REVIEW ARTICLE

Progressive Supranuclear Palsy

A Current Review
Michael Lubarsky, MD,* and Jorge L. Juncos, MD†

Background: Progressive supranuclear palsy (PSP) is the second

most common cause of parkinsonism after Parkinson’s disease (PD).
A 68-year-old woman presents with a 1-year progression of
slowness, unexplained falls, dysarthria, and 8 months of
intermittent dysphagia. The family is also concerned with the
The classic syndrome of PSP is widely recognized by neurologists
woman’s apathy at her plight.
as a combination of down gaze palsy with progressive rigidity and
The above history of bradykinesia followed in short
imbalance leading to falls. At the same time, few clinicians are
order by unexplained falls is highly suggestive of a neurode-
proficient at treating PSP and recognizing the nonclassic presenta-
generative condition termed progressive supranuclear palsy
tions of this debilitating disorder often resulting in delays in diag-
(PSP). It is an increasingly recognized akinetic-rigid syn-
nosis and misguided treatment.
drome with features that may initially mimic those of idio-
Review Summary: Over the last decade many lines of investigation
pathic Parkinson’s disease (PD). After PD, PSP is the most
have helped refine PSP at the clinical, neuroimaging, pharmacologic
common form of parkinsonism with a prevalence of 10% of
and molecular levels. It is the purpose of this literature review to
that of PD.1 It was first formally described by Steele, Rich-
help clinicians identify PSP earlier in its course, to better understand
ardson, and Olszewski in 1964,2 but there had been earlier
its pathophysiology, and to provide a more focused, symptom-based
descriptions of similar cases in the literature including one by
treatment approach. Eighty-two peer-reviewed articles on the topic
Charles Dickens in his novel The Lazy Tour of Two Idle
of PSP and other neurodegenerative disorders have been reviewed.
Apprentices, as reported by Larner.3,4
Conclusion: It is clear that PSP continues to be an under-recognized
disorder with multilevel involvement of the neuraxis that helps
differentiate it from other akinetic rigid syndromes such as PD. A
greater appreciation of its atypical presentations, more attention to
its neurobehavioral signs and better imaging techniques are some of
The clinical hallmarks of progressive
the advances that will help facilitate earlier detection, which may supranuclear palsyare vertical gaze palsy,
reduce morbidity by helping anticipate early falls and minimizing
unnecessary diagnostic procedures. Surgical approaches to PSP have pseudobulbar palsy, axial rigidity, and
been ineffective so far. Carefully targeted symptomatic treatment cognitive impairment.
with drugs and other therapies is available and effective at reducing
morbidity and improving quality of life.
Key Words: progressive supranuclear palsy, Parkinson’s disease,
The clinical hallmarks of PSP are vertical gaze palsy,
neurodegeneration, gaze palsy, fall, apathy
pseudobulbar palsy, axial rigidity, and cognitive impair-
(The Neurologist 2008;14: 79 – 88) ment.2 Since 1964, these criteria were expanded to include
falls within the first year of illness, and more specifically,
supranuclear gaze palsy. In the last decade, there have been
further refinements at the clinical, neuroimaging, pharmaco-
logic, and molecular levels. The goal of this review is to
outline this progress and to point out how this knowledge and
From the *Emory University School of Medicine, and †Movement Disorders clinical experience has paved the way to better management
Program, Department of Neurology, Emory University School of Med- of patients. The information should allow clinicians to iden-
icine, Atlanta, Georgia.
Supported in part by Emory University’s American Parkinson’s Disease
tify PSP earlier in its course to better anticipate and prevent
Association Center of Excellence in Parkinson’s Disease Research, and falls, aspiration, unnecessary testing, and misguided therapy.
by grant 1 R01 AG024040-01A1 (to J.L.J.).
Reprints: Jorge L. Juncos, MD, Movement Disorders Program, Emory
University School of Medicine, 1841 Clifton Rd., Atlanta, GA 30329. METHODS
E-mail: jjuncos@emory.edu.
Copyright © 2008 by Lippincott Williams & Wilkins The databases MEDLINE and MDConsult were
ISSN: 1074-7931/08/1402-0079 searched from January 1996 through January 2007 using the
DOI: 10.1097/NRL.0b013e31815cffc9 search engine Ovid. We requested all English-language arti-

The Neurologist • Volume 14, Number 2, March 2008 79

Lubarsky and Juncos
cles with the term progressive supranuclear palsy. The result-
ing reference lists were retrieved and searched for additional
relevant sources. We have included material from articles
that, in the opinion of the authors, are pivotal to our current
understanding of PSP, or relevant to its clinical management.
The clinical utility of these reports was weighed against the
25-year experience of one of the authors (J.L.J.) in managing
these patients.
Unlike typical Parkinson’s disease, falls begin
within the first year and by year 3 they are
common unless precautions are taken to
prevent them.
CLASSIC PRESENTATIONS, SIGNS,
AND PROGNOSIS
Progressive supranuclear palsy presents insidiously af-
ter age 40 with an average age of onset of 63. The symptoms
consist of bradykinesia, decreased fine motor skills, and
hypophonia. In the absence of tremor, this condition is easily
missed until the more specific symptoms of gait and visual
problems begin. Gait difficulties progress at a faster rate than
in PD. Slow walking evolves into lurching steps and a
tendency to topple forward or backward.2,3 Unlike typical PD,
falls begin within the first year and by year 3 they are common
unless precautions are taken to prevent them. The evolution of
the above features can be quite variable and thus difficult to
differentiate early from other forms of parkinsonism (Table 1).
Presentations can range from unexplained falls, to visual (eg,
blurred vision, diplopia), cognitive (eg, apathy, gradual loss of
executive functions and word fluency), or parkinsonian symp-
toms with little or no tremor.
General Appearance
Much like patients with PD, PSP patients have a ten-
dency to drop the shoulders, flex at the waist, and not swing
their arms while walking. Compared with PD, PSP patients
have more axial than appendicular rigidity, more dystonia
and a more symmetric examination. Retrocollis is more
TABLE 1. Typical Diagnostic Criteria for Parkinsonian Disorders
PD PSP
Typical Diagnostic Bradykinesia, Progressive course, Chronic Progressive Early behavioral
Criteria11 Tremor, Rigidity, Onset after age course. Akinesia,
Asymmetric 40, Supranuclear Rigidity, Limb
onset Ophthalmoplegia, Apraxia. Cortical
Early onset falls, sensory loss. Focal Progressive non
Symmetric Axial myoclonus.
Rigidity and Dementia—can be
Bradykinesia presenting feature. of memory.
PD indicates Parkinson’s disease; PSP, progressive supranuclear palsy; CBD, corticobasal degeneration; FTD, frontotemporal degeneration; MSA, multiple system atrophy; LBD,
Lewy Body Disease.
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The Neurologist • Volume 14, Number 2, March 2008
common than the antecollis seen in PD and can be accom-
panied by scoliosis of the lower spine. In later stages, severe
dystonic deformities of the distal limbs can also appear.
Cogwheel rigidity is present in both conditions.
Early ocular symptoms include blurred vision (due to
convergence insufficiency, slow saccades, and probably other
factors), photophobia (due to decreased blinking), and invol-
untary eyelid closure due to blepharospasm (Fig. 2). Eyelid
apraxia, or impaired voluntary opening of the eyelids with
otherwise preserved eyelid movements, develops later.5
Weak voice with pseudobulbar features can develop early;
swallowing difficulties develop later.
The cranial nerve examination reveals facial hypo-
mimia, a decreased blink rate (0 – 4/min compared with a
normal rate of 15/min), lid retraction, and prominent nasola-
bial folds that lead to the classic deeply furrowed appearance
of PSP (Fig. 1). In short, the facial hypomimia of PD has less
of a fixed stare than PSP. In PSP, the voice is often reduced
to a soft, slurring growl, which transforms into a pseudobul-
bar speech over time.3 Additional morbidity results from
sialorrhea and dysphagia, which are compounded by “messy”
eating owing to an inability to look down at the plate of food
due to impaired down gaze.3,6
Down gaze is affected before up gaze, whereas
lateral eye movements are usually preserved.
Vertical eye movements are reduced well beyond that
seen in aging. Down gaze is affected before up gaze, whereas
lateral eye movements are usually preserved. However, lat-
eral saccades are slowed in relation to neck movements due to
a relative dissociation in the oculocephalic reflex. Saccadic
velocity is progressively reduced so that, in more advanced
cases, the eyes tend to follow the head as it turns. A preserved
vestibulo-ocular reflex rounds up the “supranuclear” charac-
ter of the eye movements in PSP. Compared with PD
patients and controls, PSP patients exhibit slowed voluntary
vertical saccades and frequent small, paired, horizontal sac-
cadic intrusions (eg, square wave jerks) during fixation.7,8 In
comparison, patients with corticobasal degeneration (CBD),
CBD FTD12,13 MSA LBD
Autonomic Dysfunction Progressive cognitive
problems and or Urinary decline prior to
personality changes, incontinence, motor symptoms,
Semantic Dementia, Parkinsonism with Parkinsonism,
poor response to Hallucinations,
fluent aphasia. levodopa, Cerebellar Delusions,
Relative preservation dysfunction Syncope, Falls
13
predominant in 20%.
© 2008 Lippincott Williams & Wilkins
The Neurologist • Volume 14, Number 2, March 2008
FIGURE 1. Patient with early PSP attempting to look up with
overflow activation of perioral and tongue musculature gen-
erated in the process. The bruise below the left orbit is the
result of a recent a fall.
FIGURE 2. Patient with advanced PSP attempting to over-
come the blepharospasm with her finger. She has lost verti-
cal eye movement and has chronic tearing due to corneal
irritation from decreased blinking.
another degenerative hypokinetic rigid syndrome, have pre-
served saccadic velocity and increased saccadic latency ipsi-
lateral to the apraxic side.9
Motor symptoms include slowness, stiffness, dystonic
pain (eg, neck and back), clumsiness of the hands, loss of fine
and later gross motor dexterity, and a tendency to trip easily.
The motor examination reveals axial hypertonia that is out of
proportion to limb tone, which may be normal in contrast to
PD patients who have more limb rigidity with cogwheeling.
Tremor can be present, but is much less frequent (10%–20%
in the authors’ experience) and less prominent than it is in
PD. Limb-kinetic apraxia, or difficulty performing simple
gestures and fine finger movements, although most often
associated with CBD (71%), also occurs in PSP (36%).10
Also present in PSP is ideomotor apraxia in which patients
exhibit difficulty sequencing and executing familiar tasks.5,10
© 2008 Lippincott Williams & Wilkins
Progressive Supranuclear Palsy
Gait disturbances in PSP vary from patient to patient
but often include “gait apraxia,” which is particularly impor-
tant because it has been directly linked to falls.5 For instance,
while turning the patient may attempt to pivot in one leg
while generating the angular momentum with the other. In the
process, he or she appears to “forget” to move the pivot leg
leading to an awkward stance at the end of the turn that
compounds the intrinsic imbalance. Once they start falling,
they are slow to engage the righting reflexes making patients
look as if they were “toppling like a tree.” PSP patients can
also develop ataxia due to involvement of dentate gyrus and
cerebellum in the pathologic process. Over time, most pa-
tients develop corticospinal signs with proximal leg weakness
(also due to deconditioning), spasticity, increased reflexes,
and extensor plantar responses. This multiprong assault on
balance virtually warrants that most patients will end up
wheel chair bound within 4 to 7 years.
Despite these striking clinical features, in PSP there is
a mean delay of 4 to 5 years from the onset of symptoms to
diagnosis.3,11
DIFFERENTIAL DIAGNOSIS AND
ATYPICAL PRESENTATIONS
The clinical diagnosis of PSP is based on the following
validated criteria:
a. Progressive akinetic-rigid syndrome starting after age 40.
b. Progressive vertical supranuclear gaze palsy.
c. Slowing of vertical saccades.
d. Progressive and prominent postural instability with falls in
the first year of illness.
To meet criteria for diagnosis a subject must meet
criteria a and b, or a and c.
Additional features supportive of the clinical diagnosis
are axial rigidity out of proportion to appendicular rigidity,
symmetric onset of symptoms, paucity of tremor, and relative
lack of response to levodopa therapy. Exclusion criteria for
the diagnosis include evidence of Alzheimer disease or de-
mentia with Lewy bodies, evidence of lateralized CBD-type
cognitive features such as aphasia, apraxia, sensory neglect,
or alien limb. Also exclusionary are unilateral pyramidal
features, cerebellar dysmetria, autonomic failure, history
of repeated strokes, and treatment in the last 12 months
with dopamine blocking agents. Also important is making
sure the signs and symptoms cannot be explained by
structural changes in the brain (eg, large ventricles, tumor,
lobar atrophy) or by other conditions in Table 1. Treatable
conditions that may mimic PSP include NPH,12 B-cell
lymphoma associated paraneoplastic syndrome, and Whipple
disease.8,13,14
The apparent clarity of these criteria notwithstanding,
in practice the differentiation of these conditions can be
difficult. In a 2004 study by Williams,15 only 54% of 103
pathologically confirmed cases of PSP exhibited the classic
signs described by Richardson in 1964.2 This typical PSP
group had a mean duration of disease of 5.9 years with a
slight male preponderance (64%). In the same study, 32% of
patients exhibited features atypical of PSP such as asymmet-
81
Lubarsky and Juncos
ric onset, rest tremor, and a moderate initial response to
levodopa. This group had no gender differences and had
mean disease duration of 9.1 year.
In light of the above, it should not be surprising that
these clinical diagnoses are far from perfect. In 2003 Dickson
et al examined the brains of 180 cases diagnosed in life with
PSP.16 At autopsy, 137 had PSP and 43 had other diagnoses.
Multiple system atrophy (MSA), Dementia with Lewy Bod-
ies (LBD) and CBD comprised 70% of misdiagnosed pa-
tients. These cases included many with atypical features of
PSP such as tremor and asymmetric findings.16 In a 2003
study by Nath, among 187 patients ultimately diagnosed
with PSP at autopsy, 42 (29%) had received the diagnosis
of parkinsonism, 21% were thought to have a nonspecific
balance disorder, 10% stroke, and 7% depression.11 Of
those with visual impairment who had been referred to an
ophthalmologist (8%), none was diagnosed with PSP at
that visit. Nonetheless, in recent years, the diagnostic
accuracy of PSP has been dramatically improved to a
specificity of 95% to 100% when applying the above
clinical criteria using post mortem pathology as the gold
standard.17,18
SPECIAL SIGNS AND SYMPTOMS OF PSP
Clinical refinements in the original description of PSP
include the “applause sign,” a test of impaired motor control
leading to perseveration due to frontal dysfunction. It may
differentiate PSP from frontotemporal dementia (FTD) and
PD.19 In this test, the patient is asked to clap 3 times as
quickly as possible. A normal performance consists of 3
claps (score ⫽ 3). Any score below 3 is abnormal, that is
clapping 4 times (score ⫽ 2), 5 to 10 times (score ⫽ 1), or
more (score ⫽ 0). In this report, for instance, none of 39
normal controls, 24 FTD patients, and 24 patients with PD
had scores below 3. In contrast, 30 of 42 patients with PSP
had scores below 3, suggesting that the applause sign may be
specific and moderately sensitive (71%) in PSP.
In contrast, other signs of neurodegeneration, such as
the glabelar (GR) and palmomental reflexes (PMR) were
found to be nonspecific and thus not helpful in sorting out
neurodegenerative disorders.18 For instance, in a study by
Jankovic et al, the GR was present in 52.5% of healthy
controls, 92% of patients with PSP, 80% of patients with
PD, and 86% of patients with MSA. At the same time, the
PMR was present only in 25% of patients with PSP.20
Patients with progressive supranuclear palsy
develop frontal cognitive impairment.
NEUROBEHAVIORAL FEATURES
Patients with PSP develop frontal cognitive impairment
characterized by the following: slowness of thinking and
response time, impaired attention, diminished verbal fluency,
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The Neurologist • Volume 14, Number 2, March 2008
and difficulty shifting cognitive sets. Also affected are work-
ing memory, concept formation, planning, and execution.21,22
Involvement of these domains is thought to be due to the loss
of connections between the basal ganglia and frontal lobes.
Although the timelines for cognitive and motor decline do not
necessarily correlate, a 2000 study by Soliveri demonstrated
that patients with PSP undergo a faster cognitive decline than
those with PD or MSA.22
Apathy seems to predominate over other
neurobehavioral abnormalities in progressive
supranuclear palsy.
Apathy seems to predominate over other neurobe-
havioral abnormalities in PSP when compared with other
neurodegenerative disorders.23 Because apathy shares
some features with depression it is often misdiagnosed as
such; many clinicians do not recognize the difference
between the two.23–25 Using the apathy subscale of the
Neuropsychiatric Inventory (NPI), Levy and Cummings
reported that most PSP patients score high in items related
to the loss of interest, motivation, decreased spontaneity,
and lack of enthusiasm, and having normal scores in items
related to sadness.24,25 In 1996 Litvan et al, used the NPI
to compare 22 PSP patients to 50 Alzheimer disease (AD)
patients.23 Ninety-one percent of PSP patients suffered
from moderate to severe apathy. Disinhibition occurred in
36% and depression in only 9%. Dysphoria was mild,
presenting as a sad affect without neurovegetative symp-
toms. Only 1 of 22 patients had dysphoria without the
apathy. One of 22 patients exhibited agitation. In compar-
ison, apathy occurred in 72% of Alzheimer patients, and
agitation was the second most common finding (60%). In
this study demented patients with high apathy and low
agitation and anxiety scores were more likely to have PSP
than AD (positive predictive value of 85%). It is important
to note that apathy and disinhibition did not correlate with
duration of motor symptoms. The authors inferred that, in
PSP, dysfunction in different frontal-subcortical-thalamic
circuits does not proceed in parallel.23
In a subsequent study, Levy et al compared the above
group of PSP patients to 30 AD patients, 28 FTD patients,
34 Huntington disease (HD) patients and 40 PD patients.
They concluded that the presence of depression does not
predict the presence of apathy and vice versa. In this
sample, apathy correlated with disinhibition, lower cogni-
tive function and aberrant motor behaviors, but not with
depression.25 Depression, on the other hand, correlated
with anxiety, agitation, irritability, and hallucinations. Ap-
athy and depression co-occured with statistical signifi-
cance only in the PD subgroup, in which only 5% of PD
patients had apathy without depression, whereas 77% of
PSP patients had apathy without depression. Unlike the PD
© 2008 Lippincott Williams & Wilkins
The Neurologist • Volume 14, Number 2, March 2008
and AD patients, in PSP and HD, there was no correlation
between apathy and lower cognition.
Median survival is reported to be 6 years from
symptom onset, with few patients surviving 15
years or more.
SYMPTOM PROGRESSION AND PROGNOSIS
In a 2003 report from the United Kingdom, poor mobility
or bradykinesia was the presenting symptom in 69% of patients,
cognitive problems in 15%, and bulbar dysfunction in 14%.11 In
contrast, the time from onset of symptoms to first fall (12
months), and the time to develop severe gait disturbances (48
months) seem to be fairly consistent.17 In this report diplopia
occurred in 10% of patients whereas only 1% of patients re-
ported symptoms attributable to eye movement abnormalities
detectable at the bedside.11 Changes in speech led to unintelli-
gible speech by 6 years, and dysphagia severe enough to require
a feeding tube by 7 years. Bulbar problems were closely asso-
ciated with early mortality, with early falls being a distant
second indicator of poor prognosis.11 In most studies, median
survival is reported to be 6 years from symptom onset, with few
patients surviving 15 years or more.16,17 Finally, prognosis and
survival of individual patients could be estimated using the PSP
rating scale (PSPRS) recently described by Golbe et al26 PSPRS
tool takes about 10 minutes to administer and provides survival
estimates for specific PSPRS score ranges.
EPIDEMIOLOGY AND GENETICS
The prevalence of PSP is age-dependent and estimated at
6% to 10% that of PD, or 6 to 7 cases per 100,000.1,3,27–34 It is
typically a sporadic disorder with peak onset at age 63 and no
reported cases before the age of 40. In contrast, the peak age of
onset of PD is 59 to 60 years and cases with debut before age 40
have been well documented. There are a few familial cases of
PSP with an apparent autosomal dominant inheritance and
reduced penetrance.35 Nonfamilial clusters due to environmental
factors have also been identified. In a study from the island of
Guadeloupe, where the incidence of PSP is 14/100,000,36 there
seemed to be an association between long-term consumption of
certain tropical fruits and herbal teas containing tetrahydroiso-
quinolones (TIQs), and the development of PSP or atypical
parkinsonism. Champy et al were able to develop an experimen-
tal animal model of the neuropathology in PSP using IV injec-
tions of the TIQ annocin.36 –38 Specifically, they found a dose-
dependent degeneration in nigral and striatal neurons with
parallel increases in the number of astrocytes and microglial
cells.37 Annocin is a highly lipophilic inhibitor of mitochondrial
complex I, an enzyme thought to be defective in PD and
PSP.39,40
The above and other epidemiologic discoveries of the
past few years support the theory that PSP can be influenced
by environmental factors.27 Despite this field and laboratory
© 2008 Lippincott Williams & Wilkins
Progressive Supranuclear Palsy
work, PSP has yet to be linked to any specific occupational
exposure.27,37,38 For instance, although there are case reports
of PSP associated with repeated traumatic brain injury,27 this
association has failed to reach statistical significance when
formally tested.
Studies of the genetics of PSP have focused on tau, a
microtubule-associated protein coded by a gene in chro-
mosome 17, and thought to be central to the pathogenesis
of PSP. Mutations in the MAPT gene also on chromosome
17 are associated with another tauopathy, FTD.41 The
expression of tau in region 17q21 of this chromosome is
regulated by 2 alternative splicing mechanisms resulting in
2 extended haplotypes. The inclusion or exclusion of exon
10 gives rise to the 4R repeat (or H1 haplotype), or the 3R
repeat (or H2 haplotype) isoforms of tau.35 The 2 haplo-
types are expressed about equally in normals. In PSP and
CBD, however, H1:H2 ratios have been consistently 3:1
suggesting that the H1 haplotype predisposes to, or that the
H2 protects against, PSP.3,42 In contrast, this ratio is
reversed in Senile Dementia of the Alzheimer Type
(SDAT).43 The total levels of CSF tau are highest in CBD,
intermediate in PSP and lower but still abnormally ele-
vated in SDAT compared with controls.42 The lower levels
of tau in SDAT when compared with the primary tauopa-
thies (eg, PSP and CBD) may reflect tau’s secondary role
in this illness.
DIAGNOSTIC AND FUNCTIONAL IMAGING
Although the gold standard for the diagnosis of PSP is its
neuropathology, recent studies have used imaging techniques in
an effort to refine the clinical diagnosis. Regions in PSP autopsy
brains that appear atrophic at autopsy have been imaged using
MRI (T1- and diffusion-weighted sequences) and positron emis-
sion tomography (PET). These regions include the rostral mid-
brain, pons and superior cerebellar peduncles (SCP). In 2005
Terada et al prospectively studied the MRIs of 21 patients with
PSP, 23 patients with PD, 25 patients with MSA, and 31 normal
controls.44 The average midbrain area of patients with PSP (56.0
mm2) was significantly smaller than that of PD (103.0 mm2) and
MSA patients (97.2 mm2) compared with controls (117.7 mm2).
The midbrain-pons ratio in PSP patients was significantly
smaller than that in the PD group (average 0.208), MSA group
(average 0.266), and normal control group (average 0.236).
There was no overlap of the midbrain-pons ratio between PSP
patients and the other groups.44 On the basis of these results, the
authors postulated that midbrain area of ⬍70 mm2 strongly
suggests a diagnosis of PSP (sensitivity ⫽ 100%, specificity ⫽
91.3%), whereas a ratio of midbrain tegmentum area to pons
area of ⬍0.15 (sensitivity ⫽ 100%, specificity ⫽ 100% for
PSP) excludes the diagnosis of PD and MSA. Finally, the
authors proposed a new imaging sign for PSP, the “penguin
silhouette” sign, which was present in all patients with PSP
on the midsagittal MRI (Fig. 3).
Another 2005 study by Paviour used the volume of the
SCP as a tool for diagnosing PSP with T1 weighted MRI.45 The
SCP consists mainly of efferent projections from the cerebellar
dentate nucleus, which run in the lateral wall of the fourth
ventricle and then merge into the midbrain. The study examined
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Lubarsky and Juncos The Neurologist • Volume 14, Number 2, March 2008

FIGURE 3. Penguin silhouette sign: Midsagittal MRI image of a patient with Parkinson’s disease (PD, normal), PSP
showing marked atrophy of midbrain tegmentum (arrow), and multiple-system atrophy of the Parkinson’s type (MSA-P)
showing marked atrophy of pons (arrow). The midbrain to pons ratio is always small in PSP: the shapes of the midbrain
tegmentum (bird’s head) and pons (bird’s body) on midsagittal MR images look like a lateral view of a standing penguin
with a small head and big body. Reproduced with permission from Oba H, Yagishita A, Terada H, et al. New and reliable
MRI diagnosis for progressive supranuclear palsy. Neurology. 2005;64:2050 –2055.

19 patients with clinical PSP, 10 with MSA, 12 with PD and 12
healthy controls. SCP atrophy differentiated PSP from other
neurodegenerative conditions and controls with a sensitivity of
74% and specificity of 94%. Both non-PSP cases of SCP
atrophy had a clinical diagnosis of MSA.
In a 2005 study by Eidelberg using blinded computer-
supported assessment of positron emission tomography (PET),
investigators reported glucose hypometabolism in the midline
frontal regions and in the brainstem of PSP patients.46 Decreased
metabolism was also observed in the caudate nucleus, whereas
the metabolic rate was increased in the cortical motor areas,
parietal cortex, and thalamus. In general, there was an 85%
agreement between these positive imaging findings and the
clinical diagnosis of PSP and correlation between the degree of
cortical involvement and level of clinical disability.46 Because
the medial frontal lobes and the brainstem serve as relay stations
to the reticular activating system, functional hypometabolism in
these regions may lead to the abnormalities in attention, arousal,
and sleep, which are such common problems in PSP.46 In
addition, a functional disconnect between the frontal cortex and
paralimbic structures may contribute to apathy.25 Apraxia is
seen in a smaller number of patients and may result from
disruption of other diencephalic-cortical connections.5
In addition to dopamine and acetylcholine, PET technol-
ogy has helped demonstrate involvement of other neurotrans-
mitters in PSP. In 2000, Foster et al demonstrated a reduction of
GABA receptors in the cerebral cortex, particularly the anterior
cingulate gyrus.47 In contrast, the density of GABA receptors in
the brainstem was normal.
PATHOLOGY AND PATHOPHYSIOLOGY
The pathology of PSP is characterized by widespread
neurodegeneration associated with tau protein deposition in
subcortical regions that include the substantia nigra, globus
pallidus, subthalamic nucleus, midbrain, pontine reticular
formation, dentate nucleus of the cerebellum and the superior
cerebellar peduncle (see imaging section). In PSP and other
tauopathies, the tau protein loses its affinity for microtubules
and becomes resistant to proteolysis. This results in the
accumulation of tau and the formation of neurofibrillary
tangles. High levels of these tangles along with neurophil
threads and tufted astrocytes comprise the basis for the
pathologic diagnosis of PSP (Fig. 4).21,48
Regional destruction of cholinergic premotor nuclei in
the midbrain is thought to contribute to the vertical gaze
abnormalities, convergence defects, and axial dystonia in
PSP.21,49 Affected regions include the rostral interstitial nu-
cleus of the medial longitudinal fasciculus, the nucleus of
Edinger-Westphal, the interstitial nucleus of Cajal, and the
deep layers of the superior colliculus.5,49 Similar lesions in
the pedunculopontine nucleus and lateral tegmental nucleus
are thought to be responsible for impairment of horizontal
smooth pursuit. Diencephalic and cortical regions affected in
PSP include the mediodorsal nucleus of the thalamus, the
caudate nucleus, putamen, nucleus accumbens, substantia
innominata, and nucleus basalis of Meynert (nbM) and fron-
tal cortex.21
Pathologic findings that exclude the diagnosis of PSP
include the presence of Lewy bodies, argyrophilic oligoden-
droglial inclusions, Pick bodies, diffuse spongiform changes,
or prion protein-positive amyloid plaques.48

The pathology of progressive supranuclear palsy CLINICAL MANAGEMENT

is characterized by widespread
neurodegeneration associated with tau protein
deposition in subcortical regions.
The pathophysiology of PSP remains complex and
poorly understood. It is not surprising therefore, that there is
no cure and treatment has to be tailored to selected symp-
toms. These treatments, imperfect as they are, can make a
significant difference in the quality of life of individual
patients. The negative or inconclusive results of therapeutic

84 © 2008 Lippincott Williams & Wilkins

The Neurologist • Volume 14, Number 2, March 2008 Progressive Supranuclear Palsy

FIGURE 4. A, Pathologic section from the subthalamic nucleus (STN) using a silver impregnation stain to demonstrate neurofi-
brillary tangles (arrows) in autopsy material from a case with longstanding PSP. B, Tau-immunolabeled section from the stria-
tum illustrating tau-positive tufted astrocytes (arrows). Courtesy of M. Gearing, PhD, Center for Neurodegenerative Disease,
Emory University School of Medicine.

studies conducted so far have been attributed to the fact that

TABLE 2. Symptomatic Treatment of PSP
these initiatives were driven by the availability of drugs
developed for use in other disorders, rather than a sound Symptom Supportive Measures
understanding of the pathophysiology of PSP.50 Randomized Apathy and depression Stimulants, antidepressants, individual
and properly powered controlled trials have been few due in psychotherapy, support groups,
part to the relatively small number of PSP patients compared spousal support
with other neurodegenerative conditions such as PD. Other Difficulty looking down Separate glasses for close and far
and convergence while distances (unable to use bifocals)
factors that hamper the development of new therapies include reading; diplopia Limited and temporary benefit
the myriad of symptoms to be targeted, diagnostic errors and from prism glasses
diagnostic delays.50,51 This limited therapeutic experience Encourage care givers to place items
has been previously reviewed by Lang,52 Burn,50 and at eye level
Litvan.51 These authors agree that supportive and targeted Eyelid apraxia, Botulinum toxin, eyelid crutches
blepharospasms
symptomatic therapy continues to be the best approach
Dry eyes, photophobia Artificial tears, dark glasses
(Table 2).
Dysphagia Modified food consistency and allowances.
Feeding gastrostomy in advance cases
to avoid aspiration
Dysarthria Speech therapy may help early on.
The first therapeutic step in progressive No effect in advanced cases
Communication aids, sign language
supranuclear palsy is identifying and prioritizing Sialorrhea Anticholinergics, oral/topical
(eg, oral glycopyrrolate)
target symptoms. Pseudobulbar palsy Same as above plus tricyclic antidepressants,
sertraline or dextromethorphan
Gait Instability Fall precautions, walkers (with
4 wheels and hand breaks),
physiotherapy and exercise to maintain
The first therapeutic step in PSP is identifying and fitness and elasticity
prioritizing target symptoms. For instance, dopaminomimet-
Adapted with permission from Burn DJ, Warren NM. Toward future therapies in
ics are used to target parkinsonian motor symptoms such as progressive supranuclear palsy. Mov Disord. 2005;20 (Suppl 12):S92–S98
bradykinesia and rigidity. Imbalance, dystonia, supranuclear
gaze palsy, dizziness, and speech and swallowing difficulties
generally do not respond to these agents. Similarly, cognitive
and behavioral symptoms respond poorly, or may worsen in motor symptoms in 51%,53 54%,54 and 38%55 of cases.
response to these agents. It is important to be explicit with the Unfortunately, in most instances neither the magnitude nor
patient and family about the target symptom to be addressed the duration of the responses was specified.50 In a retrospec-
with a particular therapy. This prevents confusion when a tive study, 12 patients treated with dopaminomimetics evi-
patient reports “no benefit at all,” when in reality is they are denced modest, unsustained improvement in parkinsonian
referring to symptoms not targeted by the therapy. symptoms.56 Unfortunately, more than half the patients also
experienced significant side effects including worsening of
Pharmacotherapy of Motor Symptoms parkinsonian features and postural hypotension.56 In a 2002
Between 1984 and 1993 a number of studies using study, PSP patients were shown to be less responsive to
levodopa-carbidopa in PSP demonstrated improvement in levodopa therapy (0/7) than were other patients with “parkin-

© 2008 Lippincott Williams & Wilkins 85

Lubarsky and Juncos
sonism” in which 5 of 8 experienced “some benefit.”57 In
other studies, patients with PSP treated with dopamine ago-
nists have fared comparably or worse than patients treated
with levodopa.50 The adjunctive antiparkinsonian agent, aman-
tadine, has been reported to produce a transient therapeutic
benefit in 15% of patients.58
It is our experience that the dose response is
not linear in progressive supranuclear palsy,
and the threshold levodopa dose required to
trigger any motor response is often higher than
that in Parkinson’s disease.
From this and the experience in our institution, the take
home message is that compared with PD, PSP patients derive
a limited benefit from dopaminomimetics. Nonetheless, ex-
perience dictates that in individual patients this benefit can be
clinically important. It is our experience that the dose re-
sponse is not linear in PSP, and the threshold levodopa dose
required to trigger any motor response is often higher than
that in PD. For instance, it is not unusual for PSP patients to
respond to 1 g of levodopa (in the form of carbidopa-
levodopa) even after failing to respond to 400 to 600 mg.
Even at these high doses, the responses remain modest and
short-lived (eg, 3–5 years).
Given this broad dose range and narrow therapeutic
window, it is difficult to decipher whether, in early stages, the
reported low response rates of PSP to dopaminomimetics is
due to a conservative use of levodopa (⬍600 mg/d), or to
judgments based on patients too advanced to respond to any
treatment. Even in those who do respond, it is important to
remember that, over time, dopaminomimetics may elicit re-
versible worsening of most motor and behavioral symptoms
of PSP. Time to reach this tipping point is difficult to predict
and varies across individuals. Accordingly, one of the most
difficult therapeutic decisions in the management of PSP is to
determine when to reduce or stop these agents. Postural
hypotension, worsening dystonia, rapid deterioration of mo-
tor signs, and aberrant behaviors are indicators that a patient
may be past the therapeutic tipping point. This late drug-
induced deterioration may be dose dependent, and it is im-
portant to consider this before concluding that these agents
are no longer helpful. Accordingly, a gradual de-escalation of
dopaminomimetics allows time to explore the possibility that
smaller doses may still beneficial, and avoid the possibility of
a neuroleptic-like syndrome provoked by the sudden with-
drawal of all therapy.59,60
Given the above caution, it is worth considering initi-
ating and possibly limiting dopaminomimetic treatment in
PSP to levodopa-based preparations. Unlike PD patients, PSP
patients are less likely to develop severe motor fluctuations
and dyskinesias. Similarly, the incidence of dopaminomi-
86
The Neurologist • Volume 14, Number 2, March 2008
metic-induced visual hallucinations seems to be lower in PSP
when compared with that in PD.61 These differences in the
sensitivity to drug-induced side effects may be attributed to
the more extensive nonstriatal, and thus dopamine resistant
pathology in PSP, and to the more severe presynaptic striatal
dopaminergic denervation in PD compared with PSP. The
latter leads to postsynaptic hypersensitivity and possibly
dyskinesias and hallucinations.
Beyond dopamine, GABA receptors seem to be de-
creased in the frontal cortex of PSP patients (see neuroimag-
ing above). Based on this, investigators conducted a double-
blind study in 10 PSP patients using the GABA agonist,
zolpidem. Using a cross over trial design patients received
zolpidem (5 and 10 mg), levodopa-carbidopa (25/250 mg
q.d.) and placebo.62 Zolpidem 5 mg improved voluntary
saccades and induced statistically significant improvements
in motor function as recorded in the motor subscale of the
United Parkinson’s Disease Rating Scale. Given the paucity
of clinical trails, it is obvious further work is needed to
examine the potential roles of GABA and other dopaminergic
neurotransmitters in PSP.
Pseudobulbar palsy is an important symptom of PSP
associated with high morbidity and decreased survival.15 In
patients with ALS, pseudobulbar affect has been treated
effectively with the weak NMDA antagonist, dextromethor-
phan (in combination with small doses of quinidine sulfate to
slow its metabolism).63 This combination should be avoided
in patients using other drugs metabolized by the CYP-2D6
system. In brain injury induced pseudobulbar affect, sertra-
line, and in a recent report, escitalopram and paroxetine were
found to be helpful.64 It is unknown whether these agents
help other aspects of pseudobulbar palsy such as dysarthria
and dysphagia, and there is little experience with their use in
PSP. Similarly, agents to treat spasticity in other disorders,
such as lioresal and tizanidine, have not been tested formally
in PSP. It is the authors’ impression that PSP patients are
generally more disabled by dystonic than spastic symptoms.
Drugs in these categories provide modest relief at best to
individual patients for a limited time early in the course of
their illness.
Ataxia in PSP is due to frontal, visual, cerebellar and
brainstem pathology. Like other ataxias with multifactorial
pathology, this symptom cannot be addressed directly. How-
ever, maintaining conditioning, musculature and joint elas-
ticity through exercise (even if sitting or recumbent) and
physical therapy will increase the patient’s ability to com-
pensate for the otherwise relentless balance problems.
Management of Visual Symptoms
Deficits in visual accommodation such as trouble fo-
cusing and photophobia, and symptoms associated with the
supranuclear gaze palsy, such as decreased down gaze, are
generally not responsive to therapy. Because patients with
PSP do poorly with bifocals, it is best to recommend they use
separate glasses for near and far vision. Items of interest,
including meals, should be placed as close to eye level as
possible. Diplopia can respond to prisms. The prisms are
expensive, and the prescription needs to be revised periodi-
cally to remain effective. Selective injection of botulinum
© 2008 Lippincott Williams & Wilkins
The Neurologist • Volume 14, Number 2, March 2008
toxin can ameliorate blepharospasm, apraxia of eyelid open-
ing and focal dystonic symptoms.65
Management of Cognitive and
Behavioral Symptoms
Apathy is perhaps the most common neuropsychiatric
symptom in PSP.23,25 It is often comorbid with, and difficult
to differentiate from, depression. As noted above, in PSP it is
often independent of depression and associated instead with
early frontal cognitive dysfunction.25,66 When comorbid with
depression, apathy improves modestly with antidepressants in
PSP.67 Methylphenidate (5–30 mg/d) has been shown to help
alleviate apathy in other disorders affecting frontal lobe
function.25,66,68 Anecdotal reports that agents such as this or
acetylcholinesterase inhibitors may help apathy in PSP re-
main unsubstantiated.
Based on the well-established cholinergic deficits ob-
served in PD, acetycholinesterase inhibitors have been used in
the treatment of dementia and other symptoms in PSP. In a 1999
double– blind, placebo-controlled trial with physostigmine,
visuospatial attention improved in 7 of 8 patients but had no
acute effect on motor, extraocular or pseudobulbar symptoms in
8 patient with PSP.69 In contrast, apathy was not examined. In
2001 2 studies tested this approach with donepezil, another
acetylcholinesterase inhibitor, again with negative results.70,71 It
is speculated that the limited response to these agents may be
due to the severe destruction of presynaptic acetylcholine ele-
ments that limit acetylcholine release in PSP.21 This view is not
supported by a report using the nonselective m1/m2 muscarinic
agonist, RS-86. It too had no effect on PSP symptoms.21,50,72
The use of antipsychotics for the treatment of hallucinations and
other psychotic symptoms in PSP has not been examined, and it
is probably fraught with the same risks and limitations of
antipsychotic drugs in the elderly.73
Surgical Management
Based on a limited and unpublished experience in 3
PSP patients treated with Deep Brain Stimulation (DBS) at
our institution in the 1990s, the surgical team concluded the
procedure was of no benefit and abandoned it. Reports of
failed DBS in PSP misdiagnosed as PD at the time of
implantation support this experience.74
Multidisciplinary Approach
Given the broad array of symptoms in PSP, patients
will benefit from a neurology-led interdisciplinary team that
includes speech, physical and occupational therapists, an
ophthalmologist with experience in prisms, and the educa-
tional support offered by lay support groups (Table 2).50,75,76
Better therapies will require addressing the many currently
untreated symptoms and a better understanding of PSP patho-
physiology. Given the relatively small number of patients
with PSP compared with PD, we anticipate that advances in
symptomatic and neuroprotective therapy will continue to
take advantage of agents currently developed for use in PD.
Finally patients and families can be referred for additional
information and support to the Society for PSP in the United
States (http://www.psp.org), and to the PSP Association
(http://www.pspeur.org/) in Europe.
© 2008 Lippincott Williams & Wilkins
Progressive Supranuclear Palsy
ACKNOWLEDGMENTS
Dr. Juncos was supported in part by NIH 1RO1AG024040-
01A2 (PI Litvan), 1U10NSA053379-02 (PI Kiebutz), and the
Emory University American Parkinson’s Disease Center for
Research Excellence.
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