry 1980; 137:11631172.

110. Jeste DV, Lacro JP, Palmer B, Rockwell E, Harris MJ, CaligiuriMP. Incidence of tardive dyskinesia in early stages of low-dose treat-

ment with typical neuroleptics in older patients. Am J Psychiatry1999; 156:309311.

111. Woerner MG, Alvir JMJ, Saltz BL, Lieberman JA, Kane JM.Prospective study of tardive dyskinesia in th e elderly: rates and riskfactors. A m J Psychiatry 1998; 155:15211528.

112. Jeste D V, Okamoto A , N apolitano J, Kane JM, Martinez RA. Lowincidence of persistent tardive dyskinesia in elderly patients with demen-tia treated with risperidone. Am J Psychiatry 2000; 157:11501155.

113. Emsley R, Turner HJ, Schronen J, Botha K, Smit R, Oosthuizen PP.A single-blind, randomized trial comparing quetiapine and haloperidol inthe treatment of tardive dyskinesia. J Clin Psychiatry 2004; 65:696701.

114. Bacher N M, Lewis HA . Reserpine and tardive dyskinesia. Am JPsychiatry 1 984; 141:719.

115. Ondo WG, Hanna PA, Jankovic J. Tetrabenazine treatment fortardive dyskinesia: assessment by randomized videotape protocol.Am J Psychiatry 1999; 156:12791281.

116. Trottenberg T, Paul G, Meissner W, Maier-Hauff K, Taschner C,

Kupsch A. Pallidal and thalamic neurostimulation in severe tardivedyston ia. J Neurol N eurosurg Psychiatry 2001; 70:557559.

117. Schrader C, Peschel T, Petermeyer M, Dengler R, Hellwig D.Unilateral deep brain stimulation of the internal globus pallidusalleviates tardive dyskinesia. Mov Disord 2004; 19:583585.

118. Lavigne GJ, Montplaisir JY. Restless legs syndrome and sleep bruxism:prevalence and association am ong Can adians. Sleep 1994; 17:739743.

119. Walters AS, Hickey K, Maltzman J, et al. A question naire study of138 pat ients with restless legs syndrome: t he N ight-Walkers survey.Neu rology 1996; 46:9295.

120. Allen RP, Picchietti D, Hening WA, et al, for the InternationalRestless Legs Syndrome Study G roup. Restless legs syndrom e: diag-nostic criteria, special considerations, and epidemiology: a reportfrom the restless legs syndrome diagnosis and epidemiology workshopat the National Institutes of Health. Sleep Med 2003; 4:101119.

121. Phillips B, Young T, Finn L, Asher K, Hening WA, Purvis C.Epidemiology of restless legs symptom s in adults. A rch In tern Med

2000; 160:21372141.122. Allen RP, Earley CJ. Augmentation of the restless legs syndrome

with carbidopa/levodopa. Sleep 1996; 19:205213.123. Garcia-Borreguero D, Larrosa O, de la Llave Y, Verger K, Masramon

X, H ernandez G. Treatment of restless legs syndrome with gabapentin :a double-blind, cross-over study. N eurology 2002; 59:15731579.

124. Walters AS, Winkelmann J, Trenkwalder C, et al. Long-term fol-low-up on restless legs syndrome pat ients treat ed with opioids. MovDisord 2001; 16:11051109.

125. Ondo WG. Methadone for refractory restless legs syndrome. MovDisord 2005; 20:345348.

BA RO N

ccjm movement disorders in the older patient

Documents