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Acta Neuropathol (1996) 91 : 427–431
© Springer-Verlag 1996
R E G U L A R PA P E R
M. Verny · K. A. Jellinger · J.-J. Hauw · C. Bancher · I. Litvan · Y. Agid
Progressive supranuclear palsy: a clinicopathological study of 21 cases
Received: 16 August 1995 / Revised, accepted: 23 October 1995
Abstract The symptoms and signs used to diagnose progressive supranuclear palsy (PSP) should be easily identifiable by neuropathologists and neurologists as well as by movement disorder experts. The presence, at the time of death, of symptoms and signs that are used in published clinical criteria for the diagnosis of this disorder was searched for in 21 pathologically confirmed typical PSP cases. The following items, present in at least 80% of pathologically confirmed cases, can be considered as the most accurate clinical data for the diagnosis of PSP: nonfamilial parkinsonism, not improved by L-dopa therapy, with vertical voluntary gaze palsy; postural instability and falls; pseudobulbar palsy and dementia with frontal lobelike syndrome; and a progressive course of less than 10 years. The definite diagnosis of PSP must be clinicopathological, and these minimal clinical data may be used for this purpose. Key words Progressive supranuclear palsy · Symptoms · Diagnostic criteria
M. Verny Neurology Department, Division Mazarin, Hôpital de la Salpêtrière, 47 bvd de l’Hôpital, Paris, France M. Verny (Y) · J.-J. Hauw Laboratory of Neuropathology R. Escourolle, INSERM U360, Association Claude Bernard, Hôpital de la Salpêtrière, 47 bvd de l’Hôpital, F-75651 Paris Cedex 13, France Tel: 33-1-42 16 18 81; Fax: 33-1-44 23 98 28 K. A. Jellinger · C. Bancher Ludwig Boltzmann Institute of Clinical Neurobiology, Krankenhaus der Stadt Wien-Lainz, Wolkersbergenstrasse 1, A-1130 Vienna, Austria I. Litvan Neuroepidemiology Branch, NINDS NIH, Federal Bldg, Rm 714, Bethesda, MD 20892, USA Y. Agid INSERM U289 and Federation of Neurology, Hôpital de la Salpêtrière, 47 bvd de l’Hôpital, Paris, France
Introduction Progressive supranuclear palsy (PSP) usually presents as an akinetic, rigid parkinsonian syndrome nonresponsive to L-dopa, associated with supranuclear gaze palsy, pseudobulbar palsy, axial dystonia, and frontal lobe-like symptomatology [10]. A clinical diagnosis of PSP is difficult both at disease onset and at later stages, particularly because akinesia, dementia with frontal lobe-like symptomatology, or ophthalmoplegia can be absent [1, 6, 10]; only pathologically confirmed cases can be considered as definite. On clinical grounds, the major differential diagnostic considerations are Parkinson’s disease (PD), multiple system atrophy (MSA), corticobasal degeneration (CBD), the multilacunar status, diffuse Lewy body disease (DLBD), and postencephalitic parkinsonism [4, 5, 8–12, 24, 29]. In one clinicopathological study of idiopathic PD, 6 of 100 cases had histologically proven PSP [17]. In fact, the “gold standard” can be neither only pathological nor only clinical, but must be clinicopathological [22]. To achieve better characterization of the clinical signs and symptoms compatible with PSP, we searched for those used in published criteria for diagnosing PSP at the time of death [2, 4, 10, 13, 21, 27] in 21 pathologically confirmed typical PSP cases. These cases were chosen on a neuropathological basis from the files of the Ludwig Boltzmann Institute of Clinical Neurobiology (LBI), Vienna, Austria, and from those of the Raymond Escourolle Laboratory (REL) at La Salpêtrière Hospital, Paris, France. To avoid selection bias, all consecutive pathologically proven typical PSP cases [16] with clear-cut clinical data were collected in the two series.
Materials and methods Cases For this study 21 histologically proven PSP cases were evaluated: 11 at LBI from 1967 to 1991, and 10 at REL from 1979 to 1989. The clinical records of these 21 PSP cases (15 men, 6 women; age at disease onset: mean ± SD, 62 ± 7 years; range: 43–70 years)
428 Table 1 Clinical symptoms and signs during the course of the disease for the 21 histologicaly proven progressive supranuclear palsy (PSP) cases. Sets of criteria are given in the references cited Symptoms and signs
Number % of of cases cases
Progressive course [2, 4, 10, 14, 21, 27] No focal lesion on examination or CT [2, 4, 27] Onset over 40 years of age[4, 10, 14, 21, 27] Bradykinesia [4, 14, 21, 27] Parkinsonism [2, 21] Postural instability [4, 10, 21, 27] Falls [2, 4, 10, 14, 21, 27] Dysarthria or dysphagia [14] Pseudobulbar palsy or dysarthria [2, 4, 21, 27] Duration less than 10 years [2] Vertical voluntary gaze palsy [2, 4, 10, 14, 21, 27] Pseudobulbar signs (2 of dysarthria, dysphagia, affect) [4, 21, 27] Dementia or personality change [4] Frontal lobe-like syndrome [2, 10, 21, 27] No significant improvement with L-dopa [2, 4, 10, 27] Staring, nonblinking face [4] Pyramidal tract signs [4, 10, 14] Axial dystonia [4, 10, 14, 21] Tremor: postural or action [10] Focal or segmental dystonia [4, 10] Tremor at rest [4] Depression [10] Apraxia of eyelid opening and/or closing [10] Echolalia, palilalia [10] Sleep disorders [10] Upper limb apraxia [4] Amyotrophy [10] Myoclonus [4] Chorea [4] Respiratory disturbances [4]
21 21 21 20 20 19 19 19 19 19
100 100 100 95 95 90 90 90 90 90
19
90
17 17 17
81 81 81
17 15 11 7 7 5 4 3 2 2 2 2 1 1 1 1
81 71 52 33 33 24 19 14 9 9 9 9 5 5 5 5
were analyzed (Table 1). All patients were examined by neurologists. The neuropathology of 16 of these cases has already been reported in part [15, 19, 28]. Methods Neurological signs and symptoms at the time of death and the final clinical diagnosis were recorded from the medical files by two of us (K.J., M.V.). The medical records were not standardized, and no defined set of clinical criteria for the diagnosis of PSP had been implemented by the neurologists at the time of the patients’ death. In addition, in clinical records there was no specific mention of some items, such as “the presence of axial rigidity greater than limb” [10, 13, 27] and “neck in a posture of extension” [4, 13] in cases 7396, 7679, 40581, 9688, and 7396, 9688, 10581, 23091, 23372, 24278, 31685, respectively. Furthermore, “unilateral presentation, or pronounced asymmetry” [4] was never mentioned. Previously published clinical diagnostic criteria for PSP [2, 4, 10, 13, 21, 27] were applied to each record. The brains were fixed in 4% buffered formaldehyde for 3 weeks to 3 months. The thalamus and subthalamic nuclei, lenticular nucleus, substantia innominata, midbrain, pons, medulla oblongata, cerebellum, and cortical areas (frontal cortex: A9; precentral
cortex: A4; parietal cortex: A40; and hippocampus) were systematically sampled. After paraffin embedding, 7-µm-thick sections were stained with hematoxylin-eosin and Bodian’s silver method (coupled with Luxol fast blue in the REL series). In the LBI series and some of the REL cases, modified Bielschowsky silver impregnation and immunohistochemistry for tau protein were also used. The pathological diagnosis of “typical cases” of PSP was made independently by two neuropathologists in each laboratory, according to the preliminary NINDS criteria [16]. The lesions consisted of gliosis, neuronal loss, neuropil threads and neurofibrillary tangles (NFTs). The presence of NFTs or neuropil threads, or both, in the basal ganglia and the brain stem was essential for a diagnosis of PSP. These lesions were found in the subthalamic nucleus, pallidum, substantia nigra, some brain-stem nuclei, periaqueductal gray areas, and several cranial nerve nuclei [16, 18, 20, 26].
Results The clinical diagnosis at the time of death made by the examining neurologist at the two institutions was correct in 5 of 11 neuropathologically proven cases (nos. 24278, 7679, 40581, 31685, and 9688 at LBI). The remaining cases were considered to have PD, with or without dementia. At REL, the clinical diagnosis was correct in 7 of the 10 neuropathologically proven cases. Two cases were diagnosed as parkinsonism with or without dementia (REL 5684, 6046); one was normal pressure hydrocephalus (REL 7165). Overall, the clinical diagnosis was accurate in only 57% at the time of death. The signs and symptoms at the onset and during the course of the disease are given in Tables 1 and 2. The results of applying the published diagnostic criteria to this series are presented in Table 3. When Lees’s clinical criteria [21] for the diagnosis of PSP were applied, 19 of 21 histologically proven cases were detected; 17 cases were identified applying the clinical criteria of Golbe et al. [13]. As previously mentioned, two signs used in this criterion were rarely found in the clinical records: “axial rigidity greater than limb” and “neck in the posture of extension.” If all cases had presented one of the unmentioned signs 18 cases would have been correctly identified. Using the clinical criteria of Blin et al. [2], 20 cases were correctly identified; 10 were probable PSP (all nine criteria), and 10 possible (at least seven verified criteria). With the clinical criteria of Tolosa et al. [27], 17 of 21 histologically proven cases were identified; 15 would have been classified as probable and 2 as possible (nos. 882710 Table 2 Symptoms and signs at disease onset in 21 histologically proven PSP cases Symptoms and signs
No.
Percent
Falls and paroxysmal dysequilibrium Unsteady gait Depression Dysarthria Visual disturbances Hypertonia and/or bradykinesia Tremor Mild cognitive dysfunction
17 14 6 5 4 3 2 2
81 67 29 24 19 14 5 9
1 Duvoisin’s criteria when considering that all cases had greater axial rigidity a Using
1 0 1 Collins et al. [4] Positive diagnosis
0
1
0
0 1 1
1
1
0
1
1
1
0
1
15 1 1 1
1 0
1 0
1 0
1 0
0 0
15 2 1 0 1 0 1 0 1 0 0 0 1 0 Tolosa et al. [27] Probable Possible
0 1
1 0
1 0
0 0 1 0 1 0
0 0
1 0
0 1
1 0
0 1
1 1
1 1
0 1
0 0
4 19 1 1 0 1 0 1 0 1 0 1 0 0 Duvoisin [10] Diagnosis Diagnosisa
0 1
0 1
0 1
0 0 1 1 0 1
0 1
0 1
0 1
0 1
1
1
1
1
0
17 1 1 1 1 1 1 Golbe et al. [13] Diagnosis
0
1
0
0 1 1
1
1
1
1
1
1
1
1
0
19 1 1 1 1 1 1 Lees [21] Diagnosis
1
1
1
0 1 1
1
1
1
1
1 0 0 0 0 0 1 1 0 1 0 1 0
0 1 0
Blin et al. [2] Probable: 9 items verified Possible: 8 or 7 items verified
1
0
1 0 1
0 0 0 1 0
6882 7165
7301
1
1
1
0 1 1 1 1 1
Assessing the value of clinical symptoms and signs is necessary for both neuropathological and clinical studies. Three items were always present, but do not seem very specific for the diagnosis of PSP:
0
0
0
10 0 0
Discussion
10 1 1
and 28772). The criterion: “greater axial than limb dystonia/rigidity” was not systematically mentioned in the medical records of this series. Assuming its presence, 1 additional case would have been considered possible (no. 6046). The clinical criteria of Collins et al. [4] identified 15 cases when considering the “verification criterion” (minimal or unsustained – < 2 years – L-dopa response) as mandatory. If we had not used this criterion, 20 cases would have beeen correctly identified. The clinical criteria proposed by Duvoisin [10] were difficult to apply to this series, because the presence or absence of rigidity with axial predominance (“a mandatory criterion”) was mentioned in only four medical records. If we considered that all the other cases had rigidity with axial predominance, 19 PSP cases would have been correctly recognized. The cases not identified with these six sets of criteria were not always the same according to the choice of mandatory and exclusion items.
88264 7396 6046 87996 882710 89124 5684
Cases Sets of diagnostic criteria
Table 3 Diagnostic criteria applied to 21 definite PSP cases (1 present, 0 absent)
23372 28772 13267 12577 24278 7679
10581 40581 9688
31685 23091 Sum
429
1. A nonfamilial disease of progressive course. Although familial PSP cases have occasionally been described [3, 7, 14, 23, 25], autopsy was performed in only one case in these families, and the neuropathological changes were atypical or uncertain in two of these reports [23, 25]. Thus, this item seems valid for the majority of PSP cases. 2. Onset of disease at over 40 years of age. This sign (proposed in five of the sets of criteria) appears to be confirmed by the earliest age of onset in the literature, 47 years [8], and in this series, 43 years (no. 23372), and may help to rule out most cases of postencephalitic parkinsonism. 3. “No evidence of a focal lesion on a sensorimotor examination or computed tomography scan” may allow diseases that could mimic PSP, such as CBD (cortical sensory loss) or the lacunar state [9, 12], to be excluded. Some of these items were present in more than 80% of the cases in this series (Table 2), and are probably the most significant when diagnosing PSP. Since they were not present in all patients, the diagnosis of PSP can be made in their absence, however. “Vertical voluntary gaze palsy” and the “absence of significant improvement with L-dopa therapy” may be particularly useful for distinguishing PSP from idiopathic PD. The unusual signs mentioned in this series were previously reported in other series of pathologically confirmed PSP: focal dystonia, tremor at rest, eyelid disturbances, echolalia and palilalia, sleep disorders, limb apraxia, amyotrophy, myoclonus, chorea, and respiratory disturbances [4, 6, 8, 10, 27]. Thus, those features do not exclude PSP. The usefulness of the items “axial rigidity greater than limb” [4, 10, 13, 27] and “neck in
430
a posture of extension” [4, 10, 13, 21] could not be assessed using our data, because they were rarely mentioned. Exclusion criteria have been proposed by some authors [4, 10, 13, 27]. The items “prominent or early noniatrogenic dysautonomia”, “prominent polyneuropathy”, and “early or prominent cerebellar sign” are related to MSA. In a clinicopathological study of 35 MSA cases [29], 12 presented with parkinsonism associated with autonomic failure, 10 with parkinsonism and pyramidal signs, 9 with parkinsonism associated with pyramidal signs and cerebellar signs, and 3 with parkinsonism associated with autonomic failure and cerebellar signs. Signs of polyneuropathy were present in 20% of cases. Another report of pathologically proven MSA [5] also emphasized the importance of autonomic dysfunction associated with parkinsonian signs in MSA cases compared with pathologically proven PSP cases. The item “alien limb sign” seems to be pertinent for CBD exclusion. Limb dystonia and limb apraxia, also characteristic of this disease, were, however, observed in some pathologically proven PSP cases in our series (Table 1) and in the literature [4, 6, 8]. The usefulness of “unilateral presentation or pronounced asymmetry” (exclusion item in [4]) needs further evaluation. It was never mentioned in the medical records of the present series and we have taken it as not being present. There are no exclusion items in the previously published criteria that exclude DLBD. Early cortical dementia and noniatrogenic hallucinations, thought to be significant features of DLBD [24], should be evaluated in future studies. In Duvoisin’s criteria [10], the presence of seizures was proposed as an exclusion criterion. Although, we did not find any seizures in this series, some have been reported in definite PSP cases [8, 27]. Our study emphasizes the relevant features characteristic of patients with confirmed PSP and underscores clinical features that, even if unusual, should not exclude the diagnosis of PSP. Further studies, preferably prospective, are needed to determine whether these features distinguish PSP from other related disorders. The low accuracy (57% correct diagnosis) achieved by the neurologists who followed the cases that are part of the present study suggests that PSP is underdiagnosed. Acknowledgements We thank Profs. and Drs. A. Buge, P. Castaigne, D. Klingler, F. Lhermitte, G. Rancurel, H. Reisner, M. Serdaru, and M. Simanyi for giving access to the clinical files of their patients; Mrs. Eder, Fenoy, Raiton and Rappelsberger for providing technical help, and Mrs D. Schoenberg, M.S. for skillful editing.
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