THE YALE JOURNAL OF BIOLOGY AND MEDICINE 60 (1987), 119-122 Progressive Supranuclear Palsy: A Brief Personalized History ROBERT B. DAROFF, M.D.

Gilbert W. Humphrey Professor and Chairman, Department ofNeurology, Case Western Reserve University, and Director, Department ofNeurology, University Hospitals ofCleveland, Cleveland, Ohio Received May 12, 1986 Progressive supranuclear palsy (PSP) was originally described in 1964. Although some contended it was merely a variant of Parkinson's disease, a specific electron microscopic finding of straight, rather than twisted, filaments in the neurofibrillary tangles established PSP as a distinct entity. The almost pathognomonic early clinical finding of paralysis of downward gaze is due to lesions involving the lateral portions of the rostral interstitial nucleus of the medial longitudinal fasciculus. Recent neurochemical studies have identified both a decrease in central and acetylcholine. The etiology of PSP is unknown, and the therapy is generally ineffective. "It looks like afunny kind ofparkinsonism." Professor Gilbert H. Glaser, 1963 While a resident in New Haven Hospital in 1963, I presented a demented patient who carried a diagnosis of Parkinson's disease but was unable to move his eyes. He had no and his neck was quite rigid. After examining the patient, Dr. Glaser made the comment quoted above but was puzzled about the actual diagnosis. Steele, Richardson, and Olszewski (S-R-O) "named" and first fully described progressive supranuclear palsy (PSP) clinically and pathologically in the April 1964 issue of the Archives ofNeurology [1]. Since then, I have closely followed the literature odyssey of this curious malady and made some minor contributions to its phenomenology. A personalized review follows. The subtitle of the S-R-O paper described "a heterogenous degeneration involving the brainstem, and cerebellum with vertical gaze and , nuchal and ." It seemed like a "new" disease, and I was pleased to have seen a case previously. At the time of the publication, I discussed the with Dr. Noble David of Miami, who was following several cases. Doctor David later published the first good description of the eye movement abnormality [2] which he had presented previously at the 1967 American Academy of Neurology meetings in San Francisco [3]. The discussant, Dr. Morris Bender, doubted that PSP was a separate disease and criticized David's pathophysiological explanation of the eye movement abnormality. Bender contended that these patients merely had Parkinson's disease with rigidity of their extraocular muscles. In 1969, we gave L-dopa (then an experimental drug) to two patients with PSP [4]. One of these patients did not respond, but the generalized rigidity and bradykinesia of the other definitely improved; the ophthalmoparesis did not change. This seemed to 119 Address reprint requests to: Robert B. Daroff, M.D., Director, Dept. of Neurology, University Hospitals of Cleveland, Cleveland, OH 44106 Copyright © 1987 by The Yale Journal of Biology and Medicine, Inc. All rights of reproduction in any form reserved. 120 ROBERT B. DAROFF strengthen David's position that the eye signs were more than simple parkinsonian rigidity. A report soon followed, describing correction of the ophthalmoparesis with L-dopa [5]. However, the patient had a major tremor which made PSP a tenuous diagnosis. In a 1980 review of 75 pathologically verified and 310 clinical cases, only nine clinical and one anatomical case had tremor [6]. A more extensive experience with L-dopa found an improvement in one-third, but there was no improvement in the eye movements [7]. When I read the infrequent report of the eyes improving with treatment in PSP, I become skeptical of the diagnosis and/or the observation (admittedly for what might represent no more than an old bias). Although dopamine agonists (bromocriptine and pergolide) are reported occasionally to be effective [8], it usually does not significantly improve a patient's functional performance for more than several months. We performed the first quantitative oculographic analysis in PSP [9]. A surprising finding, which we did not appreciate clinically, was square-wave jerks (SWJ), a sign then regarded as somewhat specific for cerebellar dysfunction. It is now recognized that excessive SWJ, the most common saccadic intrusion [10], occurs in almost all central diseases including Parkinson's, schizophrenia [11], affective disorders [12], and unaffected relatives of schizophrenics [13]. The concept of PSP as a distinct diagnostic entity remained challenged, particularly by Bender's group [14]. Dr. Stanley Fahn classified it as " Plus" [15] (coined from "ophthalmoplegia plus," another condition in which we have an avuncular interest). Fahn used the term generically to categorize which manifest, in addition to other clinical signs, features of parkinsonism. We used it as a hedge: "Although the typical clinical and pathological findings in PSP distinguish the complete form of this disease from Parkinson's, there occasionally are patients with seemingly typical Parkinson's (except for the tremor) who have the gaze disturbance suggestive of PSP. Such patients may be best described as 'parkinsonism plus' " [16]. The neurofibrillary tangles in PSP are non-specific, as originally discussed by S-R-O. However, the fine structure of these tangles has a unique characteristic; they are straight rather than "twisted." This observation was originally described in 1973 [17], and it has been verified by others [18]. These tangles show positive immunolabel- ing with antisera against a purified human microtubule fraction that also binds specifically to the tangles of Alzheimer's disease but not Parkinson's disease or striatonigral degeneration [19]. Before his death, Dr. Bender accepted PSP as being different from Parkinson's disease [20]. Since supranuclear ophthalmoplegias usually spare downward gaze [21], the characteristic downgaze palsy of PSP is intriguing. The extensive pathology prevented pathologic correlation, but the opportunity arose when a case of isolated downgaze palsy was presented by Dr. Larry Jacobs at the 1972 meeting of the American Neurological Association [22]. The lesion was superior and medial to the red nuclei bilaterally and the single previous case had a similar lesion. All pathologically proven cases of PSP demonstrating downgaze palsy had identically situated lesions [23]. Buttner-Ennever and colleagues [24] later identified the critical structure as the rostral interstitial nucleus of the medial longitudinal fasciculus, the lateral portions of which have concerned primarily with downward eye movements. It is now evident that patients with PSP may not have ophthalmoparesis or it may be delayed [25-27]. These were some of the patients constituting the "border zone" between PROGRESSIVE SUPRANUCLEAR PALSY 121

Parkinson's and PSP which prompted us to embrace "parkinsonism plus." The indeterminate cases can now be safely designated as PSP. The dementia in PSP has attracted considerable attention. Although regarded as a subcortical dementia [28,29], with a bradyphrenia and only a mild dementia [30], many cases do have significant cognitive impairment [27,31,32]. The concept of "subcortical dementia" is quite misleading [33] and should probably be abandoned. The November 1985 issue of the Annals ofNeurology included two reviews of the neurochemical abnormalities of PSP [32,34], preceded by an excellent summarizing editorial [35]. There is decreased dopamine concentration in the , but not to the degree found in Parkinson's, and only a 20 percent decrease of choline acetyltrans- ferase in the . The latter was said to support a "subcortical" etiology for the dementia. Loss of cholinergic interneurons in the basal ganglia might explain both the lack of tremor and the relative ineffectiveness of dominergic or anticholinergic drugs in PSP. Whereas in Parkinson's disease there is an imbalance between dopamine and acetylcholine (the former being relatively decreased and the latter relatively increased), in PSP they both are decreased, preserving the balance. For those who want a current review of PSP, I recommend Kristensen's [36]. The etiology of PSP is unknown, and the therapy remains generally ineffective. However, the clinical phenomenology, neuropathology, and neurochemical pathology is becom- ing better defined in this "funny kind of parkinsonism." REFERENCES 1. Steele JC, Richardson JC, Olszewski J: Progressive supranuclear palsy. Arch Neurol 10:333-359, 1964 2. David NJ, Mackey EA, Smith JL: Further observations in progressive supranuclear palsy. Neurology 18:349-356, 1968 3. David NJ, Mackey EA: Further clinicopathological observations in progressive supranuclear palsy. Neurology 17:294, 1967 4. Wagshul A, Daroff RB: L-dopa for progressive supranuclear palsy. Lanced ii:105-106, 1969 5. Mendell JR, Chase TN, Engel WK: Modification by L-dopa of a case of progressive supranuclear palsy. Lancet i:593-594, 1970 6. Brusa A, Mancardi GL, Bugiani 0: Progressive supranuclear palsy 1979: an overview. Ital J Neurol Sci 4:205-222, 1980 7. Klawans HL, Ringel SP: Observations on the efficacy of L-dopa in progressive supranuclear palsy. European Neurol 5:115-129, 1971 8 Jackson J, Jankovic J, Ford J: Progressive supranuclear palsy: clinical features and response to treatment in 16 patients. Ann Neurol 13:273-278, 1983 9. Troost BT, Daroff RB: The ocular motor defects in progressive supranuclear palsy. Ann Neurol 2:397-403, 1977 10. Abel LA, Traccis S, Dell'Osso LF, Daroff RB, Troost BT: Square wave oscillations. The relationship of saccadic intrusions and oscillations. Neuro-ophth 4:21-25, 1984 11. Levin S, Jones A, Stark L, Merrin EL, Holzman PS: Identification of abnormal patterns in eye movements of schizophrenic patients. Arch Gen Psychiatry 39:1125-1130, 1982 12. Hertle RW, Abel LA, Daroff RB: Unpublished observations 13. Whicker L, Abel LA, Dell'Osso LF: Smooth pursuit eye movements in the parents of schizophrenics. Neuro-ophth 5:1-8, 1985 14. Corin MS, Mones RB, Elizan TS, Bender MB: Paresis of vertical gaze in basal ganglia disease. Mt Sinai J Med 39:330-342, 1972 15. Fahn S: Secondary parkinsonism. In Scientific Approaches to Clinical Neurology. Edited by ES Goldensohn, SH Appel. Philadelphia, Lea & Febiger, 1977, pp 1159-1189 16. Daroff RB, Troost BT: Supranuclear disorders of eye movements. In Neuro-Ophthalmology. Edited by JS Glaser. Hagerstown, Harper & Row, 1978, pp 201-218 122 ROBERT B. DAROFF

17. Tellez-Nagel I, Wisniewski HM: Ultrastructure of neurofibrillary tangles in Steel-Richardson- Olszewski syndrome. Arch Neurol 29:324-327, 1973 18. Bugiani 0, Mancardi GL, Brusa A, Ederli A: The fine structure of subcortical neurofibrillary tangles in progressive supranuclear palsy. Acta Neuropathol 45:147-152, 1979 19. Yen S-H, Horoupian DS, Terry RD: Immunocytochemical comparison of neurofibrillary tangles in senile dementia of Alzheimer type, progressive supranuclear palsy, and postencephalitic parkinsonism. Ann Neurol 13:172-175, 1983 20. Bender MB, Rudolph SH, Stacy CB: The neurology of the visual and oculomotor systems. In Clinical Neurology. Edited by AB Baker, RJ Joynt. Philadelphia, Harper & Row, 1985, chapter 12, p 69 21. Daroff RB, Hoyt WF: Supranuclear disorders of ocular control systems in man: Clinical, anatomical and physiological correlations, 1969. In Control of Eye Movements. Edited by P Bach-y-Rita, CC Collins, JE Hyde. New York, Academic Press, 1971, pp 175-235 22. Jacobs L, Anderson PJ, Bender MB: The lesions producing paralysis of downward but not upward gaze. Trans Amer Neurol Assoc 97:57-60, 1972 23. Daroff RB: Discussion of "The lesions producing paralysis of downward but not upward gaze," by Jacobs L et al. Trans Amer Neurol Assoc 97:60-61, 1972 24. Buttner-Ennevar JA, Buttner U, Cohen B, Baumgartner G: Vertical gaze paralysis and the rostal interstitial nucleus of the medial longitudinal fasciculus. Brain 105:125-149, 1982 25. Perkins GD, Lees AJ, Stern GM, Kocek RS: Problems in the diagnosis of progressive supranuclear palsy. Can J Neurol Sci 5:167-173, 1978 26. Dubas F, Gray F, Escourolle R: Maladie de Steele-Richardson-Olszewski scans ophtalmoplegie: six cas anatomo-cliniques. Rev Neurol (Paris) 139:407-416, 1983 27. Davis PH, Bergeron C, McLachlan DR: Atypical presentation of progressive supranuclear palsy. Ann Neurol 17:337-343, 1985 28. Albert ML, Feldman RG, Willis AL: The "subcortical dementia" of supranuclear palsy. J Neurol Neurosurg Psychiatry 37:121-130, 1974 29. D'Antona R, Baron JC, Samson Y, Serdaru M, Viader F, Agid Y, Cambier J: Subcortical dementia. Brain 108:785-799, 1985 30. Fisk JD, Goodale MA, Burkhart G, Barnett HJM: Progressive supranuclear palsy: The relationship between ocular motor dysfunction and psychological test performance. Neurology (NY) 32:698-705, 1982 31. Cambier J, Masson M, Viader F, Limodin J, Strube A: Le syndrome frontal de la paralysie supranucleaire progressive. Rev Neurol (Paris) 141:528-536, 1985 32. Kish SJ, Chang LJ, Mirchandani L, Shannak K, Hornykiewicz 0: Progressive supranuclear palsy: Relationship between extrapyramidal disturbances, dementia, and brain neurotransmitter markers. Ann Neurol 18:530-536, 1985 33. Whitehouse PJ: The concept of subcortical and cortical dementia: Another look. Ann Neurol 19:1-6, 1986 34. Ruberg M, Javoy-Agid F, Hirsch E, Scatton B, LHeureux R, Hauw J-J, Duyckaerts C, Gray F, Morel-Maroger A, Rascol A, Serdaru M, Agid Y: and cholinergic lesions in progressive supranuclear palsy. Ann Neurol 18:523-529, 1985 35. Young AB: Progressive supranuclear palsy: Postmortem chemical analysis. Ann Neurol 18:521-522, 1985 36. Kristensen MO: Progressive supranuclear palsy-20 years later. Acta Neurol Scand 71:177-189, 1985