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Table 1. 
Progressive Supranuclear Palsy: Clinical Features*
Progressive Supranuclear Palsy: Clinical Features*
Table 2. 
Exposure to Medications and Specific Areas of Improvement*
Exposure to Medications and Specific Areas of Improvement*
1.
Levy  RRuberg  MHerrero  MT  et al.  Alterations of GABAergic neurons in the basal ganglia of patients with progressive supranuclear palsy: an in situ hybridization study of GAD67 messenger RNA. Neurology. 1995;45127- 134Article
2.
Agid  YJavoy-Agid  FRuberg  M  et al.  Progressive supranuclear palsy: anatomoclinical and biochemical considerations. Adv Neurol. 1987;45191- 206
3.
Neophytides  ALieberman  ANGoldstein  M  et al.  The use of lisuride, a potent dopamine and serotonin agonist, in the treatment of progressive supranuclear palsy. J Neurol Neurosurg Psychiatry. 1982;45261- 263Article
4.
Rafal  RDGrimm  RJ Progressive supranuclear palsy: functional analysis of the response to methysergide and antiparkinsonian agents. Neurology. 1981;311507- 1518Article
5.
Jankovic  J Controlled trial of pergolide mesylate in Parkinson's disease and progressive supranuclear palsy. Neurology. 1983;33505- 507Article
6.
Haldeman  SGoldman  JWHyde  JPribram  HF Progressive supranuclear palsy, computed tomography, and response to antiparkinsonian drugs. Neurology. 1981;31442- 445Article
7.
Kertzman  CRobinson  DLLitvan  I Effects of physostigmine on spatial attention in patients with progressive supranuclear palsy. Arch Neurol. 1990;471346- 1350Article
8.
Blin  JMazetti  PMazoyer  B  et al.  Does the enhancement of cholinergic neurotransmission influence brain glucose kinetics and clinical symptomatology in progressive supranuclear palsy? Brain. 1995;1181485- 1495Article
9.
Litvan  IBlesa  RClark  K  et al.  Pharmacological evaluation of the cholinergic system in progressive supranuclear palsy. Ann Neurol. 1994;3655- 61Article
10.
Litvan  I Cholinergic approaches to the treatment of progressive supranuclear palsy. J Neural Transm Suppl. 1994;42275- 281
11.
Litvan  IGomez  CAtack  JR  et al.  Physostigmine treatment of progressive supranuclear palsy. Ann Neurol. 1989;26404- 407Article
12.
Foster  NLAldrich  MSBluemlein  LWhite  RFBerent  S Failure of cholinergic agonist RS-86 to improve cognition and movement in PSP despite effects on sleep. Neurology. 1989;39257- 261Article
13.
Newman  GC Treatment of progressive supranuclear palsy with tricyclic antidepressants. Neurology. 1985;351189- 1193Article
14.
Schneider  LSGleason  RPChui  HC Progressive supranuclear palsy with agitation: response to trazodone but not to thiothixine or carbamazepine. J Geriatr Psychiatry Neurol. 1989;2109- 1125Article
15.
Ghika  JTennis  MHoffman  ESchoenfeld  DGrowdon  J Idazoxan treatment in progressive supranuclear palsy. Neurology. 1991;41986- 991Article
16.
Litvan  IHauw  JJBartko  JJ  et al.  Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders. J Neuropathol Exp Neurol. 1996;5597- 105Article
17.
Hauw  JJDaniel  SEDickson  D  et al.  Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology. 1994;442015- 2019Article
18.
Polo  KBJabbari  B Botulinum toxin-A improves the rigidity of progressive supranuclear palsy. Ann Neurol. 1994;35237- 239Article
19.
Lepore  VDefazio  GAcquistapace  D  et al.  Botulinum A toxin for the so-called apraxia of lid opening. Mov Disord. 1995;10525- 526Article
20.
Barclay  CLDuff  JSandor  PLang  AE Limited usefulness of electroconvulsive therapy in progressive supranuclear palsy. Neurology. 1996;461284- 1286Article
21.
Hauser  RATrehan  R Initial experience with electroconvulsive therapy for progressive supranuclear palsy. Mov Disord. 1994;9467- 469Article
22.
Sandyk  RIacono  RP Naloxone ameliorates presyncopal sensations in progressive supranuclear palsy. Int J Neurosci. 1987;3589- 90Article
23.
Gordon  MFDiaz-Olivo  RHunt  ALFahn  S Therapeutic trial of milacemide in patients with myoclonus and other intractable movement disorders. Mov Disord. 1993;8484- 488Article
24.
Litvan  IChase  TN Traditional and experimental therapeutic approaches. Litvan  IAgid  YedsProgressive Supranuclear Palsy Clinical and Research Approaches. New York, NY Oxford University Press Inc1992;254- 269
25.
Bugiani  OMancardi  GLBrusa  AEderli  A The fine structure of subcortical neurofibrillary tangles in progressive supranuclear palsy. Acta Neuropathol (Berl). 1979;45147- 152Article
26.
Jellinger  K Progressive supranuclear palsy (subcortical argyrophilic dystrophy). Acta Neuropathol (Berl). 1971;19347- 352Article
27.
Jellinger  KRiederer  PTomonaga  M Progressive supranuclear palsy: clinico-pathological and biochemical studies. J Neural Transm Suppl. 1980;(suppl 16)111- 128
28.
Kish  SJChang  LJMirchandani  LShannak  KHornykiewicz  O Progressive supranuclear palsy: relationship between extrapyramidal disturbances, dementia, and brain neurotransmitter markers. Ann Neurol. 1985;18530- 536Article
29.
Litvan  IAgid  YJankovic  J  et al.  Accuracy of clinical criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome). Neurology. 1996;46922- 930Article
30.
Nieforth  KAGolbe  LI Retrospective study of drug response in 87 patients with progressive supranuclear palsy. Clin Neuropharmacol. 1993;16338- 346Article
31.
Collins  SJAhlskog  JEParisi  JEMaraganore  DM Progressive supranuclear palsy: neuropathologically based diagnostic clinical criteria. J Neurol Neurosurg Psychiatry. 1995;58167- 173Article
Original Contribution
August 1998

Pharmacological Therapy in Progressive Supranuclear Palsy

Author Affiliations

From the Rush-Presbyterian-St Luke's Medical Center, Chicago, Ill (Drs Kompoliti and Goetz); Neuroepidemiology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Md (Dr Litvan); Ludwig Boltzmann Institute of Clinical Neurobiology, Vienna, Austria (Dr Jellinger); and Hôpital Charles Foix, Paris, France (Dr Verny).

Arch Neurol. 1998;55(8):1099-1102. doi:10.1001/archneur.55.8.1099
Abstract

Background  To our knowledge, previous reports on drug treatment in progressive supranuclear palsy have not evaluated autopsy-confirmed cases.

Objective  To evaluate pharmacological treatment responses from detailed clinical records in patients with autopsy-confirmed progressive supranuclear palsy.

Subjects and Methods  We reviewed medical records for clinical presentation and pharmacological response in 12 patients with autopsy-confirmed progressive supranuclear palsy diagnosed using the National Institute of Neurological Disorders and Stroke pathologic criteria. For each drug class, exposure, global positive response, and specific positive response (parkinsonism, other movement disorders, or gaze dysfunction) were recorded.

Results  Drug classes examined were dopaminergics (all patients), tricyclics (3 patients), methysergide maleate (3 patients), 5-hydroxytryptophan (2 patients), and anticholinergics and selective serotonin inhibitors (1 patient). Positive clinical response was detected in 7 of the patients receiving dopaminergic drugs and in 1 patient each receiving tricyclics, methysergide, and 5-hydroxytryptophan, respectively. None of the patients responded markedly however, and there was no persistent beneficial effect. Use of dopaminergic drugs most frequently improved parkinsonian features, but disabling adverse effects included orthostatic hypotension (6 patients), hallucinations and delusions (3 patients), gastrointestinal complaints (3 patients), and dizziness (1 patient). Only 1 patient developed dyskinesia.

Conclusion  Use of antiparkinsonian medications and other neurotransmitter replacement therapies was largely ineffective and caused frequent adverse effects in this series of patients with autopsy-confirmed with progressive supranuclear palsy.

PROGRESSIVE supranuclear palsy (PSP) is a neurodegenerative disease characterized by parkinsonism with prominent axial involvement and postural reflex abnormality, bulbar symptoms, supranuclear ophthalmoplegia, and higher cortical dysfunction. Dysfunction of multiple brain systems has complicated attempts to treat the disease. In PSP there is involvement of the dopaminergic, cholinergic, GABAergic (γ-aminobutyric acid), and to a lesser degree of the serotonergic and noradrenergic systems.1,2 Pharmacological therapy has focused on the manipulation of the central dopaminergic,36 cholinergic,712 serotonergic,3,4,13,14 and more recently, noradrenergic systems.15 The clinical overlap of PSP with other neurodegenerative syndromes is significant, making conclusions regarding medication responses tentative. To identify putatively effective pharmacotherapies, we assessed clinical response and detailed clinical records in a series of patients with autopsy-confirmed PSP assessed by specialists of movement disorder.

PATIENTS AND METHODS

We collected clinical information on 12 patients from the Salpètrière Hospital, Paris, France, and the Ludwig Boltzmann Institute of Clinical Neurology, Vienna, Austria. The diagnosis of PSP was made by 2 neuropathologists according to the National Institute of Neurological Disorders and Stroke neuropathologic criteria for typical PSP.16,17

We reviewed the complete medical records of these 12 patients with regard to clinical presentation and response to dopaminergic therapeutic manipulations and exposure to other drugs. The data were collected by the primary investigator (K.K.). Signs were categorized into the following domains: parkinsonism (at least 2 of bradykinesia, rigidity, tremor, and gait abnormalities), other movement disorders (dystonia or myoclonus), gaze difficulties, bulbar signs, higher cortical signs, pyramidal signs, and other. Minimal criterion for improvement was improvement in at least 1 domain. Improvement or deterioration were classified as either absent, modest, or marked.

RESULTS

The mean age of the 12 patients was 64 years at onset of symptoms (range, 53-70 years). Parkinsonism and ocular signs were present in all patients, bulbar signs and higher cortical dysfunction in 11 patients, other movement disorders in 10, pyramidal signs in 2, and other signs in 1 patient (Table 1).

Of the parkinsonian signs, bradykinesia, rigidity, and gait abnormalities were present in all, while tremor was found in only 2 of 12 patients. All patients had supranuclear gaze abnormalities, with 2 having additional ocular signs, consisting of blepharospasm, which was associated in 1 of the patients with eyelid retraction. One patient developed delusional thinking while receiving a stable dose of levodopa (400 mg/d) in conjunction with a peripheral decarboxylase inhibitor for many months before the onset of the psychotic phenomena. Table 1 shows detailed information of the clinical presentation of this group of patients.

All 12 patients received 1 or several types of dopaminergic medication. Treatment was initiated, on average, 2 years after onset of symptoms. Improvement from 1 dopaminergic agent did not predict response to the other dopaminergic agents administered subsequently. Eleven received levodopa with a peripheral decarboxylase inhibitor, 6 an agonist, and 5 amantadine (Table 2). Seven experienced clinical improvement. Levodopa with a peripheral decarboxylase inhibitor produced improvement in 4 of the 11 patients. This improvement was marked in 1 patient and modest in the other 3 patients. The features improving were parkinsonism in 4 patients, and dystonia and supranuclear gaze palsy in 1 patient, respectively. The patient who experienced improvement of gaze palsy was treated with levodopa and a peripheral decarboxylase inhibitor (400 mg/d of levodopa) 2 years after onset of disease. The improvement lasted 3 months. While receiving levodopa therapy, 4 patients experienced exacerbation of parkinsonism, bulbar symptoms, and higher cortical dysfunction, and 2 experienced exacerbation of supranuclear gaze palsy.

The patient with the levodopa-induced dyskinesias was initially diagnosed as having idiopathic Parkinson disease and was started on a regimen of levodopa and a peripheral decarboxylase inhibitor 1 year after onset of symptoms. He experienced a 60% improvement in response to levodopa treatment and this remained stable for 2 years requiring dose increments in regular intervals. Postural instability and falls first occurred 2.5 years and supranuclear gaze impairment 3 years after onset. The latter consisted of vertical supranuclear gaze palsy. The dyskinesias were observed toward the end of the 2-year treatment with levodopa, were confined to the face, and lasted 2 to 4 months, resolving following discontinuation of levodopa. Subsequently, therapy with bromocriptine mesylate was initiated but without clinical response. The patient succumbed to his disease 5 years from onset of symptoms.

Dopamine agonists were given mostly in the form of bromocriptine, except for 1 patient who received piribedil at a dosage of 1250 mg/d for 6 months. This treatment produced modest improvement of parkinsonism in 1 patient and marked deterioration of the primary condition in another patient.

Five patients received amantadine and 2 demonstrated questionable improvement of parkinsonism (both patients) and neck dystonia (1 patient). Three patients complained of deterioration of their primary condition, which was modest in 2 and marked in 1. Other medications used were tricyclic antidepressants and methysergide in 3 patients, 5-hydroxytryptophan in 2, selective serotonin reuptake inhibitors, anticholinergics, and mianserin hydrochloride in 1 patient each. The tricyclic antidepressants used were amitriptyline hydrochloride in 1 patient and chlomipramine in 2 patients. The patient receiving amitriptyline experienced modest improvement of his parkinsonism.

Three patients received methysergide with modest clinical improvement in one and worsening of the underlying condition in another. The elements that improved were parkinsonism and dystonia and the worsening involved the bulbar symptoms. Adverse effects included delusions/hallucinations and gastrointestinal disturbances in 1 patient each. Two patients received 5-hydroxytryptophan with 1 experiencing modest improvement of his parkinsonism. No adverse effects were reported. Finally, 1 patient received fluoxetine hydrochloride, mianserin, and biperiden hydrochloride, respectively, without experiencing clinical improvement. The patient treated with fluoxetine experienced confusion and had to discontinue the medication.

COMMENT

Empirical treatment of clinically defined PSP has thus far been disappointing, but it has been unclear to what degree the poor response is due to inclusion of patients with degenerative diseases other than PSP. Most therapeutic attempts have been based on the neurotransmitter replacement strategy. Other approaches include botulinum toxin,18,19 electroconvulsive therapy,20,21 naloxone,22 and milacemide.23 Litvan and Chase24 reviewed 381 published cases of PSP from 1969 to 1990 with regard to their response to pharmacological intervention. With the exception of a few autopsy-confirmed patients,2528 the vast majority of patients were clinically diagnosed. Although interrater agreement for the clinical diagnosis of PSP varies from substantial to near perfect, none of the published criteria has both high sensitivity and predictive value.29 To our knowledge, this is the first report of the clinical presentation and response to pharmacological intervention in a series composed exclusively of patients with autopsy-confirmed PSP each in a detailed clinical chart maintained by a movement disorder specialist. The pathologic diagnosis of these patients was made by 2 neuropathologists and the interrater agreement and validity for the pathologic diagnosis of PSP have been found to be high.16

In this series, one third of the patients had modest improvement while receiving levodopa with a peripheral decarboxylase inhibitor. This improvement, though, was not sustained and was accompanied by adverse effects in more than half of the patients. Litvan and Chase24 suggested that when effective, therapy with levodopa altered rigidity and gait impairment. Nieforth and Golbe30 reported that 78 of 83 patients clinically diagnosed as having PSP were tried on a regimen of levodopa (usually in the form of Sinemet) and 54% experienced mild to moderate improvement on the basis of clinical impression. In their series, no other manipulation of the cholinergic, serotonergic, or adrenergic system was successful in ameliorating the debilitating features of the disease. On the other hand, adverse effects were frequent and severe, making the risk-benefit ratio unfavorable for continuation of treatment even in a disease as refractory to medical therapy as PSP. However, the lack of response to dopaminergic stimulation, particularly in the form of levodopa combined with a peripheral decarboxylase inhibitor, helps establish the diagnosis of nonidiopathic Parkinson disease parkinsonism.

A single patient with marked improvement of parkinsonism receiving levodopa-carbidopa developed dyskinesia as a result of treatment. Although dyskinesias, not attributable to medication, can rarely be part of the clinical presentation of PSP,31 drug-induced dyskinesias are unusual in parkinsonian syndromes other than idiopathic Parkinson disease. Because our patients received levodopa-carbidopa for prolonged periods, the general absence of dyskinesias suggests a fundamental difference in the dopaminergic lesions in PSP and Parkinson disease. The fact that the single patient with dyskinesia also showed improvement in his parkinsonian features following dopaminergic therapy, however, suggests a direct link between antiparkinsonian efficacy and dyskinesia, even in nonidiopathic Parkinson disease cases of parkinsonism.

All the studies assessing the response to pharmacological intervention in patients with PSP have been retrospective reviews using clinical, at times not validated, criteria for diagnosing PSP. There have been no validated, standardized scales to quantify drug response for this disease and there has been lack of consideration of the placebo effect. Our study, although based on retrospective review as well, confirms previous reports and adds the rigor of autopsy-proven diagnosis in patients uniformly exposed to dopaminergic agents.

Future strategies to treat PSP will require larger and prospective studies, with random assignment to treatment and use of appropriate controls. Because PSP is a relatively infrequent disease, multicenter trials may be necessary. Since open-label single neurotransmitter replacement strategies have already failed to produce marked or persistent symptom relief, use of drug combinations to simultaneously address affected systems interacting with each other, or disease modification strategies, such as free radical scavengers or trophic factors, are potential candidate treatments.

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Article Information

Accepted for publication January 13, 1998.

Corresponding author: Katie Kompoliti, MD, Department of Neurological Sciences, Rush-Presbyterian-St Luke's Medical Center, 1725 W Harrison St, Suite 1106, Chicago, IL 60612 (e-mail: kkompoli@rpslmc.edu).

References
1.
Levy  RRuberg  MHerrero  MT  et al.  Alterations of GABAergic neurons in the basal ganglia of patients with progressive supranuclear palsy: an in situ hybridization study of GAD67 messenger RNA. Neurology. 1995;45127- 134Article
2.
Agid  YJavoy-Agid  FRuberg  M  et al.  Progressive supranuclear palsy: anatomoclinical and biochemical considerations. Adv Neurol. 1987;45191- 206
3.
Neophytides  ALieberman  ANGoldstein  M  et al.  The use of lisuride, a potent dopamine and serotonin agonist, in the treatment of progressive supranuclear palsy. J Neurol Neurosurg Psychiatry. 1982;45261- 263Article
4.
Rafal  RDGrimm  RJ Progressive supranuclear palsy: functional analysis of the response to methysergide and antiparkinsonian agents. Neurology. 1981;311507- 1518Article
5.
Jankovic  J Controlled trial of pergolide mesylate in Parkinson's disease and progressive supranuclear palsy. Neurology. 1983;33505- 507Article
6.
Haldeman  SGoldman  JWHyde  JPribram  HF Progressive supranuclear palsy, computed tomography, and response to antiparkinsonian drugs. Neurology. 1981;31442- 445Article
7.
Kertzman  CRobinson  DLLitvan  I Effects of physostigmine on spatial attention in patients with progressive supranuclear palsy. Arch Neurol. 1990;471346- 1350Article
8.
Blin  JMazetti  PMazoyer  B  et al.  Does the enhancement of cholinergic neurotransmission influence brain glucose kinetics and clinical symptomatology in progressive supranuclear palsy? Brain. 1995;1181485- 1495Article
9.
Litvan  IBlesa  RClark  K  et al.  Pharmacological evaluation of the cholinergic system in progressive supranuclear palsy. Ann Neurol. 1994;3655- 61Article
10.
Litvan  I Cholinergic approaches to the treatment of progressive supranuclear palsy. J Neural Transm Suppl. 1994;42275- 281
11.
Litvan  IGomez  CAtack  JR  et al.  Physostigmine treatment of progressive supranuclear palsy. Ann Neurol. 1989;26404- 407Article
12.
Foster  NLAldrich  MSBluemlein  LWhite  RFBerent  S Failure of cholinergic agonist RS-86 to improve cognition and movement in PSP despite effects on sleep. Neurology. 1989;39257- 261Article
13.
Newman  GC Treatment of progressive supranuclear palsy with tricyclic antidepressants. Neurology. 1985;351189- 1193Article
14.
Schneider  LSGleason  RPChui  HC Progressive supranuclear palsy with agitation: response to trazodone but not to thiothixine or carbamazepine. J Geriatr Psychiatry Neurol. 1989;2109- 1125Article
15.
Ghika  JTennis  MHoffman  ESchoenfeld  DGrowdon  J Idazoxan treatment in progressive supranuclear palsy. Neurology. 1991;41986- 991Article
16.
Litvan  IHauw  JJBartko  JJ  et al.  Validity and reliability of the preliminary NINDS neuropathologic criteria for progressive supranuclear palsy and related disorders. J Neuropathol Exp Neurol. 1996;5597- 105Article
17.
Hauw  JJDaniel  SEDickson  D  et al.  Preliminary NINDS neuropathologic criteria for Steele-Richardson-Olszewski syndrome (progressive supranuclear palsy). Neurology. 1994;442015- 2019Article
18.
Polo  KBJabbari  B Botulinum toxin-A improves the rigidity of progressive supranuclear palsy. Ann Neurol. 1994;35237- 239Article
19.
Lepore  VDefazio  GAcquistapace  D  et al.  Botulinum A toxin for the so-called apraxia of lid opening. Mov Disord. 1995;10525- 526Article
20.
Barclay  CLDuff  JSandor  PLang  AE Limited usefulness of electroconvulsive therapy in progressive supranuclear palsy. Neurology. 1996;461284- 1286Article
21.
Hauser  RATrehan  R Initial experience with electroconvulsive therapy for progressive supranuclear palsy. Mov Disord. 1994;9467- 469Article
22.
Sandyk  RIacono  RP Naloxone ameliorates presyncopal sensations in progressive supranuclear palsy. Int J Neurosci. 1987;3589- 90Article
23.
Gordon  MFDiaz-Olivo  RHunt  ALFahn  S Therapeutic trial of milacemide in patients with myoclonus and other intractable movement disorders. Mov Disord. 1993;8484- 488Article
24.
Litvan  IChase  TN Traditional and experimental therapeutic approaches. Litvan  IAgid  YedsProgressive Supranuclear Palsy Clinical and Research Approaches. New York, NY Oxford University Press Inc1992;254- 269
25.
Bugiani  OMancardi  GLBrusa  AEderli  A The fine structure of subcortical neurofibrillary tangles in progressive supranuclear palsy. Acta Neuropathol (Berl). 1979;45147- 152Article
26.
Jellinger  K Progressive supranuclear palsy (subcortical argyrophilic dystrophy). Acta Neuropathol (Berl). 1971;19347- 352Article
27.
Jellinger  KRiederer  PTomonaga  M Progressive supranuclear palsy: clinico-pathological and biochemical studies. J Neural Transm Suppl. 1980;(suppl 16)111- 128
28.
Kish  SJChang  LJMirchandani  LShannak  KHornykiewicz  O Progressive supranuclear palsy: relationship between extrapyramidal disturbances, dementia, and brain neurotransmitter markers. Ann Neurol. 1985;18530- 536Article
29.
Litvan  IAgid  YJankovic  J  et al.  Accuracy of clinical criteria for the diagnosis of progressive supranuclear palsy (Steele-Richardson-Olszewski syndrome). Neurology. 1996;46922- 930Article
30.
Nieforth  KAGolbe  LI Retrospective study of drug response in 87 patients with progressive supranuclear palsy. Clin Neuropharmacol. 1993;16338- 346Article
31.
Collins  SJAhlskog  JEParisi  JEMaraganore  DM Progressive supranuclear palsy: neuropathologically based diagnostic clinical criteria. J Neurol Neurosurg Psychiatry. 1995;58167- 173Article
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