Journal of Neuro-Ophthalmology, September 1988, Volume 8, Issue 3

Neuropathologic findings in progressive supranuclear palsy. A brief review with two additional case reports.

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.

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. 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