Pharmacological Therapy in Progressive Supranuclear Palsy

ORIGINAL CONTRIBUTION Pharmacological Therapy in Progressive Supranuclear Palsy

K. Kompoliti, MD; C. G. Goetz, MD; Irene Litvan, MD; K. Jellinger, MD; M. Verny, MD

Background: To our knowledge, previous reports on ticholinergics and selective serotonin inhibitors (1 pa- drug treatment in progressive supranuclear palsy have tient). Positive clinical response was detected in 7 of the not evaluated autopsy-confirmed cases. patients receiving dopaminergic drugs and in 1 patient each receiving tricyclics, methysergide, and 5-hydro- Objective: To evaluate pharmacological treatment re- xytryptophan, respectively. None of the patients responses from detailed clinical records in patients with sponded markedly however, and there was no persis- autopsy-confirmed progressive supranuclear palsy. tent beneficial effect. Use of dopaminergic drugs most frequently improved parkinsonian features, but dis- Subjects and Methods: We reviewed medical records abling adverse effects included orthostatic hypotension for clinical presentation and pharmacological response (6 patients), hallucinations and delusions (3 patients), in 12 patients with autopsy-confirmed progressive supra- gastrointestinal complaints (3 patients), and dizziness nuclear palsy diagnosed using the National Institute of Neu- (1 patient). Only 1 patient developed dyskinesia. rological Disorders and Stroke pathologic criteria. For each drug class, exposure, global positive response, and specific Conclusion: Use of antiparkinsonian medications and positive response (parkinsonism, other movement disor- other neurotransmitter replacement therapies was largely ders, or gaze dysfunction) were recorded. ineffective and caused frequent adverse effects in this series of patients with autopsy-confirmed with progres- Results: Drug classes examined were dopaminergics (all sive supranuclear palsy. patients), tricyclics (3 patients), methysergide maleate (3 patients), 5-hydroxytryptophan (2 patients), and an- Arch Neurol. 1998;55:1099-1102

ROGRESSIVE supranuclear response and detailed clinical records palsy (PSP) is a neurodegen- in a series of patients with autopsy- erative disease character- confirmed PSP assessed by specialists of ized by parkinsonism with movement disorder. prominent axial involve- mentP and postural reflex abnormality, bul- RESULTS bar symptoms, supranuclear ophthal- moplegia, and higher cortical dysfunction. The mean age of the 12 patients was 64 Dysfunction of multiple brain systems has years at onset of symptoms (range, 53-70 complicated attempts to treat the dis- years). Parkinsonism and ocular signs were ease. In PSP there is involvement of the present in all patients, bulbar signs and From the Rush-Presbyterian-St dopaminergic, cholinergic, GABAergic higher cortical dysfunction in 11 patients, Luke’s Medical Center, (␥-aminobutyric acid), and to a lesser de- other movement disorders in 10, pyrami- Chicago, Ill (Drs Kompoliti and gree of the serotonergic and noradrener- dal signs in 2, and other signs in 1 patient Goetz); Neuroepidemiology gic systems.1,2 Pharmacological therapy (Table 1). Branch, National Institute of has focused on the manipulation of the Of the parkinsonian signs, bradyki- Neurological Disorders and central dopaminergic,3-6 cholinergic,7-12 nesia, rigidity, and gait abnormalities were Stroke, National Institutes of serotonergic,3,4,13,14 and more recently, nor- present in all, while tremor was found in Health, Bethesda, Md adrenergic systems.15 The clinical over- only 2 of 12 patients. All patients had su- (Dr Litvan); Ludwig Boltzmann Institute of Clinical lap of PSP with other neurodegenerative pranuclear gaze abnormalities, with 2 hav- Neurobiology, Vienna, Austria syndromes is significant, making conclu- ing additional ocular signs, consisting of (Dr Jellinger); and Hoˆpital sions regarding medication responses ten- blepharospasm, which was associated in Charles Foix, Paris, France tative. To identify putatively effective phar- 1 of the patients with eyelid retraction. One (Dr Verny). macotherapies, we assessed clinical patient developed delusional thinking

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 Table 1. Progressive Supranuclear Palsy: Clinical Features* PATIENTS AND METHODS Clinical Features No. of Patients Parkinsonism (n = 12) We collected clinical information on 12 patients from Bradykinesia 12 the Salpe`trie`re Hospital, Paris, France, and the Lud- Rigidity 12 wig Boltzmann Institute of Clinical Neurology, Vi- Tremor 2 enna, Austria. The diagnosis of PSP was made by 2 Gait problems 12 neuropathologists according to the National Insti- Ocular signs (n = 12) tute of Neurological Disorders and Stroke neuro- Supranuclear 12 pathologic criteria for typical PSP.16,17 Other 2 We reviewed the complete medical records of Bulbar function (n = 11) these 12 patients with regard to clinical presenta- Dysarthria 11 tion and response to dopaminergic therapeutic ma- Dysphagia 11 nipulations and exposure to other drugs. The data Both 11 were collected by the primary investigator (K.K.). Higher cortical function (n = 11) Signs were categorized into the following domains: Dementia 11 parkinsonism (at least 2 of bradykinesia, rigidity, Palilalia 7 tremor, and gait abnormalities), other movement dis- Frontal signs 2 orders (dystonia or myoclonus), gaze difficulties, bul- Delusions 1 bar signs, higher cortical signs, pyramidal signs, and Other movement disorders (n = 10) other. Minimal criterion for improvement was im- Dystonia 10 Axial 8 provement in at least 1 domain. Improvement or de- Neck 7 terioration were classified as either absent, modest, Both 6 or marked. Trismus 1 Myoclonus 1 Pyramidal (n = 7) Hyperreflexia 7 Other (n = 1) while receiving a stable dose of levodopa (400 mg/d) in Orthostatic hypotension 1 conjunction with a peripheral decarboxylase inhibitor for many months before the onset of the psychotic phenom- *N = 12. ena. Table 1 shows detailed information of the clinical presentation of this group of patients. The latter consisted of vertical supranuclear gaze palsy. All 12 patients received 1 or several types of dopa- The dyskinesias were observed toward the end of the 2- minergic medication. Treatment was initiated, on aver- year treatment with levodopa, were confined to the face, age, 2 years after onset of symptoms. Improvement from and lasted 2 to 4 months, resolving following discon- 1 dopaminergic agent did not predict response to the other tinuation of levodopa. Subsequently, therapy with bro- dopaminergic agents administered subsequently. Eleven mocriptine mesylate was initiated but without clinical re- received levodopa with a peripheral decarboxylase in- sponse. The patient succumbed to his disease 5 years from hibitor, 6 an agonist, and 5 amantadine (Table 2). Seven onset of symptoms. experienced clinical improvement. Levodopa with a pe- Dopamine agonists were given mostly in the form ripheral decarboxylase inhibitor produced improve- of bromocriptine, except for 1 patient who received piribe- ment in 4 of the 11 patients. This improvement was dil at a dosage of 1250 mg/d for 6 months. This treat- marked in 1 patient and modest in the other 3 patients. ment produced modest improvement of parkinsonism in The features improving were parkinsonism in 4 pa- 1 patient and marked deterioration of the primary con- tients, and dystonia and supranuclear gaze palsy in 1 pa- dition in another patient. tient, respectively. The patient who experienced im- Five patients received amantadine and 2 demon- provement of gaze palsy was treated with levodopa and strated questionable improvement of parkinsonism (both a peripheral decarboxylase inhibitor (400 mg/d of le- patients) and neck dystonia (1 patient). Three patients vodopa) 2 years after onset of disease. The improve- complained of deterioration of their primary condition, ment lasted 3 months. While receiving levodopa therapy, which was modest in 2 and marked in 1. Other medica- 4 patients experienced exacerbation of parkinsonism, bul- tions used were tricyclic antidepressants and methyser- bar symptoms, and higher cortical dysfunction, and 2 ex- gide in 3 patients, 5-hydroxytryptophan in 2, selective perienced exacerbation of supranuclear gaze palsy. serotonin reuptake inhibitors, anticholinergics, and mi- The patient with the levodopa-induced dyskine- anserin hydrochloride in 1 patient each. The tricyclic an- sias was initially diagnosed as having idiopathic Parkin- tidepressants used were amitriptyline hydrochloride in son disease and was started on a regimen of levodopa and 1 patient and chlomipramine in 2 patients. The patient a peripheral decarboxylase inhibitor 1 year after onset receiving amitriptyline experienced modest improve- of symptoms. He experienced a 60% improvement in re- ment of his parkinsonism. sponse to levodopa treatment and this remained stable Three patients received methysergide with modest for 2 years requiring dose increments in regular inter- clinical improvement in one and worsening of the un- vals. Postural instability and falls first occurred 2.5 years derlying condition in another. The elements that im- and supranuclear gaze impairment 3 years after onset. proved were parkinsonism and dystonia and the wors-

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Duration of Improvement Parkinsonism Dystonia Gaze Dose, mg Therapy, mo Medicine N (Range)† (Range)† +++++++ + Adverse Effects Levodopa 11 500 (120-1200) 30 (3-60) 3 1 3 1 1 1 OH (4), GI disturbances (1), dyskinesias (1) Bromocriptine 6 15 (7.5-50) 12 (1-36) 1 . . . 1 ...... OH (3), GI disturbances (2) Amantadine hydrochloride 5 80 (50-200) 24 (6-60) 2 . . . 2‡ . . . 1‡ . . . OH (1), delusions and hallucinations (1) TCAs 3 75 4 (1-6) 1 . . . 1 ...... OH (1) Methysergide maleate 3 7 (6-8) 3 (2-6) 1 . . . 1 . . . 1 . . . OH (1), delusions and hallucinations (1) 5-Hydroxytryptophan 2 225 (150-300) 13 (2-24) 1 . . . 1 ......

*Plus sign indicates modest improvement; double plus signs, marked improvement; OH, orthostatic hypotension; GI, gastrointestinal; TCAs, tricyclic antidepressants; and ellipses, no improvement. †Values represent median, except 5-hydroxytryptophan, for which means are used. ‡Questionable improvements.

ening involved the bulbar symptoms. Adverse effects the form of Sinemet) and 54% experienced mild to mod- included delusions/hallucinations and gastrointestinal erate improvement on the basis of clinical impression. disturbances in 1 patient each. Two patients received 5- In their series, no other manipulation of the choliner- hydroxytryptophan with 1 experiencing modest improve- gic, serotonergic, or adrenergic system was successful in ment of his parkinsonism. No adverse effects were ameliorating the debilitating features of the disease. On reported. Finally, 1 patient received fluoxetine hydro- the other hand, adverse effects were frequent and se- chloride, mianserin, and biperiden hydrochloride, re- vere, making the risk-benefit ratio unfavorable for con- spectively, without experiencing clinical improvement. tinuation of treatment even in a disease as refractory to The patient treated with fluoxetine experienced confu- medical therapy as PSP. However, the lack of response sion and had to discontinue the medication. to dopaminergic stimulation, particularly in the form of levodopa combined with a peripheral decarboxylase COMMENT inhibitor, helps establish the diagnosis of nonidiopathic Parkinson disease parkinsonism. Empirical treatment of clinically defined PSP has thus far A single patient with marked improvement of par- been disappointing, but it has been unclear to what de- kinsonism receiving levodopa-carbidopa developed dys- gree the poor response is due to inclusion of patients with kinesia as a result of treatment. Although dyskinesias, not degenerative diseases other than PSP. Most therapeutic attributable to medication, can rarely be part of the clini- attempts have been based on the neurotransmitter re- cal presentation of PSP,31 drug-induced dyskinesias are placement strategy. Other approaches include botuli- unusual in parkinsonian syndromes other than idio- num toxin,18,19 electroconvulsive therapy,20,21 nalox- pathic Parkinson disease. Because our patients received one,22 and milacemide.23 Litvan and Chase24 reviewed 381 levodopa-carbidopa for prolonged periods, the general published cases of PSP from 1969 to 1990 with regard absence of dyskinesias suggests a fundamental differ- to their response to pharmacological intervention. With ence in the dopaminergic lesions in PSP and Parkinson the exception of a few autopsy-confirmed patients,25-28 disease. The fact that the single patient with dyskinesia the vast majority of patients were clinically diagnosed. also showed improvement in his parkinsonian features Although interrater agreement for the clinical diagnosis following dopaminergic therapy, however, suggests a di- of PSP varies from substantial to near perfect, none of rect link between antiparkinsonian efficacy and dyski- the published criteria has both high sensitivity and pre- nesia, even in nonidiopathic Parkinson disease cases of dictive value.29 To our knowledge, this is the first report parkinsonism. of the clinical presentation and response to pharmaco- All the studies assessing the response to pharmacological intervention in a series composed exclusively of logical intervention in patients with PSP have been ret- patients with autopsy-confirmed PSP each in a detailed rospective reviews using clinical, at times not validated, clinical chart maintained by a movement disorder spe- criteria for diagnosing PSP. There have been no vali- cialist. The pathologic diagnosis of these patients was made dated, standardized scales to quantify drug response for by 2 neuropathologists and the interrater agreement and this disease and there has been lack of consideration of validity for the pathologic diagnosis of PSP have been the placebo effect. Our study, although based on retro- found to be high.16 spective review as well, confirms previous reports and In this series, one third of the patients had modest adds the rigor of autopsy-proven diagnosis in patients uni- improvement while receiving levodopa with a periph- formly exposed to dopaminergic agents. eral decarboxylase inhibitor. This improvement, though, Future strategies to treat PSP will require larger and was not sustained and was accompanied by adverse ef- prospective studies, with random assignment to treat- fects in more than half of the patients. Litvan and Chase24 ment and use of appropriate controls. Because PSP is a suggested that when effective, therapy with levodopa al- relatively infrequent disease, multicenter trials may be tered rigidity and gait impairment. Nieforth and Golbe30 necessary. Since open-label single neurotransmitter re- reported that 78 of 83 patients clinically diagnosed as hav- placement strategies have already failed to produce marked ing PSP were tried on a regimen of levodopa (usually in or persistent symptom relief, use of drug combinations

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©1998 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/23/2021 to simultaneously address affected systems interacting 13. Newman GC. Treatment of progressive supranuclear palsy with tricyclic antide- with each other, or disease modification strategies, such pressants. Neurology. 1985;35:1189-1193. 14. Schneider LS, Gleason RP, Chui HC. Progressive supranuclear palsy with agi- as free radical scavengers or trophic factors, are poten- tation: response to trazodone but not to thiothixine or carbamazepine. J Geriatr tial candidate treatments. Psychiatry Neurol. 1989;2:109-1125. 15. Ghika J, Tennis M, Hoffman E, Schoenfeld D, Growdon J. Idazoxan treatment in Accepted for publication January 13, 1998. progressive supranuclear palsy. Neurology. 1991;41:986-991. Corresponding author: Katie Kompoliti, MD, Depart- 16. Litvan I, Hauw JJ, Bartko JJ, et al. Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disor- ment of Neurological Sciences, Rush-Presbyterian-St Luke’s ders. J Neuropathol Exp Neurol. 1996;55:97-105. Medical Center, 1725 W Harrison St, Suite 1106, Chicago, 17. Hauw JJ, Daniel SE, Dickson D, et al. Preliminary NINDS neuropathologic crite- IL 60612 (e-mail: [email protected]). ria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology. 1994;44:2015-2019. 18. Polo KB, Jabbari B. Botulinum toxin-A improves the rigidity of progressive su- REFERENCES pranuclear palsy. Ann Neurol. 1994;35:237-239. 19. Lepore V, Defazio G, Acquistapace D, et al. Botulinum A toxin for the so-called 1. Levy R, Ruberg M, Herrero MT, et al. Alterations of GABAergic neurons in the apraxia of lid opening. Mov Disord. 1995;10:525-526. basal ganglia of patients with progressive supranuclear palsy: an in situ hybrid- 20. Barclay CL, Duff J, Sandor P, Lang AE. Limited usefulness of electroconvulsive ization study of GAD67 messenger RNA. Neurology. 1995;45:127-134. therapy in progressive supranuclear palsy. Neurology. 1996;46:1284-1286. 2. Agid Y, Javoy-Agid F, Ruberg M, et al. Progressive supranuclear palsy: anato- 21. Hauser RA, Trehan R. Initial experience with electroconvulsive therapy for pro- moclinical and biochemical considerations. Adv Neurol. 1987;45:191-206. gressive supranuclear palsy. Mov Disord. 1994;9:467-469. 3. Neophytides A, Lieberman AN, Goldstein M, et al. The use of lisuride, a potent 22. Sandyk R, Iacono RP. Naloxone ameliorates presyncopal sensations in progres- dopamine and serotonin agonist, in the treatment of progressive supranuclear sive supranuclear palsy. Int J Neurosci. 1987;35:89-90. palsy. J Neurol Neurosurg Psychiatry. 1982;45:261-263. 23. Gordon MF, Diaz-Olivo R, Hunt AL, Fahn S. Therapeutic trial of milacemide in 4. Rafal RD, Grimm RJ. Progressive supranuclear palsy: functional analysis of the patients with myoclonus and other intractable movement disorders. Mov Dis- response to methysergide and antiparkinsonian agents. Neurology. 1981;31: ord. 1993;8:484-488. 1507-1518. 24. Litvan I, Chase TN. Traditional and experimental therapeutic approaches. In: Lit- 5. Jankovic J. Controlled trial of pergolide mesylate in Parkinson’s disease and pro- van I, Agid Y, eds. Progressive Supranuclear Palsy: Clinical and Research Ap- gressive supranuclear palsy. Neurology. 1983;33:505-507. proaches. New York, NY: Oxford University Press Inc; 1992:254-269. 6. Haldeman S, Goldman JW, Hyde J, Pribram HF. Progressive supranuclear palsy, 25. Bugiani O, Mancardi GL, Brusa A, Ederli A. The fine structure of subcortical neu- computed tomography, and response to antiparkinsonian drugs. Neurology. 1981; rofibrillary tangles in progressive supranuclear palsy. Acta Neuropathol (Berl). 31:442-445. 1979;45:147-152. 7. Kertzman C, Robinson DL, Litvan I. Effects of physostigmine on spatial atten- 26. Jellinger K. Progressive supranuclear palsy (subcortical argyrophilic dystro- tion in patients with progressive supranuclear palsy. Arch Neurol. 1990;47:1346- phy). Acta Neuropathol (Berl). 1971;19:347-352. 1350. 27. Jellinger K, Riederer P, Tomonaga M. Progressive supranuclear palsy: clinico-patho- 8. Blin J, Mazetti P, Mazoyer B, et al. Does the enhancement of cholinergic neurological and biochemical studies. J Neural Transm Suppl. 1980;(suppl 16):111-128. transmission influence brain glucose kinetics and clinical symptomatology in pro- 28. Kish SJ, Chang LJ, Mirchandani L, Shannak K, Hornykiewicz O. Progressive su- gressive supranuclear palsy? Brain. 1995;118:1485-1495. pranuclear palsy: relationship between extrapyramidal disturbances, dementia, 9. Litvan I, Blesa R, Clark K, et al. Pharmacological evaluation of the cholinergic and brain neurotransmitter markers. Ann Neurol. 1985;18:530-536. system in progressive supranuclear palsy. Ann Neurol. 1994;36:55-61. 29. Litvan I, Agid Y, Jankovic J, et al. Accuracy of clinical criteria for the diagnosis of 10. Litvan I. Cholinergic approaches to the treatment of progressive supranuclear progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome). Neu- palsy. J Neural Transm Suppl. 1994;42:275-281. rology. 1996;46:922-930. 11. Litvan I, Gomez C, Atack JR, et al. Physostigmine treatment of progressive su- 30. Nieforth KA, Golbe LI. Retrospective study of drug response in 87 patients with pranuclear palsy. Ann Neurol. 1989;26:404-407. progressive supranuclear palsy. Clin Neuropharmacol. 1993;16:338-346. 12. Foster NL, Aldrich MS, Bluemlein L, White RF, Berent S. Failure of cholinergic 31. Collins SJ, Ahlskog JE, Parisi JE, Maraganore DM. Progressive supranuclear palsy: agonist RS-86 to improve cognition and movement in PSP despite effects on neuropathologically based diagnostic clinical criteria. J Neurol Neurosurg Psy- sleep. Neurology. 1989;39:257-261. chiatry. 1995;58:167-173.

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