OCR Text |
Show Journal of C1iniCllI Neuro-opl,/luzlmology 8(3): 161-170, 1988. Neuropathologic Findings in Progressive Supranuclear Palsy A Brief Review with Two Additional Case Reports Masatoshi Kida, M.D., Heasoo Koo, M.D., Hans E. Grossniklaus, M.D., and Robert L. Tomsak, M.D., Ph.D. © 1988 Raven Press. Ltd., New York Recent studies utilizing electron microscopy and immunohistochemistry have added to the understanding of the pathology of progressive supranuclear palsy. This article reviews the neuropathologic findings of progressive supranuclear palsy and includes two new case reports. Findings in the patients reported here include extensive neuronal loss with reactive gliosis in deep subcortical gray matter such as globus pallidus, subthalamic nuclei, substantia nigra, red nucleus, dentate nucleus, and inferior olives. Neurofibrillary tangles were also noted in thalamus, hypothalamus, striatum, nucleus basalis, locus ceruleus, basis pontis nuclei, midbrain, pontine, and medullary reticular formation as well as in various cranial nerve nuclei. Key Words: Progressive supranuclear palsy-Neuropathology- Neurofibrillary tangle-Granulovacuolar degeneration. From the Department of Pathology (M.K., H.K., H.E.G.) and Division of Ophthalmology (H.E.G., R.L.T.), University Hospitals of Cleveland, Case Western Reserve University, Cleveland, Ohio. Address correspondence and reprint requests to Dr. H. E. Grossniklaus, 2078 Abington Road, Cleveland, OH 44106, U.S.A. 161 Progressive supranuclear palsy, also known as Steele-Richardson-Olszewski syndrome (1), oculofaciocervical dystonia (2), and subcortical argyrophilic dystrophy (3), is a rare form of progressive neuronal degeneration. The disease is clinically characterized by vertical gaze palsy, dysarthria, axial rigidity, and chronic progressive dementia. This article provides a brief review of the neuropathology of progressive supranuclear palsy including recent electron microscopic and immunohistochemical findings. Also provided are two additional case reports, and the neuropathologic findings of progressive supranuclear palsy are compared with several other neuronal degenerative disorders (Table 1). TABLE 1. Sites of neuronal degeneration in neuronal degenerative diseases Site PSP AD PD ALS CJD Cerebral cortex ++ (+) (+) ++ Striatum (+) Pallidum ++ Thalamus + Subthalamic nuclei ++ Nucleus basalis + + Red nuclei + Substantia nigra ++ ++ Locus ceruleus + + ++ Tegmental raphe nuclei + (+) Pontine nuclei (+l Inferior olives (+) Purkinje cells (+) Dentate nuclei + Dorsal vagal nuclei (+) Ventral horn ++ Vestibular nuclei + Pyramidal tract + Key: PSP, progressive supranuclear palsy; AD, Alzheimer's disease; PD, Parkinson's disease: ALS, amyotrophic lateral sclerosis; CJD. Creutzfeldt·Jakob disease; + +. nearly always affected; +, commonly affected; (+), occasionally affected: -, not affected. 162 M. KIDA ET AL. CASE REPORTS Case 1 This 76-year-old man, with a history of progressive supranuclear palsy, was found dead at his nursing home. The diagnosis of progressive supranuclear palsy had been made 2 years earlier when the patient was noted to have dystonic rigidity of the face and trunk with ophthalmoplegia in all directions of gaze. Postmortem examination was limited to the brain only. The brain weighed 1,340 g and was grossly unremarkable. Blocks from various areas were embedded in paraffin, and sections were stained with hematoxylin-eosin, modified Bodian's silver (4), congo red, and myelin stain. Sections of selected areas were immunostained with the peroxidase-antiperoxidase method (5) using the monoclonal antibody to tau (anti-tau) at a 1:200 dilution (6). In addition, representative sections were stained for glial fibrillary acid protein using the peroxidase-antiperoxidase method with an antiserum dilution of 1:1,000 (7). Figure 1 summarizes the distribution and semiquantitative evaluation of histopathologic changes in this patient, including loss of neurons and neurofibrillary tangles. The globus pallid us, subthalamic nucleus, and substantia nigra showed marked loss of neurons with reactive astroglial proliferation. The remaining neurons in these areas frequently demonstrated globose-type neurofibrillary tangles (Figs. 2 and 3). Neurofibrillary tangles were best seen with Bodian's silver stain (Fig. 4A). A monoclonal antibody to tau protein showed a strong positive reaction to the neurofibrillary tangles (Fig. 4B). The red nucleus and dentate nucleus showed moderate decreased numbers of neurons and occasional neurofibriUary tangles in remaining neurons. Neurofibrillary tangles were also noted in the striatum, nucleus basalis, oculomotor nuclei, and median raphe nuclei of the midbrain and pons where loss of neurons or gliosis was inconspicuous. The globus pallidus, subthalamic nucleus, red nucleus, substantia nigra, and dentate nucleus showed some loss of myelin related to neuronal cell loss. The dentate nucleus contained an unusual form of neuronal degeneration which, as described by Steele and co-workers (I), showed enlarged cells with loss of Nissl substance and pyknotic and eccentrically placed nuclei. The superior colliculi appeared normal. No senile plaques or neurofibrillary tangles were seen in the neocortex. There was no evidence of congophilic angiopathy, Lewy bl)die<;, or spongiosis. A few neurons in the hip- 1Cli" Neuro"Ophlhalrnol, Vol. 8. No.3. 1988 pocampi and red nucleus showed granulovacuolar degeneration. Case 2 This 83-year-old man, with a his~ory of pro~essive supranuclear palsy, was admItted to Uruversity Hospitals of Cleveland in October, -:986, for evaluation of shortness of breath, coughing, and increased sputum production after apparent aspiration of gastric contents. The patient's past medical history included two remote left-sided strokes, congestive heart failure, and chronic obstructive pulmonary disease. The patient's progressive supranuclear palsy had been diagnosed in 1984 after a gradual progression of neck, trunk, and limb rigidity was noted. At the time of diagnosis and at the current admission, the patient has masked facies and ophthalmoplegia with lim.itation of all fields of gaze with the exception of horizontal movements. The remainder of his ophthalm.ic examination was unremarkable. Physical examination showed coarse breath sounds and increased fremitus in both lungs. A chest x-ray revealed bilateral lower lobe infiltrates. The patient's family requested that no resusitation be attempted, and he died of aspiration pneumonia within 36 h of admission. Significant general autopsy findings included fulminant bilateral lower lobe pneumonia and atherosclerotic vascular disease with a remote myocardial infarct. The brain weighed 1,250 g and showed subdural brownish-yellow discoloration on the left side. There was marked widening of sulci in the cerebellar hemispheres. After coronal sectioning, the cerebral hemispheres revealed a cortex of normal thickness and considerable atrophy of white matter with a moderately distended ventricular system (Fig. 5). Serial transverse sections of the brainstem demonstrated slight enlargement of the Sylvian aqueduct and considerable shrinkage of the pontine tegmentum and superior cerebellar peduncle (Figs. 6 and 7). There was no evidence of obstruction in the ventricular system. Sections from various areas of the brain were embedded in paraffin and studied with the same stains used for case 1 including immunostaining. Figure 8 shows the distribution and semiquantitative evaluation of the histopathologic changes, including loss of neurons and neurofibriIJary tangles. The changes were similar to those in case 1 except that neurofibrillary tangles were identified in periaquaductal gray matter, the medullary reticular formation, and various cranial ..... 0\ W <tTl ~ o ~§ c-o o C) '"< Q '"v A:l o C) A:l tTl VI V.....I. '<:::: tTl VI c:: ~< ~ r- ~ A:l ~ c-o VI '"< ~, Not examined "~ ~ \~~) (/ \~ft 1 • ttll,~,~f/~) --tt~fJ "t{~, () • NFTs. rare @) NFfs. frequent --------'--~ ~ loss of neurons f) ~ ~ "" z~. ::: 9 -2 :t [ ::: ~ "2 ~ '.c; .«...., FIG. 1. Distribution and semiquantitative evaluation of the histopathologic changes in Case 1, 164 M. KlDA ET AL. ....... ' ..:.. , : " .."'. FIG. 2. Globus pallidus showing extensive loss of neurons and reactive gliosis. There are two neurons with neurofibrillary tangles (arrows). Inset shows higher magnification of the neuron-containing neurofibrillary tangle (hematoxylin-eosin. x88; inset, x 560). .. ~ . .... " : .1 .. ' .. , .. ." .' -~ ...... .~..-....II" ..-, LII :_~,"7::~" ~.I' .. ' .11.- .._ I !It' ....... .... .. ~ - II ~ • .. ·'iI_ FIG. 3. Loss of nerve cells, gliosis. and extracellular pigments in substantia nigra (hematoxylin- eosin, x 88). -.....- . ..~- . . '~ .... '. '. J Cli.. Neuro-ophllullmol, Vol. 8. No}_ J. 1%:1 NEUROPATHOLOGY OF PROGRESSIVE SUPRANUCLEAR PALSY B 165 nerve nuclei including the nuclei of cranial nerves III, VI, and VII, the dorsal nucleus of X, the solitary nucleus, the spinal nucleus of V, and the accessory nucleus (Fig. 9). In addition to the globose- type neurofibrillary tangles, flame-shaped neurofibrillary tangles were noted in the globus pallidus (Fig. 10). The dentate nucleus showed neuronal degeneration as well as demyelination in the hilus (Fig. 11). The superior colliculi were unremarkable. A few neurofibrillary tangles were noted in pyramidal neurons of the hippocampi, although no senile plaques or neurofibrillary tangles were seen in the neocortex. The cerebral white matter contained diffuse moderate gliosis. There was no evidence of congophilic angiopathy, Lewy bodies, or spongiosis. DISCUSSION Pathologic findings in progressive supranuclear palsy were first described by Chavany and coworkers in 1951 (8). The clinical manifestations defining the disease as a distinct entity were described by Steele and co-workers in 1964 (1). Clinical features include (a) supranuclear ophthalmoplegia predominantly of vertical gaze; (b) pseudobulbar syndrome; (c) axial dystonia, especially of the face, neck, and upper trunk; and J Clin Neuro-opllthalmol, Vol. 8, No.3, 1988 166 M. KlDA ET AL. FIG. 5. Coronal section through the level of the thalamus showing moderate enlargement of lateral and third ventricles with thinning of the corpus callosum. There is considerable atrophy of white matter in addition to widening of sulci. The globus pallidus is markedlyatropic. FIG. 6. Transverse section through the midbrain, showing a slightly enlarged Sylvian aquaduct. The superior colliculi are unremarkable (Bodian, x 3.5). , Clin Neurcrophfhalrnol, Vol. 8, No. J, 1988 FIG. 7. Transverse section through the midlevel of the pons demonstrating severe shrinkage of the pontine tegmentum and superior cerebellar peduncle (60dian, x 3.0). NEUROPATHOLOGY OF PROGRESSIVE SUPRANUCLEAR PALSY 167 ~ t .~ z z .§E •• "0 C•C .g, ·'"0"i5 ,.; • @ " • ---- • \\\\~, ,IL ~ ( • / ) IT~ , I' , " \~ "/ r· --~ e;,--- • ~ I 168 M. KlDA ET AL. FIG. 9. A: Substantia nigra with decreased pigmented neurons, gliosis, and extracellular pigments. The remaining neurons occasionally contain neurofibrillary tangles in the perikaryon (arrow) (he matoxyl in-eosi n, x 88). B: Higher magnification of Fig. 9A. The perikaryon is filled by a skein of neurofibrils. and the nucleus is displaced to periphery (hematoxyl in-eosin, x 840). (d) dementia (3,9). The progressive gaze palsies with predominant disturbance of vertical movements, especially downgaze, are followed by loss of horizontal movements in advanced cases (10,11). In patients with pathologically proven progressive supranuclear palsy who had downgaze palsies, all had bilateral lesions located superior and medial to the red nuclei (12). This area is now called the intersitial nucleus of the medial longitudinal fasciculus (13). Clinical signs of pseudobulbar palsy, including dysarthria and dysphagia, may be present (14). The neck, proximal limbs, and trunk express a varying degree of muscular rigidity, dystonia, and tremor (3). The symptoms begin between ages 50 and 70 (mean onset, 51.6) (IS), and the survival ranges from 2 to 11 years (average, 5.7) (15). Men are affected more than women (15). Progressive supranuclear palsy is classified as a primary neuronal degeneration-a disease in which neurons of a particular type or in a particular region degenerate due to unknown reasons. Common characteristics of neuronal degenerative diseases are (a) selectivity, with involvement of one or more systems of neurons in a relatively symmetric pattern; (b) progression, although not always terminal; and (c) variability in clinical and pathologic features, often appearing to overlap with other neuronal degenerative diseases, thus rendering difficulties in accurate classification (9). Table 1 compares the structures involved in several common neuronal degenerative diseases and Crutzfeldt-Jakob disease. The principal histologic J Clin Neuro-ophlhalmol. Vol. 8. No.3, 1988 finding in neuronal degenerative diseases is the focal loss of neurons with reactive gliosis. [n many conditions, linked or chain (transneuronal) degeneration is evident. Progressive supranuclear palsy is an example of linked degeneration of the pallidum and subthalamic nucleus. Neurofibrillary tangles are present in neuronal degenerative diseases including Alzheimer's disease, progressive supranuclear palsy, Parkinson-dementia complex of Guam, and others (16). Two types of neurofibrillary tangles are identified ultrastructurally in neuronal degenerative disorders. Neurofibrillary tangles in Alzheimer's disease and other conditions are found ultrastructurally to be composed of paired helical filaments as compared with those of progressive supranuclear palsy which are composed of straight 12-15-nm-thick filaments (16-22). Coexistence of the two types of neurofibrillary tangles has been reported in progressive supranuclear palsy (23-26) as well as Alzheimer's disease (27-29) and postencephalitic parkinsonism (30). These two types of neurofibrillary tangles share immunologic types of epitopes of cytoskeletal proteins such as neurofilament, microtubules, and tau proteins (30-34). The etiology of progressive supranuclear palsy is unknown. Verhaart classified the disease as a neuronal degeneration in the presenile-senile dementia group (35). No toxic or infectious vector has been demonstrated to cause the disease. Slow virus transmissibility has been demonstrated not to occur after inoculation in monkey brain. Recent evidence suggests that putative cholinergic neu- NEUROPATHOLOGY OF PROGRESSIVE SUPRANUCLEAR PALSY 169 RG. 10. A: Neurofibrillary tangle in a neuron of the substantia nigra containing a few granules of pigment (Bodian. 840). B: Neurofibrillary flame-shaped tangle in the globus pallidus with twisted and coiled neurofibrils (Bodian x 840). '/ f ... " .. - '-., , , FIG. 11. Dentate nucleus showing severe demyelination of the hilus (myelin stain. x 3.5). I Clin Nturo-ophtluzlm(l/. Vol. 8. No.3. 1988 170 M. KlDA ET AL. rans in the pedunculopontine nucleus pars compacta are preferentially affected in progressive supranuclear palsy (36). Treatment with levodopa or carbidopa may reduce rigidity and improve pseudobulbar symptoms in some cases (3); however, the effects are tern porary. The disease leads to death, commonly due to aspiration pneumonia. REFERENCES 1. Steele jC, Richardson Je, Olszewski j. Progressive supranuclear palsy. A heterogenous degeneration involVing the brain stem, basal ganglia, and cerebellum with vertical gaze and pseudobulbar palsy, nuchal dystonia, and dementia. Arclr Ner,roI1964;10:333-59. 2, Constantinides j. Tissot R, Ajuriaguerra J de. Dystonie oculofacio-cervicale au paralysie progressive supranuc1eaire de 5teel-Richardson-0Iszewski, Pseudo-paralysie due regard, trouble visuospatiaux, pseudo-demence, alterations neuronales. ReI' Nfllrol (Paris) 1.970;122:249-62. 3. Gilroy j. Meyer Js. Degenerative diseases of the nervous system. In: Medicallwllrology. New York: MacMillan, 1979. 4. Gambetli P, Autilio-Gambetti L, Papasozomenos 5. Bodian's silver method stains neurofiJament polypeptides. Scitmcf 1981;213:1521. 5. Sternberger LA. llIlllllllwclflocilemistry. 3rd ed. New York: John Wiley, 1986. 6. Connoly JA, Kalnins VI. The distribution of tau and HMW microtubule associated proteins in different cell types. Ex/, Cdl Res 1980;127:341-50. 7. Bignami A, Dahl D, Rueger DC. Glial fibrillary acidic (GFA) protein in normal neuronal cells and in pathological conditions. In: Fedoroff 5, Hertz L, eds. Adl'all,e:: ill cdllliar lIellrobiology (vol. 1) New York: Academic Press, 1980. 8. Chavany jA, van Bogaerl L., Godlewski S. Sur un syndrome de regidite a predominance axiale avec perturbation des autonalismes oculo-palpebraux D' rgine encephalitique. PresS/? Med 1951;50:958-62. 9. Adams JH, Corsellis JAN, Duchen LW. eds. Creellfield's lIellro/,atilology New York: Wiley, 1984. 10. Ishino H, Higashi H, Kurada S. Yabuki 5, Hayahara T, Otsuki S. Motor nuclear involvement in progressive supranuclear palsy. J Nellrol Sci 1974;22:233-44. 11. Troost BT, Daroff RB. The ocular motor defects in progressive supranuclear palsy. AliI! NeuroI1977;2:397-403. 12, Daroff RB. Progressive supranuclear palsy. A brief personalized history. Yale f Bioi Med 1987;60:119-22. 13. Buttner-Ennevar JA, Buttner U, Cohen B, Baumgartner G Vertical gaze paralysis and the rostral interstitial nucleus of the medial longitudinal fasculus. Bmill 1982;105:125-49. 14. Meyer js, Perusquia E. Infante E. Blepharospasm: a rare sign of corticostriatobulbar release. TrmlS Alii N,'urol Ass(l( 1973;97:311-2. 15. Kristensen MO. Progressive supranuclear palsy-20 years later. Acta Nellrol Scmld 1985;71:177-89. 16. Wisniewski K, jervis GA, Moretz RC, Wisniewski HM. Alzheimer neurofibrillary tangl.es in diseases other than senile and presenile dementia. AWl Nellrol 1979;5:288-94. 17, Tellez-Nagel I, Wisniewski HM. Ultra tructure of neurofibrillary tangles in Steele-Richard on-Olszewski syndrome. Arch N,'lIrol 1973;29:324-7. 18 Roy S, Dalla CK, Hirano A, et al. Electron-microscopic 1eli" Nfuro-ophlhnlrnol, Vol, 8, No.3, 1988 study of neurofibrillary tangles in steele-Richardson-Olszewski syndrome. Acta Nfuropathol (Ber/) 1974;29:175-9. 19. Case Records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 32-1975. N Engl J Met! 1975;293:346-52 20. Powell He, London GW, Lampert PW. NeurofibriUary tangles in progreSSive supranuclear palsy. Electron-microscopic observations. J Nellwpathol Exp Nellrol 1974;33:98106 21. Bugiani 0, Mancardi GL, Brusa A. etaI. The fine structure of subcortical neurofibrillary tangles In progressIve supranuclear palsy. Acta Nellropa/hol (Berl) 1979;45:147:-52. 22. jellinger K, Riederer R, Tomonaga M: ProgressIve s~pranuclear palsy. Clinicopatholog'lc and blOcherrucal studies, J Nellrol Trans 1980;16(suppl):11l-28. 23. Tomonaga M. Ultrastructure of neurofibrillary tangles in progreSSive supranuclear palsy. Acta Nellropa/lrol (Berl) 1977;37:177-81. 24. Ghatak NR, Nochlin 0, Hadfield MG. Neurofibrill.ary pathology in progreSSive supranuclear palsy. Acta Neliropal/IOI (Ber/) 1980;52:73-6. 25. Yagishita 5, Itoh Y, Amano N, et al. Ultrastructure of neurofibrillary tangles in progreSSive supranuclear palsy. Acta NellropatllOl (Berl) 1979;48:27-30. 26. Yen SH, Horoupian OS, Terry RD. Immunocytochemical comparison of neurofibrillary tangles in senile dementia of Alzheimer type, progressive supranuclear palsy, and postencephalitic parkinsonism. AIIII Nellrol 1983;13:172-5. 27. Oyanagi S. Electron-microscopic observations on the brains of patients with senile dementia: conversion of neurofiJaments to twisted tubules and interrelations between Alzheimer's neurofibrillary tangles and Pick's bodies. Ad" Neurol Sci Jpn 1974;18:77-88. 28. shibayama H, Kitoh j. Elect.ron-microscopic structure of the Alzheimer's neurofibrillary changes in case of atypical senile dementia. Acla Nellropnlhol (Ber/) 1978;41:229-34. 29. Yagishita 5, Itoh Y, Nan W, et al. Reappraisal of the fine structure of Alzheimer's neurofibrillary tangles. Acla Nellropathol (Ber/) 1981;54:239-46 30. Ishii T, Nakamura Y. Distribution and ultrastructure of Alzheimer's neurofibrillary tangles in postencephalitic parkinsonism of Economo type. Acta Nellropathol (Berl) 1981; 5559-62 31. Gambelli P, Shecket G, Ghelti B. et al. Neurofibrillary change in human brain: an immunocytochemical study with neurofilament antiserum. J Nt'lIrol'alirol Exp Neurol 1983;42:69-79. 32. Kosik K5, Joakim CL. selkoe DJ. Microtubule-associated protein T is a major antigentic component of paired helical filaments in Alzheimer's disease. Proc Nat A,nd Sci USA 1986;83:4044-8 33. Wood JG, Mirra SS, Pollock Nj, Binder Ll. Neurofibrillary tangles of Alzheimer disease share antigenic determinants with the axonal micro-tubule associated protein tau (t). Prllc Nat Acold Sci USA 1986;83:4040-3. 34 Pollock NJ, Mirra 55, Binder Ll, et al. Fi.lamentous aggregate in Pick's disease, progressive supranuclear palsy, and Alzheimer's disease show antigenic determinants with microtubule-associated protein, tau. Lall<'t'l 1986;2:1211. 35. Verhaart Wj. Degeneration of brain stem reticular formation, other part of the brain stem and the cerebellum: an example of heterogenous systemic degeneration of the central nervous system. J Nell r0l'a tllOl Exp Nellrol 1958;17: 382-91. 36. Zweig RM, Whitehouse PJ, Casanova MF, et al. Loss of pedunculopontine neurons in progressive supranuclear palsy. AIlIl N"llrol 1987;22:18-25. |