unclassifiable parkinsonism in two european tertiary referral centres for movement disorders

Unclassifiable Parkinsonism in Two European Tertiary ReferralCentres for Movement Disorders

Regina Katzenschlager, MD,1 Adriana Cardozo, MD,2 M. Rosario Avila Cobo, MD,2

Eduardo Tolosa, MD, PhD,2 and Andrew J. Lees, MD, FRCP1*

1National Hospital for Neurology and Neurosurgery, Queen Square, London, United Kingdom2Parkinson’s Disease and Movement Disorders Unit, Institut Clinic de Malalties del Sistema Nervios, Hospital Clinic

Universitari, School of Medicine, University of Barcelona, Spain

Abstract: In view of reports on high frequencies of atypicalparkinsonism from different parts of the world and in non-white communities in the United Kingdom, we have prospec-tively surveyed 1,000 consecutive patients with parkinsonismpresenting to two European tertiary referral centres for move-ment disorders (London, UK, and Barcelona, Spain). The aimsof our study were to assess in a cross-sectional, prospectivemanner the proportion of patients who could not be classifieddiagnostically, to identify the factors precluding classification,and to determine which diagnostic measures would increase therate of classifiable cases. Diagnoses were established usingpublished clinical diagnostic criteria for Parkinson’s disease(PD) and for other conditions associated with parkinsonism.Twenty-nine patients in London and 25 in Barcelona wereinitially considered unclassifiable; nine could be classified afterfurther investigations. Levodopa (L-dopa) responsiveness was

found to have a pivotal role in establishing a clinical diagnosisin previously unclassifiable patients: In those 45 patients whoremained unclassifiable, failure to respond to L-dopa withoutother exclusion criteria for PD was the most common finding ineach centre. Our results show that 4.0 to 5.0% of parkinsonianpatients presenting to specialist clinics in Western Europecannot be categorised using currently available clinical diag-nostic criteria for parkinsonian syndromes. Prolonged fol-low-up and neuropathological diagnosis will be needed todetermine whether all these cases represent atypical presenta-tions of established clinico-pathological entities or whethersome represent unrecognised new disorders. © 2003 Move-ment Disorder Society

Key words: atypical parkinsonism; clinical diagnosticcriteria

The clinical syndrome of parkinsonism1 can either becaused by primary neurodegenerative conditions or oc-cur secondary to other underlying causes, such as dopa-mine blocking drugs, cerebrovascular disease, cumula-tive head trauma, neoplasia, toxins, or encephalitis.Parkinson’s disease (PD) is the commonest cause ofparkinsonism in neurological practice in North Americaand Western Europe. The frequent occurrence of atypicalparkinsonism on the Pacific island of Guam2 and other

Pacific islands3,4 has been known for more than half acentury but there is now increasing evidence for a higherproportion of conditions other than idiopathic PD inother geographical isolates and ethnic groups: A higherproportion of patients with atypical, poorly levodopa(L-dopa) -responsive parkinsonism has been observedboth in hospital clinics in India and in South Asianimmigrants to the United Kingdom (UK).5 A report6

from the only neurology service in Guadeloupe in theFrench West Indies showed that progressive supranu-clear palsy (PSP) made up 36% of patients with parkin-sonism, and in 35% of all patients, the clinical picturewas atypical and did not meet any of currently recog-nised diagnostic criteria. Figures from a recent follow-upreport7 were 26.5% for PSP and 43.8% for undeterminedparkinsonism, whereas parkinsonism with amyotrophiclateral sclerosis was found in 6.8%. Moreover, there is

*Correspondence to: Dr. Andrew J. Lees, Reta Lila Weston Instituteof Neurological Studies, Windeyer Building, 46 Cleveland Street,London W1T 4JF, United Kingdom.E-mail: [email protected]

Received 27 August 2002; Revised 15 April 2003; Accepted 15April 2003

DOI 10.1002/mds.10523

Movement DisordersVol. 18, No. 10, 2003, pp. 1123–1131© 2003 Movement Disorder Society

1123

now also evidence of a high frequency of atypical par-kinsonism on another West Indian island, Martinique.7

In the absence of specific biological markers for any ofthe neurodegenerative conditions causing parkinsonism,their diagnosis and differentiation are largely based onclinical examination. Although the clinical diagnosis ofthe fully established syndromes is usually straightfor-ward, atypical signs or partial syndromes in the earlystages may present formidable challenges. Even whenconsidering clinical diagnoses made during the entirecourse of the disease, some diagnostic uncertainty re-mains: A clinicopathological study8 showed that among100 patients who had been diagnosed with idiopathic PDby neurologists, autopsy confirmation occurred in only76%. Neurofibrillary tangle pathology (tauopathies),multiple system atrophy (MSA), and vascular diseasewere found to be the most frequent neuropathologicaldiagnoses in the other 24%. Another study9 found thesame rate of diagnostic inaccuracy. A more recent com-parative study10 demonstrated an improved figure of90%. This finding is likely to reflect a greater diagnosticawareness among clinicians of the clinical spectrum ofparkinsonian syndromes, and it coincides with the pub-lication of sets of clinical diagnostic criteria for most ofthese conditions in recent years.

The aim of this study was to apply sets of currentlyused and published diagnostic criteria to survey 1,000consecutive patients with parkinsonism of any etiologyin two large tertiary referral centres for movement dis-orders to assess the proportion of patients in whomdiagnostic uncertainty remained, to identify the con-founding clinical features, to establish which diagnosticmeasures would increase the rate of classifiable cases,and finally, to provide a basis for future comparison inview of an increasing number of reports on atypicalparkinsonism from different geographical areas.

PATIENTS AND METHODS

Between November 1999 and April 2000, all patientsattending the outpatient clinics for movement disordersunder the respective consultants (A.J.L. and E.T.) at thetwo centres (National Hospital for Neurology and Neu-rosurgery, Middlesex Hospital, and Private ConsultingRooms at University College London Hospital in Lon-don, and Neurology Department/Hospital Clinic at theUniversity of Barcelona) were screened prospectively forparkinsonism, until 500 consecutive patients had beenidentified in each centre. Parkinsonism was defined ac-cording to the Parkinson’s Disease Society Brain Re-search Centre of the United Kingdom criteria,1 requiringthe presence of bradykinesia and at least one of the

following: 4 to 6 Hz rest tremor, rigidity, or posturalinstability not caused by primary visual, vestibular, cer-ebellar, or proprioceptive dysfunction. In each case, anattempt was made to classify the cause of parkinsonismaccording to the currently accepted clinical diagnosticcriteria.

These sets of criteria were as follows: for idiopathicPD, the Parkinson’s Disease Society Brain ResearchCentre of the United Kingdom criteria1 (with the modi-fications that neither an isolated Babinski sign attribut-able to other causes nor more than one affected relativecounted as exclusion criteria); for MSA, the ConsensusStatement11; for PSP, either the NINDS-SPSP criteria12

or the criteria published by Tolosa and colleagues13; forcorticobasal degeneration (CBD), criteria proposed byLang and coworkers14; and the respective consensusguidelines for dementia with Lewy bodies (LBD),15 Alz-heimer’s disease (AD)16 and frontotemporal dementia(FTD).17 For DLB, onset of dementia within the first 12months, as recommended by the authors of the diagnosticcriteria, was included as a requirement. For Pick’s dis-ease, in the absence of generally accepted publishedcriteria, the definition of the DSM-IV Classification ofDiseases was used.18 Vascular parkinsonism (VP) wasdiagnosed according to published criteria,19 with themodification that localisation of vascular magnetic reso-nance imaging (MRI) changes was taken into accountrather than absolute numbers, as outlined by Zijlmansand colleagues,20 who found vascular lesions in VP to beeither strategically located in the basal ganglia or to bewidespread and bilateral in the hemispheres. Probabledrug-induced parkinsonism was defined as parkinsonismoccurring during dopamine blockade and persisting forup to 12 months after withdrawal.

Those patients with parkinsonism who did not meetthe criteria for a clinically definite (PD) or probablediagnosis (MSA, PSP, DLB, AD, FTD, or VP) wereassessed further, according to the same protocol in bothcentres, and had the following investigations, unlessdone previously: MRI (or computed tomography whenMRI was not possible); detailed clinical assessment ofeye movements; blood pressure and heart rate supine andstanding (1 minute); history with respect to autonomicfunction; Mini Mental State Examination21 (formal neu-ropsychological testing when indicated); University ofPennsylvania Smell Identification Test (UPSIT)22 inLondon; family history, genetic testing when indicated;and single photon emission computerised tomography(SPECT) of the presynaptic dopaminergic system ifappropriate.

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Movement Disorders, Vol. 18, No. 10, 2003

L-dopa responsiveness was rated as present (sustainedor temporary), absent, or equivocal based on the historyby patients, carers, and treating physicians. Wheneverthis rating was considered equivocal or absent, attemptswere made to obtain objective measures. Unified Parkin-son’s Disease Rating Scale (UPDRS)23 part III was usedto assess motor function. In the first instance, L-dopa wasslowly pushed up to either the highest dose well toleratedby the patient or to 1,000 mg daily,11 unless a dose belowthis led to a clear improvement in UPDRS. If the re-sponse remained unclear, or if lack of tolerability pre-vented a meaningful dose increase, an acute dopaminer-gic challenge was performed after formal consentwhenever possible. A total of 200 mg of L-dopa � 50 mgof benserazide in dispersible form were administeredafter overnight medication withdrawal and fasting. Inaccordance with published guidelines,24 an improvementof 20% in UPDRS motor score counted as a positiveresponse. Patients whose responsiveness remainedequivocal were asked to withhold L-dopa for up to 1week, if it was believed that this could be done safely.They were asked to come back for re-assessment 1 weeklater or, in case of a rapid or unpleasant deterioration, toeither contact an emergency number or to resume takingtheir medication immediately. Whenever it was deemedjustifiable taking due consideration of the patients’ andrelatives’ emotional state, postmortem brain tissue dona-tion to the respective Brain Banks in London and Bar-celona was requested.

RESULTS

Unclassifiable Patients: Clinical Features andFurther Investigations

Table 1 shows the diagnoses made at the two centres.The patients listed as initially unclassifiable (29 in Lon-don and 25 in Barcelona) are those in whom, based on allclinical information available, no diagnostic agreementwas reached. Table 2 lists the subgroups of unclassifiablepatients which were identified based on clinical charac-teristics and atypical features.

After further investigations, classification became pos-sible in 4 more patients in London and 5 in Barcelona(Table 3). The final figures for unclassifiable patientswere 25 (5.0%) in London and 20 (4.0%) in Barcelona.Mean age in the unclassifiable group was 70.3 years(range, 47–83 years) in London and 66.8 years (range,53–83 years) in Barcelona, with a mean disease durationof 6.4 years in London and 6.9 years in Barcelona.

In each centre, 5 patients had poor or absent L-doparesponsiveness without any other clinical features that

would rule out PD. Of the 45 patients who remainedunclassifiable, 31 responded poorly and one moderatelyto L-dopa, 2 had unsustained initial benefit, and in 5,response remained equivocal or borderline despite for-mal testing. Only 5 had a good and sustained response.

There were 6 unclassifiable cases in Barcelona and 4in London in whom full assessment of L-dopa respon-siveness was not possible because the patients developedadverse effects on small to medium dosages. These sideeffects included nausea, dizziness, and indigestion in 3patients and, in 1 patient each, facial dystonia, neuropsy-chiatric symptoms including hallucinations, or subjectiveworsening of tremor.

Ethnic Origin

Of the 25 unclassifiable patients in London, 3 (or12%), were non-white (1 Indian, 1 African Caribbean,and 1 Mauritian), compared to 6.5% in the total surveyedclinic population. This difference was not statisticallysignificant (Fisher’s exact test). All non-white unclassi-fiable patients showed a lack of response to L-dopa.

Olfactory Function

In the unclassifiable patients, mean UPSIT was 22.5(95% confidence interval [CI], 19.7, 25.3) of 40 possible

TABLE 1. Final clinical diagnoses in 500 consecutiveparkinsonian patients in each centre

Diagnosis

London Barcelona

Patients,n (%)

Patients,n (%)

Parkinson’s disease 416 (83.2) 425 (85.0)Probable multiple system atrophy 14 (2.8) 12 (2.4)Probable progressive supranuclear

palsy 12 (2.4) 9 (1.8)Probable dementia with Lewy

bodies 10 (2.0) 5 (1.0)Vascular parkinsonism 8 (1.6) 14 (2.8)Drug-induced parkinsonism 5 (1.0) 3 (0.6)Probable corticobasal degeneration 3 (0.6) 4 (0.8)Posttraumatic parkinsonism 2 (0.4) —Postencephalitic parkinsonism 1 (0.2) —Dentato-rubro-pallido-luysian

atrophy 1 (0.2) —Phenylketonuria 1 (0.2) —Huntington’s disease 1 (0.2) —Essential tremor � psychogenic gait

disorder 1 (0.2) —Wilson’s disease — 2 (0.4)Hallervorden Spatz syndrome — 2 (0.4)Methanol intoxication — 1 (0.2)Essential tremor — 1 (0.2)Normotensive hydrocephalus — 1 (0.2)Alzheimer’s disease — 1 (0.2)Unclassifiable parkinsonism 25 (5.0) 20 (4.0)Total 500 (100) 500 (100)

UNCLASSIFIABLE PARKINSONISM 1125


TABLE 2. Unclassifiable patients in both centres

Subgroups: clinical characteristics and atypical features L-Dopa responsivenessPatients

(n)Age, mean

(range)

Diseaseduration, yr

(range)

1. Lack of L-dopa responsiveness only atypical feature for PD. Poor 10 72 (56–83) 7.2 (2–15)2. L-Dopa responsiveness cannot be assessed 3 criteria for PD not

fulfilled.Cannot be assessed fully

due to adverse reaction.6 69 (60–83) 7.7 (2–20)

3. Disease duration too short to fulfil three supportive criteria forPD.

Good in 1, not tried in 1because too mild.

2 64 and 83 2.5

4. Fulfilling criteria for a possible diagnosis:a) Possible PSP/NINDS-SPSP

Falls in first year � slow vertical saccades. Good 1 66 3Falls later than first year � slow vertical saccades. Transient: initially good,

poor after first year.1 67 5

b) Possible PSP/Tolosa Initially good, later 1 71 5Parkinsonism � SNGP � frontal lobe syndrome. moderate.

c) Possible MSA Poor 1 53 105. Possible PSP/NINDS-SPSP � possible MSA, no exclusion

criterion:a) Parkinsonism with: intermittent incontinence � slow vertical

saccades � falls in first year.Poor 2 64 and 77 8 and 5

b) Parkinsonism, falls first symptom � slow vertical saccades �blood pressure drop/40 mm Hg (� abnormal autonomictests).

Poor 1 70 5

6. PSP-like but at least one atypical feature/exclusion criterion:a) Parkinsonism � early falls. Poor 2 71 and 74 3

Eye movements normal.b) Parkinsonism � SNGP. Good 1 73 13

Falls later than first year � L-dopa response.c) Parkinsonism � slow vertical saccades � supportive PSP

criteria/Tolosa (cognitive decline, frontal lobe signs, erectposture, 2 blink rate), no falls.

Moderate 1 66 2

d) Parkinsonism � slow vertical saccades.Falls later than first year, SNGP uncertain due to 2 vision. Poor 1 78 14Falls later than first year. Moderate to poor 1 65 5Falls later than first year � prominent dementia. Against

DLB: onset of dementia later than 12 months after diseaseonset.

Poor 1 76 4

e) Parkinsonism � early falls � prominent frontal lobe signs. Good 1 66 2No SNGP � sustained L-dopa response (with dyskinesias).

7. MSA-like but at least one atypical feature/exclusion criterion:Parkinsonism � early incontinence.

Dementia � exclusion criterion. Dose increase: equivocal 1 64 14Atypical for DLB: onset of dementia too late. Challenge: negative

8. Insufficient features for MSA criteria:Parkinsonism � blood pressure drop/20 mm Hg. Painful facial

dystonia.Equivocal with delayed

deterioration onwithdrawal.

1 59 12

9. Criteria for probable MSA fulfilled but possibly confoundingfactors:

Parkinsonism � incontinence. Poor 1 81 3But: history of repeated prostate surgery.

10. Exclusion criteria/atypical features for more than onecondition:

a) Parkinsonism � incontinence � jerky tremor and myoclonus� dementia with hallucinations � slow vertical saccadesand dystonic eye deviations � marked dysarthria anddysphagia � falls (�1 year).

Poor 1 69 7

Against PSP: early autonomic features.Against MSA: dementia and prominent oculomotor

abnormalities.b) Rapidly progressive parkinsonism with falls � fist year � 1

SNGP � urinary urgency and occasional incontinence �BP drop/20 mm Hg.

Poor 1 58 3

Against PSP: no 2 SNGP (Tolosa): no falls � 1 year(NINDS).

Against MSA: eye movement disorder � exclusion criterion.c) Symmetrical parkinsonism without tremor � urinary urgency

� BP drop 25 mm Hg � vertical eye movements: reducedamplitude and slow saccades.

Equivocal: no subjectiveresponse but positivechallenge.

1 59 2

Against PD: only 2 supportive criteria fulfilled.Against MSA: no definitive lack of L-dopa response; no

incontinence or cerebellar signs.Against PSP: no SNGP (Tolosa); no falls � 1 year (NINDS).



correct answers. This was compared to age and gendermatched, identically large normal control and PD groups(Mann–Whitney U test). Mean values were 27.9 (95%CI, 26.2, 29.6) in the normal controls and 15.8 (95% CI,13.4, 18.2) in PD. The differences between all thesegroups were significant (P � 0.01). Mean UPSIT scorein the subgroup of 5 unclassifiable patients with L-dopahyporesponsiveness as the only atypical feature was 25.4(95% CI, 20.3, 30.5).

Neuropathologically Confirmed Cases

Two of the patients who had agreed to brain tissuedonation have come to postmortem.

Case 1.

A 69-year-old woman (subgroup 10 a/Table 2) inLondon had a progressive akinetic–rigid syndrome witha peculiarly erect posture and broad-based gait. She hadirregular, jerky tremor with intermittent myoclonus inher hands and face; lost balance early with falls a fewyears into her disease; and developed early incontinence,dementia with hallucinations, and severe dysphagia anddysarthria. Eye movements showed limitation of upgaze,which was overcome by oculocephalic reflex, slow sac-cades in all directions, but full range for downgaze. Blinkrate was reduced and frontalis muscle was hyperactive,leading to a startled facial expression. None of her symp-toms and signs responded to L-dopa or other antiparkin-sonian treatment. Disease duration until death was 7

years. Neuropathological examination showed wide-spread predominantly glial cytoplasmic inclusions,mainly involving striatum, substantia nigra, and locuscaeruleus, thus leading to a pathological diagnosis ofmultiple system atrophy/striatonigral degeneration type.

Case 2.

In Barcelona, a 78-year-old man (subgroup 11/Table2) came to postmortem with a history of severe depres-sion and anxiety who subsequently developed dementiaand behavioural problems requiring anti-psychotic drugs.An akinetic–rigid syndrome including tremor was at firstattributed to neuroleptics, but progression continued afterdrug withdrawal. Parkinsonism increased in a step-wisemanner. L-dopa did not improve motor symptoms, al-though a trial of high dose L-dopa was not attempted inview of the underlying psychiatric symptoms. The de-menting illness could not be classified as either AD,Pick’s disease, or FTD. Total disease duration was 4years. Neuropathological examination revealed both id-iopathic PD and multiple vascular changes involving thebasal ganglia, compatible with vascular parkinsonism.Lewy bodies, which were immunoreactive to ubiquitinand alpha-synuclein, were almost exclusively found inthe brainstem, locus caeruleus, and substantia nigra, andthe cause of the dementia was attributed to widespreadvascular lesions, which involved cortex, white matter,striatum, and thalamus. Hypertension and hypercholes-terolaemia had been present. An MRI had been carried

TABLE 2. (Continued)

Subgroups: clinical characteristics and atypical features L-Dopa responsivenessPatients

(n)Age, mean

(range)

Diseaseduration, yr

(range)

d) Rapidly progressive parkinsonism � falls � 1 year � earlyincontinence. Good 1 54 3

Against MSA: L-dopa responsiveness and lack of cerebellarsigns.

Against PSP: normal eye movements.11. Unclassifiable dementia with parkinsonism:

Primary psychiatric condition; progressive parkinsonism afterdiscontinuation of neuroleptics; predominantly gait disorder� tremor; stepwise worsening.

Poor but cannot be fullyassessed due topsychiatric condition. 1 78 4

12. CBD-like syndrome, but not all criteria fulfilled:a) Rapidly progressive, highly asymmetric parkinsonism � early

falls � marked dystonia � cognitive decline � slowsaccades, 2 upgaze, square wave jerks. Poor 1 63 3

No cortical sensory loss, apraxia, or alien limb signNo focal reflex myoclonus

b) Highly asymmetrical parkinsonism with marked rigidity; notremor.

No cortical sensory loss, apraxia, or alien limb sign Poor 2 47 and 65 6 and 10No focal reflex myoclonus or dystonia

13. Features atypical for any of the classifiable syndromes:L-dopa unresponsive parkinsonism � ALS-like syndrome. Poor 1 71 2

PD, Parkinson’s disease; PSP, progressive supronuclear palsyi SNGP, supranuclear gaze palsy involving downgaze;1 SNGP, supranuclear gaze palsy for upgaze only;Tolosa, criteria for PSP (see Tolosa et al., 1995); MSA, multiple system atrophy; DLB, dementia with Lewy bodies; ALS, amyotrophic lateral sclerosis; CBD, corticobasaldegeneration; BP, blood pressure; NINDS, National Institute of Neurological Disorders and Stroke.



out 2 years after disease onset and had shown only a mildto moderate degree of vascular change, mostly smalllacunar lesions in the basal ganglia.

DISCUSSIONOur findings show that even in specialised movement

disorders clinics, there is a proportion of patients whoseparkinsonian syndrome cannot be classified according tocurrently used clinical diagnostic criteria. On cross-sec-tional, prospective assessment, this percentage wasfound to be 5.0% in the UK centre and 4.0% in theSpanish centre. The similarity between these figures andbetween the respective figures for classifiable patientssuggests that our findings are likely to be representativeof similar Western European movement disorder clinics,although many factors may have had an impact on thecomposition of the patient cohorts in the two centres.

The clinical diagnostic criteria for this survey werechosen as a consensus of the two participating centres.We aimed to select those which, in the experience ofeach centre, are currently most widely used and acceptedfor each condition. It could be argued that the use ofother diagnostic criteria would have led to the inclusionor exclusion of different patients. We attempted to ac-count for this fact in the case of PSP using two sets,because each includes rather strict inclusion criteria: fallswithin 1 year of disease onset in the NINDS-SPSP cri-teria,12 and presence of supranuclear gaze palsy involv-ing downgaze in the criteria by Tolosa and coworkers.13

In very selected other sets of criteria, slight modificationswere made that appeared appropriate in light of morerecent information and that reflect the common applica-tion of these criteria, for instance with respect to affected

TABLE 3. Investigations leading to classification

CentreAge(yr)

Diseaseduration Clinical features Investigations

Final clinicaldiagnosis

London 71 6 Asymmetrical parkinsonism withjerky tremor; incontinence.Initially good L-dopa response,later equivocal.

Increase to 1,000 mg 3 nochange in UPDRS.

MSA

70 12 Akinetic–rigid syndrome withouttremor. No subjectiveimprovement on anymedication.

L-Dopa withdrawal 3 cleardeterioration.

PD

60 14 Long-standing depression andanxiety disorder.Tremor/positive family history.Later: slow and cautious gait;equivocal bradykinesia.Subjective benefit from L-dopa.

L-Dopa dose increase andwithdrawal 3 no change.FP-CIT SPECT: normaltracer uptake in dopaminetransporter system.

Essential tremor andpsychogenic gaitdisorder

58 10 Bradykinesia, walking difficulty,dysarthria, cognitive decline.Former amateur boxer.

L-Dopa dose increase andwithdrawal 3 no change.Genetic test 3 46 tripletrepeats in HD gene.

Huntington’s disease

Barcelona 71 5 Akinetic-rigid syndrome.Equivocal L-dopa response.

L-Dopa dose increase 3clear improvement.

PD

68 6 Akinetic–rigid syndrome withtremor. No subjective benefitfrom medication.

L-Dopa withdrawal 3 cleardeterioration.

PD

69 2 L-Dopa–unresponsiveparkinsonism, predominantlylower body bradykinesia;urinary incontinence; nocognitive deficits.

MRI Normotensivehydrocephalus

69 7 Cognitive decline, behaviouralabnormalities and apraxia; L-dopa unresponsiveparkinsonism.

Detailed neuropsychologicalassessment.

Alzheimer’s disease

72 8 Asymmetrical postural andresting tremor; equivocalbradykinesia. No improvementon L-dopa.

FP-CIT SPECT: normaltracer uptake in dopaminetransporter system.

Essential tremor

UPDRS, Unified Parkinson’s Disease Rating Scale; MSA, multiple system atrophy; PD, Parkinson’s disease; HD, Huntington’s disease; MRI,magnetic resonance imaging; SPECT, single photon emission computerised tomography.



relatives in PD in the absence of an identifiable single-gene defect. However, overall, it seems unlikely thatchoosing different sets of criteria would have had a hugeimpact on our findings.

This study was not designed to test the sets of criteriaused. Most sets of criteria were not specifically designedto aim either at high sensitivity or at high specificity, andsensitivity is usually lower in the early stages of disease.For instance, some of our unclassifiable patients did notfulfil all three supportive criteria for PD required by theUK Brain Bank criteria because these include a specificduration for certain features. This could lead to theexclusion of some patients who do have early PD butwho do not have tremor or unilateral onset. Conversely,in other parkinsonian syndromes, disease-specific fea-tures are often absent at onset. A 6-year follow-up re-port25 on the patient cohort enrolled in the DATATOPtrial26 found a modification rate of 6.8% of the initialdiagnosis of PD made by movement disorder specialists.

An example where the authors of diagnostic criteriaopted for higher specificity at the expense of sensitivityis CBD:14 There is increasing evidence for cognitivedysfunction as an early feature of CBD.27 The authors ofthe criteria emphasise that using early dementia as anexclusion criterion will exclude patients who actuallyhave CBD but will reduce the risk of including patientswith other, more common dementing processes.

As expected, the unclassifiable patients identified inour study form a fairly heterogeneous group. The featuremost commonly found in the unclassifiable cohort waslack of or unsatisfactory L-dopa response, which waspresent in 40 of 45, or 88.9%, of unclassifiable patients.

Although unresponsiveness to L-dopa has been de-scribed in up to 6%28 of pathologically confirmed casesof idiopathic PD,10,29–31 this is unusual if confirmed byobjective assessment methods and is an exclusion crite-rion in all published diagnostic criteria.1,32–35

There is no consensus on how L-dopa responsivenessshould be determined, and there are no generally ac-cepted definitions of various degrees of L-dopa respon-siveness, although the UK Brain Bank criteria for PD1

define an improvement of 70 to 100% as excellentresponse.

There are guidelines in the literature for the perfor-mance of acute dopaminergic challenges,24 and bothL-dopa and apomorphine challenges have repeatedlybeen shown to be useful tools, because they predictlong-term response in the vast majority of cases.36 How-ever, there are limitations to their use: The doses requiredare occasionally not well tolerated, and false-negativeresponses in patients who respond to chronic L-dopa

administration may occur. These shortcomings of chal-lenge tests can be avoided by slowly building up the doseof L-dopa in a patient’s drug regimen. The dose thatshould be aimed at has not been universally agreed on,but we found increasing the dose up to 1,000 mg/day, asrecommended in the diagnostic criteria for MSA,11 to behelpful in determining the presence or absence of L-doparesponsiveness.

Patients also fail to fulfil the requirement of a positiveL-dopa response if this cannot be assessed due to lack oftolerability. The addition of a peripheral dopamine re-ceptor blocker (domperidone) was helpful in severalpatients, allowing a dose increase with resultant clarifi-cation of the drug effect. Failure to attempt an assess-ment of L-dopa responsiveness may lead to a patientbeing described inappropriately as a “nonresponder.”

Other additional investigations led to a classificationin 9 patients or 16.7% of all initially unclassifiable pa-tients. Normotensive hydrocephalus has been well doc-umented as a differential diagnosis of PD and otherneurodegenerative disorders,37,38 and so has late-onsetHuntington’s disease.39

In a small number of patients, dopamine transporterSPECT (DAT scan) enabled a diagnosis to be made. Thisfinding adds to increasing evidence of a role of SPECT indistinguishing neurodegenerative diseases involving thedopaminergic system from other conditions such as es-sential tremor, or—in conjunction with other diagnosticprocedures—psychogenic movement disorders.

Although our study was carried out prospectively andthe closest standardisation possible was attempted be-tween the two centres, there were practical limitations, aswould be expected with a large unselected outpatientcohort. Factors such as difficulties with repeated travel-ling to the clinic or concomitant medical conditions insome patients precluded the strict performance of addi-tional tests as outlined in our protocol. These limitationsarose to approximately the same extent in both centres.

Recent reports have shown a significantly larger per-centage of atypical parkinsonism in non-white than inwhite patients in the UK.5,40 One outpatient department-based study40 found the percentage of atypical parkin-sonism to be 22% in African-Caribbean and 20% inSouth Asian patients, compared to 7% in whites. Al-though our observation of a higher number of non-whitepatients in the unclassifiable group suggests a similartrend, the present study did not address differences inethnic origin as a parameter and was not powered to doso.

In the 5 London patients whose only atypical featurewas lack of L-dopa responsiveness, smell test results



were much closer to normal controls than to PD, sug-gesting that the majority of these patients are less likelyto have idiopathic PD than one of the other parkinsoniansyndromes.41 Overall olfactory results in the unclassifi-able group were, as could be expected, between those inPD and in normal controls, reflecting the heterogeneityof likely ultimate diagnoses.

The 2 patients from our series who have come topostmortem highlight two of the possible confoundingfactors, which will be difficult to overcome even with thestrictest application of diagnostic criteria: Diagnostic dif-ficulties during life will occur in the presence of twodifferent neuropathological processes in the same pa-tient, as in the case of the Barcelona patient, who hadboth cerebrovascular disease and PD. In the Londonpatient, neuropathology revealed MSA, despite the pres-ence of two formal clinical exclusion criteria, dementia,and prominent eye movement disorder. This finding addsto evidence that the clinical spectrum of parkinsoniansyndromes may be wider than recognised to date.

Formal request of brain tissue donation whenever pos-sible was part of the study protocol. It is expected thatneuropathological results from our patient cohorts willhelp broaden our knowledge of the clinical spectrum ofthe parkinsonian syndromes.

Acknowledgments: We thank Yoav Ben-Shlomo MD,MRCP, for valuable comments on the manuscript and HilaryWatt, MSc, Institute of Neurology, London, for statistical ad-vice. We also thank Dr. F. Vallderiola and Dr. M.S. Marti forallowing us to study patients under their care. This study wassupported in part by Generalitat de Catalunya, Spain (SGR00387).

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unclassifiable parkinsonism in two european tertiary referral centres for movement disorders

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