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
drug treatment in progressive supranuclear palsy have
not evaluated autopsy-confirmed cases.
Objective: To evaluate pharmacological treatment re-
sponses 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 supra-
nuclear palsy diagnosed using the National Institute of Neu-
rological Disorders and Stroke pathologic criteria. For each
drug class, exposure, global positive response, and specific
positive response (parkinsonism, other movement disor-
ders, 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 an-
ticholinergics and selective serotonin inhibitors (1 pa-
tient). Positive clinical response was detected in 7 of the
patients receiving dopaminergic drugs and in 1 patient
each receiving tricyclics, methysergide, and 5-hydro-
xytryptophan, respectively. None of the patients re-
sponded markedly however, and there was no persis-
tent beneficial effect. Use of dopaminergic drugs most
frequently improved parkinsonian features, but dis-
abling 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 se-
ries of patients with autopsy-confirmed with progres-
sive supranuclear palsy.
Arch Neurol. 1998;55:1099-1102

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).
P
ROGRESSIVE supranuclear
palsy (PSP) is a neurodegen-
erative disease character-
ized by parkinsonism with
prominent axial involve-
ment and postural reflex abnormality, bul-
bar symptoms, supranuclear ophthal-
moplegia, and higher cortical dysfunction.
Dysfunction of multiple brain systems has
complicated attempts to treat the dis-
ease. In PSP there is involvement of the
dopaminergic, cholinergic, GABAergic
(g-aminobutyric acid), and to a lesser de-
gree of the serotonergic and noradrener-
gic systems.1,2 Pharmacological therapy
has focused on the manipulation of the
central dopaminergic,3-6 cholinergic,7-12
serotonergic,3,4,13,14 and more recently, nor-
adrenergic systems.15 The clinical over-
lap of PSP with other neurodegenerative
syndromes is significant, making conclu-
sions regarding medication responses ten-
tative. To identify putatively effective phar-
macotherapies, we assessed clinical
response and detailed clinical records
in a series of patients with autopsy-
confirmed PSP assessed by specialists of
movement disorder.
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, pyrami-
dal signs in 2, and other signs in 1 patient
(Table 1).
Of the parkinsonian signs, bradyki-
nesia, rigidity, and gait abnormalities were
present in all, while tremor was found in
only 2 of 12 patients. All patients had su-
pranuclear gaze abnormalities, with 2 hav-
ing additional ocular signs, consisting of
blepharospasm, which was associated in
1 of the patients with eyelid retraction. One
patient developed delusional thinking

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 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 Salpètrière 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)
Dystonia 10
other. Minimal criterion for improvement was im-
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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 Table 2. Exposure to Medications and Specific Areas of Improvement*
Duration of Improvement Parkinsonism
Dose, mg Therapy, mo
Medicine N (Range)† (Range)† + ++ + ++
Levodopa 11 500 (120-1200) 30 (3-60) 3 1
Bromocriptine 6 15 (7.5-50) 12 (1-36) 1 ...
Amantadine hydrochloride 5 80 (50-200) 24 (6-60) 2 ...
TCAs 3 75 4 (1-6) 1 ...
Methysergide maleate 3 7 (6-8) 3 (2-6) 1 ...
5-Hydroxytryptophan 2 225 (150-300) 13 (2-24) 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
included delusions/hallucinations and gastrointestinal
disturbances in 1 patient each. Two patients received 5-
hydroxytryptophan with 1 experiencing modest improve-
ment of his parkinsonism. No adverse effects were
reported. Finally, 1 patient received fluoxetine hydro-
chloride, mianserin, and biperiden hydrochloride, re-
spectively, without experiencing clinical improvement.
The patient treated with fluoxetine experienced confu-
sion 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 de-
gree the poor response is due to inclusion of patients with
degenerative diseases other than PSP. Most therapeutic
attempts have been based on the neurotransmitter re-
placement strategy. Other approaches include botuli-
num toxin,18,19 electroconvulsive therapy,20,21 nalox-
one,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,25-28
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 pre-
dictive value.29 To our knowledge, this is the first report
of the clinical presentation and response to pharmaco-
logical intervention in a series composed exclusively of
patients with autopsy-confirmed PSP each in a detailed
clinical chart maintained by a movement disorder spe-
cialist. 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 periph-
eral decarboxylase inhibitor. This improvement, though,
was not sustained and was accompanied by adverse ef-
fects in more than half of the patients. Litvan and Chase24
suggested that when effective, therapy with levodopa al-
tered rigidity and gait impairment. Nieforth and Golbe30
reported that 78 of 83 patients clinically diagnosed as hav-
ing PSP were tried on a regimen of levodopa (usually in
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Dystonia Gaze
+ + Adverse Effects
3 1 1 1 OH (4), GI disturbances (1), dyskinesias (1)
1 ... ... ... OH (3), GI disturbances (2)
2‡ ... 1‡ ... OH (1), delusions and hallucinations (1)
1 ... ... ... OH (1)
1 ... 1 ... OH (1), delusions and hallucinations (1)
1 ... ... ... ...
the form of Sinemet) and 54% experienced mild to mod-
erate improvement on the basis of clinical impression.
In their series, no other manipulation of the choliner-
gic, serotonergic, or adrenergic system was successful in
ameliorating the debilitating features of the disease. On
the other hand, adverse effects were frequent and se-
vere, making the risk-benefit ratio unfavorable for con-
tinuation 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 par-
kinsonism receiving levodopa-carbidopa developed dys-
kinesia as a result of treatment. Although dyskinesias, not
attributable to medication, can rarely be part of the clini-
cal presentation of PSP,31 drug-induced dyskinesias are
unusual in parkinsonian syndromes other than idio-
pathic Parkinson disease. Because our patients received
levodopa-carbidopa for prolonged periods, the general
absence of dyskinesias suggests a fundamental differ-
ence 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 di-
rect link between antiparkinsonian efficacy and dyski-
nesia, even in nonidiopathic Parkinson disease cases of
parkinsonism.
All the studies assessing the response to pharmaco-
logical intervention in patients with PSP have been ret-
rospective reviews using clinical, at times not validated,
criteria for diagnosing PSP. There have been no vali-
dated, 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 retro-
spective review as well, confirms previous reports and
adds the rigor of autopsy-proven diagnosis in patients uni-
formly exposed to dopaminergic agents.
Future strategies to treat PSP will require larger and
prospective studies, with random assignment to treat-
ment and use of appropriate controls. Because PSP is a
relatively infrequent disease, multicenter trials may be
necessary. Since open-label single neurotransmitter re-
placement 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 poten-
tial candidate treatments.
Accepted for publication January 13, 1998.
Corresponding author: Katie Kompoliti, MD, Depart-
ment of Neurological Sciences, Rush-Presbyterian-St Luke’s
Medical Center, 1725 W Harrison St, Suite 1106, Chicago,
IL 60612 (e-mail: kkompoli@rpslmc.edu).
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