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1、5 Progressive Supranuclear Palsy Update5 Progressive Supranuclear Palsy UpdateProfessor D BurnProfessor D BurnProfessor of Movement Disorder Neurology and Honorary Consultant Neurologist,Institute forAgeing and Health,Newcastle UniversityIntroductionIntroductionTauopathies constitute a group of neur
2、odegenerative conditions characterised by the deposition of tauprotein-containing neurofibrillary tangles.Cognitive impairment and extrapyramidal features arefeatures common to the majority of tauopathies.Mutations in the tau gene(MAPT)or alterations inthe expression of tau protein isoforms have bee
3、n implicated in the molecular pathophysiology of thesedisorders.This,in turn,has led to a nosology of tauopathies,defined according to the nature of thepredominant tau isoform,and explained in more detail below.Progressive supranuclear palsy(PSP,or Steele-Richardson-Olszewski syndrome),corticobasal
4、generation and argyrophilic grain disease arethus classified as“four-repeat”tauopathies.In its full-blown form,the clinical picture of PSP is highly characteristic.The patient has a fixed“Mona Lisa”stare,with a markedly reduced blink frequency.The head is retracted and the voice isreduced to a disti
5、nctive slurred growl.The patient walksclumsily and unsteadily(like a“drunkensailor”),with a nota ble tendency to topple backwards.Motor recklessness is often an early feature,leading to the highly distinctive“rocket sign”on rising from a chair.Clothes are soiled with spilledfood,due an inability to
6、look down at the plate and difficulties swallowing(the“messy-tie”sign).The time taken to respond to a question is prolonged,because of slow cognitive processing(bradyphrenia).There is sometimes palilalia or echolaliaThis review will concentrate predominantly upon PSP,but it is important to recognise
7、 that bothclinical phenotype and molecular mechanisms may overlap with other tauopathies.Moreover,thephenotypic spectrum of PSP is broadening,thus presenting the clinician with agreater diagnosticchallenge.Historical PerspectiveHistorical PerspectiveCharles Dickens may have been first to describe a
8、subject with classical PSP in 1857 in his novel TheLazy Tour of Two Idle Apprentices:1“A chilled,slow,earthy,fixed old man.A cadaverous man ofmeasured speech.An old man who seemed as unable to wink,as if his eyelids had been nailed to hisforehead.An old man whose eyes-two spots of fire-had no more m
9、otion that sic if they had beenconnected with the back of his skull by screws driven through it,and riveted and bolted outside,among his grey hair.”“He had come in and shut the door,and he now sat down.He did not bend himself to sit,as otherpeople do,but seemed to sink bolt upright,as if in water,un
10、til the chair stopped him.”From two daguerreotypes published in 1889 in the Nouvelle Iconographie de la Salptrire by Dutil,one of Charocts interns,a case of PSP may have been described as a“hemiplegic paralysis agitanswith unusual postures of the trunk and head”.2Retrocollis and an eye movement diso
11、rder wereprominent components of the clinical picture.Charcots celebrated case history and sketches ofBachere,reported as a case of Parkinsons in extension,may be another missed early example.It is of note that although MND and PSP were described within 20 years of each other,MND,with itsaccompanyin
12、g distinctive pathology,was rapidly accepted by neurologists as a discrete morbid entity,while a full clinicopathological description of PSP had to wait almost another century.Mis-diagnosisof many cases of PSP as post-encephalitic parkinsonism(Von Economos disease)or inappropriate“lumping”with other
13、 atypical causes of Parkinsonism such as arteriosclerotic Parkinsons Syndromemay be a partial explanation for this paradox.In 1963,Dr J Clifford Richardson described eight patients with“a common syndrome of ocular,motor and mental symptoms”at the American Neurological Association(ANA)in Atlantic Cit
14、y.Richardson drew an analogy to this seemingly new condition with Von Economos disease and As aoHirano,one of the discussants,was struck by its similarity to a new disorder being found amongst theindigenous Chamorros on the Mariana Islands(lytico-bodig).More recently,Lees group have described three
15、distinct clinical phenotypes of PSP,based uponpathologically confirmed cases and retrospective notes review:Richardsons syndrome,PSP-parkinsonism and pure akinesia with gait freezing,thereby extending the clinical spectrum of thedisorder and also increasing the challenge to clinicians for an accurat
16、e ante-mortem diagnosis.3,4Descriptive Epidemiological StudiesDescriptive Epidemiological StudiesBower and colleagues studied the incidence of PSP over a 14 year period in Olmsted County,Minnesota.5 Sixteen incident cases were identified and none had an age of onset before 50 years ofage.The average
17、 annual incidence rate for ages 50 to 99 yearswas 5.3 per 100,000.There is nogender difference in susceptibility to PSP,while a recent study did not find any modifying influenceof gender upon clinical features,including age at onset.6Only three studies have directly addressed the prevalence of PSP.7
18、-9 Table 1 summarises these studies,together with other estimates of the prevalence of PSP.In the latter,standard diagnostic criteria werenot used and the primary aim of the work was to determine the prevalence of Parkinsonsdisease.Seventeen cases of PSP were identified within the community study(po
19、pulation 259,998)of Nathetal,yielding an age-adjusted prevalence figure of 5.0(95%CI 2.5-7.5)per 100,000,standardized to thehypothetical European population.When the Schrag data are standardized to the same population,anidentical prevalence figure of 5.0 is obtained.Table 1 Prevalence Data for Progr
20、essive Supranuclear PalsyTable 1 Prevalence Data for Progressive Supranuclear PalsyAuthorAuthorYear ofYear ofReportReportPSP PrevalencePSP PrevalencePrimaryPrimaryGeographical AreaGeographical AreaStudiedStudiedPopulationPopulationDenominatorDenominatorCrudeCrudePrevalencePrevalence(per 100,000)(per
21、 100,000)Golbe1988yesNew Jersey,USADe Rijk1995nonoRotterdam,NetherlandsFaroe IslandsChioSchragNath199819992001noyesyesNorthwest ItalyLondon&Kent,UKNewcastle,UK61,830121,608259,9983.24.96.5696943,70914.3*4.6799,0221.39Wermuth1997*Only persons aged 55 years of age or older were includedA high prevalen
22、ce of PSP has recently been reported in the French Antilles,with a minimumprevalence of 14 per 100,000 on the island of Guadeloupe.10Of 220 consecutive patients withParkinsons syndrome examined,58 had probable PSP,a further 96 had undetermined Parkinsonism(many of whom closely resembled the incomple
23、te or atypical bradykinetic presentation of PSP),50had Parkinsons disease and 15 had an ALS-Parkinsonian syndrome.Pathological confirmation ofPSP,with a major doublet of pathological tau at 64 and 69 kilodaltons in brain tissue homogenates(see below),has been found in all three of the probable PSP c
24、ases coming to post-mortem.A recent health economic analysis of 742 patients from 44 centres in the European NNIPPS trialincluded data from 352 PSP patients.11 The mean six-month service costs of PSP were 25,655 in theUK,compared with a cost for MSA of 19,103.Unpaid care accounted for 68-76%.Formal
25、andunpaid costs were significantly higher the more severe the illness,and there was a significant inverserelationship between service and unpaid care costsDiagnostic Accuracy for PSPDiagnostic Accuracy for PSPAge at disease onset for PSP characteristically occurs between 60 and 65 years,with no sign
26、ificantdifference in the sex ratio.The median duration from disease onset to death is 5.8 to 5.9 years.12Mean interval from symptom onset to diagnosis ranges from 3.6 to 4.9 years,indicating that manypatients with PSP may remain mis-diagnosed for much of their disease course.7Primary care diagnoses
27、on hospital referral are protean,and include Parkinsons disease(30%),“balance disorders”(20%),stroke(10%)and depression(7%).13 Combining the studies of Schrag andthe methodologically similar community-based component of the Nath study,a total of 23 PSP caseswere identified.8,14 Of these,only ten pat
28、ients(43%)carried a primary referral diagnosis of PSP.Inthe remainder,Parkinsons disease and cerebrovascular disease accounted for all but one of the mis-diagnosed cases.A recent study of the diagnostic accuracy for PSP in the Society for PSP brain bank indicated that,of180 cases referred with a cli
29、nical diagnosis of PSP,137 had this confirmed pathologically,while 43(24%)had other pathological diagnoses.15 Corticobasal degeneration(CBD),multiple system atrophy(MSA)and dementia with Lewy bodies accounted for 70%of misdiagnosed cases.A history oftremor,psychosis,dementia and asymmetric findings
30、were more frequent in misdiagnosed cases.Inanother clinicopathological study,the clinical diagnosis of PSP was confirmed in 78%of 60 patients,with MSA,DLB and PD making up the majority of mis-diagnoses.16REM sleep behaviour disorder(RBD)is reported less frequently in PSP,when compared with PD andmul
31、tiple system atrophy.A recent study reported that PSP patients had lower values for bothestimated total sleep time and sleep efficiency on polysomnography compared with PD.17 None of 20PSP patients were experiencing RBD-related symptoms,while 32%of 93 PD patients had RBD-related symptoms.Following u
32、p on an observation made in the clinic,reduced sensation of thirst(hypodipsia)may behelpful in differentiating PSP from PD and MSA-P.18 On direct questioning in a recent study,73%ofPSP patients reported hypodipsia compared with other groups(healthy controls,0%;PD,7%;MSA-P,7%;P .0001).Following hyper
33、tonic saline infusion,PSP patients reported significantly lowerthirst than did PD and MSA-P patients for all times from 20 to 95 minutes(P 0.05).The thirst scoreat 25 minutes showed good discrimination for individual PSP patients from PD and MSA-Pparticipants.Diagnostic Criteria and Clinical Heterog
34、eneityDiagnostic Criteria and Clinical HeterogeneityPostural instability,leading to falls(typically backwards)within the first year of disease onset,coupled with a vertical supranuclear gaze paresis have good discriminatory diagnostic value whenPSP is compared with other degenerative parkinsonian sy
35、ndromes.19The National Institute ofNeurological Disorders and Stroke and Society for Progressive Supranuclear Palsy,Inc.,NINDS-SPSP diagnostic criteria(Table 2)are heavily reliant upon these clinical features,together with thefact that no pathologically confirmed PSP case has had a disease onset bel
36、ow the age of 40.20 Whenapplied retrospectively to a case mix comprising various parkinsonian syndromes the NINDS-SPSPcriteria have high diagnostic sensitivity and specificity.21 These parameters have not,however,yetbeen determined for prospective series with pathological correlation,nor have they b
37、een appliedretrospectively to an independent clinicopathological series.One area where the NINDS-SPSPcriteria would be predicted to have lower sensitivity iswhen the development of“core”diagnosticfeatures is delayed.PSP patients display significantly more apathy and disinhibition than PD cases.A“fro
38、ntal”presentation is recognised in approximately 20%of PSP cases,with increased latency to diagnosiscompared with other presentations and reduced initial diagnostic accuracy.22Neuropsychologicalassessment in the early stages may assist the accurate clinical diagnosis of a parkinsonian disorder,asmay
39、 the time course and pattern of progression of cognitive and behavioural decline.23 In particular,patients with PSP show a greater decline in attention,set-shifting and categorization abilities,compared with PD and MSA.Patients with PSP also show greater impairment in both phonemic andsemantic fluen
40、cy than patients with MSA or PD.Using discriminant function analysis,variablesderived from four verbal fluency tasks(simple and alternate semantic and phonemic fluency)wereable to correctly classify over 90%of PSP patients.24Retrospective clinicopathological studies suggest that there are at least t
41、hree main phenotypic variantsof PSP:Richardsons syndrome is the classic disorder,described above.A clinical phenotype of PSP,labelled PSP-P has been described in which the disease duration is longer(9.2 years compared with5.9 years for classic“Richardson”-type PSP).3 Falls and supranuclear gaze pare
42、sis are by no meansinvariable in PSP-P and their appearance may be delayed,adding to the diagnostic conundrum.Furthermore,asymmetric onset and L-dopa responsiveness,previously considered highly atypical forPSP,occurred in 81%and 52%,respectively,of PSP-P cases.3 Pure akinesia with gait freezing is a
43、nuncommon third phenotype of PSP characterized by difficulty initiating gait and freezing duringwalking,writing and speaking.Although not specific for PSP,this phenotype has a high predictivevalue for tau pathology.4Additional rare“atypical”phenotypic variants of PSP add to the difficulty of accurat
44、e diagnosis.Unilateral limb dystonia,arm levitation,ideomotor apraxia,and palatal myoclonus,have all beendescribed in PSP,sometimes early in the disease course.Conversely,cases of fronto-temporaldementia linked to chromosome 17(tau exon 10+16 mutation,25Whipples disease,26 neurosyphilis,27CADASIL28
45、and primary antiphospholipid antibody syndrome29 may present with a PSP phenotype.In a clinicopathological study,based in a specialist movement disorders service,19 of 143 cases ofparkinsonism were pathologically confirmed as PSP.Ante-mortem clinical diagnosis was correct in16 of these cases,while M
46、SA,PD and“parkinsonism undetermined”constituted the three mis-diagnoses.30Table 2 NINDS-SPSP Diagnostic Criteria for PSPTable 2 NINDS-SPSP Diagnostic Criteria for PSP2020PSPPSPPossiblePossibleProbableProbableDefiniteDefiniteMandatory inclusionMandatory inclusioncriteriacriteriaGradually progressived
47、isorderOnset age 40 or laterEither vertical supranuclearpalsy or both slowing ofvertical saccades&posturalinstability with falls 2 of:apathy,impairment in abstractthought,decreased verbalfluency,utilisation or imitationbehaviour,or frontal releasesignsNo evidence of other diseasesthat could explain
48、theCortical dementia offoregoing features,asAlzheimer typeindicated by exclusion criteriaProminent,earlycerebellar symptoms orunexplained autonomicdysautonomiaGradually progressivedisorderOnset age 40 or laterVertical supranuclear palsyand prominent posturalinstability with falls 1 yeardisease onset
49、No evidence of other diseasesthat could explain theforegoing features,asindicated by exclusion criteriaClinically probable orpossible PSP andhistopathological evidence oftypical PSPClinical AssessmentClinical AssessmentA PSP Rating Scale(PSPRS)produces a score of 0 to 100,with 0 representing“normal”
50、.31 In thisscale 28 items are sub-divided into six categories(daily activities,behavioural symptoms,bulbarsymptoms,oculomotor deficits,limb motor deficits,gait and midline deficits).The rating takesapproximately 10 minutes to perform and appears to have excellent inter-rater reliability.Scoresincrea