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A Clinicopathological Study of Vascular Progressive Supranuclear Palsy
A Multi-infarct Disorder Presenting as Progressive Supranuclear Palsy
Keith A. Josephs, MD;
Takashi Ishizawa, MD;
Yoshio Tsuboi, MD;
Natalie Cookson, BSc;
Dennis W. Dickson, MD
Arch Neurol. 2002;59:1597-1601.
ABSTRACT
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Background Clinical features suggesting a diagnosis of progressive supranuclear
palsy (PSP) include early falls, axial rigidity, vertical supranuclear ophthalmoplegia,
and levodopa unresponsiveness. When these clinical features are present, the
diagnosis is almost always PSP, yet vascular disease sometimes has a similar
presentation, referred to as vascular PSP.
Objective To evaluate clinical and pathologic features of cases of vascular PSP
submitted to a PSP brain bank.
Design Review of gross and microscopic neuropathological features, determination
of  haplotype, and medical record review of 4 patients with an antemortem
diagnosis of PSP who did not meet the pathologic criteria for PSP and instead
had vascular pathologic abnormalities.
Results All patients had vertical supranuclear ophthalmoplegia, a history of
falls, and a gradually progressive disease course. Falls began 1 year after
symptom onset, and all patients had asymmetric findings on a neurological
examination. A magnetic resonance imaging scan revealed lacunar basal ganglia
infarcts in one patient and an increased T2-weighted signal in the corona
radiata and centrum semiovale in another. Gross and microscopic neuropathological
studies demonstrated infarcts in the cerebral cortex (n = 4), thalamus (n
= 4), basal ganglia (n = 3), and cerebellum (n = 4). The brainstem was affected
in one patient, but no infarcts were detected in the subthalamic nucleus or
substantia nigra. Of the 4 patients, 3 carried an H2 haplotype, a rare
occurrence in the general population.
Conclusions Asymmetric signs, falls after 1 year of symptom onset, vascular lesions
on a magnetic resonance imaging scan, and an H2 haplotype may help differentiate
vascular PSP from PSP. Thalamic and basal ganglia infarcts are common in patients
with vascular PSP and, when present, may contribute to misdiagnosis.
INTRODUCTION
STEELE ET AL1 first described progressive
supranuclear palsy (PSP) in 1964. Since then, several studies2-5
have tried to identify features that improve the sensitivity and specificity
of clinically diagnosing this entity. Some features that are considered fairly
specific to PSP include axial greater than appendicular rigidity, levodopa
unresponsiveness, absence of tremor, frontal lobe dysfunction, and symmetric
parkinsonism. In 1996, Litvan et al3 published
research criteria for the clinical diagnosis of PSP and defined 3 categories
of possible, probable, and definite PSP. The latter was dependent on pathologic
confirmation, while the others were based on a combination of clinical features,
including onset at age 40 years or older, vertical supranuclear ophthalmoplegia
(VSO), early falls, and no evidence of other disorders that could account
for the neurological signs. The specificity of the clinical criteria for probable
PSP was 100%, decreasing to 89% if exclusion criteria were not met. One of
the exclusion criteria was clinical evidence of central nervous system vascular
disease.
Progressive supranuclear palsy is a degenerative disorder with neuronal
and glial aggregates in specific cortical and subcortical locations,6 including the motor cortex, basal ganglia, thalamus,
subthalamic nucleus, brainstem, and cerebellum. The clinical phenotype of
the -related diseases is related to the specific anatomical areas of
involvement more than the specific biochemical or genetic aspects of the disorder,
even though both are believed to be important. In any neurological condition,
however, the clinical phenotype is not absolute and, hence, a differential
diagnosis is necessary. As early as the 1980s, there were reports7-8 of clinically diagnosed PSP with computed
tomographic, magnetic resonance imaging, and autopsy evidence of vascular
rather than degenerative pathologic abnormalities. The term vascular PSP was coined by Winikates and Jankovic9
in a report of 30 cases in a clinical series of 128 patients with PSP who
satisfied the criteria for vascular PSP. The characteristic features they
emphasized for vascular PSP were asymmetric and lower body involvement. Subsequently,
Binswanger disease presenting as PSP was described.10
Of all the features considered specific for PSP, the one that carries
the most weight is VSO. When present alone, VSO has limited value in differential
diagnosis; however, in the right clinical context, it is almost pathognomonic
for PSP. Differentiating VSO from vertical nuclear ophthalmoplegia is important
when considering a diagnosis of PSP. The latter would suggest structural lesions
involving the third and/or fourth cranial nerve nuclei or nerve roots and
would not be consistent with PSP. Yet, vascular infarcts resulting in VSO
have been described in patients with bilateral lesions11
and even in those with unilateral thalamomesencephalic and rostral interstitial
medial longitudinal fasciculus lesions.12-14
Infarcts in the pons, substantia nigra, centrum semiovale, frontal subcortex,
striatum, corona radiata, internal capsule, and basal ganglia have been described
using magnetic resonance imaging, computed tomography, and an autopsy case
of clinically diagnosed vascular PSP.7-8,10
In this report, patients with a clinical diagnosis of PSP who failed
to meet the pathologic criteria for PSP, but instead had vascular pathologic
abnormalities, were assessed to determine if specific lesion patterns could
be identified. Only a few autopsy-confirmed cases of vascular PSP have been
reported since it was first defined.7-9
To our knowledge, this is the largest clinicopathological study of vascular
PSP.
METHODS
Two hundred seven cases from the Society for Progressive Supranuclear
Palsy brain bank at Mayo Clinic were reviewed for cases that did not meet
the pathologic criteria for PSP6 but had pathologic
evidence of vascular disease. All cases underwent a standard neuropathological
assessment, including hematoxylin-eosin staining, thioflavine S fluorescent
microscopy, and immunostaining with phosphorylated monoclonal antibodies
(CP13 or PHF1) and a polyclonal antibody to  -synuclein. Fixed and frozen
tissues from all cases were dissected and analyzed for gross evidence of large-
and small-vessel infarction or hemorrhage. Sections were taken from multiple
cortices and the hippocampus, amygdala, basal ganglia, thalamus, mesencephalon,
pons, medulla, and cerebellum. The sections were microscopically studied for
evidence of infarcts, hemorrhages, and foci of ischemic gliosis. Each case
underwent systematic neuropathological assessment, including determination
of Braak stage, neurofibrillary tangle and senile plaque counts, semiquantitative
assessment of amyloid angiopathy, and semiquantitative assessment of -related
neuronal and glial pathologic features using immunohistochemistry in multiple
cortical and subcortical regions. A neurologist (K.A.J.) abstracted the following
information from medical records: sex, age of onset, duration of illness,
history of hypertension, early vs late falls, early dysarthria or dysphagia,
asymmetry, cognitive dysfunction, eye movement abnormalities, parkinsonism,
levodopa responsiveness, and imaging findings. Polymerase chain reaction was
used to determine haplotype from DNA extracted from frozen brain tissue
using previously published methods.15
RESULTS
Four patients (3 men and 1 woman; mean ± SD age, 79.0 ±
6.3 years) with a clinical diagnosis of PSP satisfied the criteria for vascular
PSP (Table 1). Of these 4 patients,
3 had thorough medical records, including documented antemortem imaging studies,
for review. All 4 patients had a documented neurological examination by at
least one neurologist. The mean age of onset was 73 years, and the mean duration
of illness was 6 years. All 4 patients had onset after the age of 40 years,
VSO, and a gradually progressive disease course. All 4 patients had a history
of falls, but these occurred after 1 year of symptom onset. Axial rigidity,
levodopa unresponsiveness, and early dysphagia or dysarthria were also reported.
All 4 patients had asymmetric findings on examination, including cranial nerve
VII palsy (n = 2), hemiparesis, the Babinski sign, tremor, rigidity, or leg
dystonia. One patient had magnetic resonance imaging evidence of lacunar infarcts
in the basal ganglia, and another showed an increased T2-weighted signal in
the corona radiata and centrum semiovale.
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Table 1. Clinical Features of Patients With Vascular PSP Compared With
Patients With Pathologically Proved PSP*
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Pathologic data are summarized in Table 2. On gross examination, all 4 patients had neocortical infarcts
in the frontal lobe, and 3 of the 4 had right-sided thalamic infarcts, with
bilateral infarcts occurring in 1 (Figure
1). Three patients also had infarcts in the basal ganglia (Figure 1). One patient had lacunar infarcts
in the pontine base and medullary tegmentum. On microscopic examination, all
4 patients had moderate to marked arteriosclerotic vascular disease, cribriform
changes in the basal ganglia, and multiple foci of ischemic gliosis. Pathologic
features consistent with PSP were absent in all patients. Age-related Alzheimer
disease–type changes were minimal. The mean Braak stage was 2.3 (range,
1-3). Cortical senile plaques were absent, except in patient 2, who had rare
senile plaques in the occipital lobe. The subthalamic nucleus was not affected
by infarcts or pathologic features in any patient. Similarly, the substantia
nigra, superior colliculus, periaqueductal gray matter, and cerebellar deep
nuclei were free of infarcts and pathologic features. A microscopic
examination in all 4 patients showed small cerebellar infarcts that were not
detected on gross inspection. Haplotype analysis revealed an H2
haplotype in 3 of the 4 patients (2 had the H1/H2 genotype and 1 had
the H2/H2 genotype).
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Table 2. Infarct Distribution in Patients With Vascular PSP Compared
With NFT Distribution in Patients With Pathologically Proved PSP*
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Macroscopic findings of 3 patients with vascular progressive supranuclear
palsy. Arrows indicate grossly apparent hemorrhages or infarcts. A and B,
Patient 4 (left hemisphere). There were infarcts in the putamen and thalamus
and an old slitlike hemorrhage in the lateral putamen. C, Patient 3 (right
hemisphere). There were multiple infarcts in the putamen and globus pallidus
and a cortical infarct. D, Patient 2 (left hemisphere). There were multiple
infarcts in the putamen and periventricular white matter. Patient 1 is not
shown.
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COMMENT
This study demonstrated that vascular PSP occurs because of multiple
vascular lesions, without the cardinal pathologic features of idiopathic PSP.
Prominent clinical features of this autopsy-confirmed vascular PSP series
were characterized by VSO, axial rigidity, hypomimia, and postural instability.
Some unusual features for the spectrum of PSP included left cranial nerve
VII palsy in 2 patients and left hemiparesis and the Babinski sign in 1. Other
asymmetric features were also seen in all 4 patients. Retrocollis and early
development of dysarthria or dysphagia, commonly seen in those with PSP, were
noted in the patients with vascular PSP. Interestingly, the substantia nigra,
subthalamic nuclei, and periaqueductal gray matter, which are prominently
affected areas in patients with PSP,4 were
not directly affected in those with vascular PSP. Instead, the right side
of the thalamus in 3 patients, the left side of the thalamus in 1 patient,
unilateral or bilateral globus pallidus, the putamen, and the caudate were
the main areas involved in those with vascular PSP.
The vertical gaze control center is known to lie in mesencephalic reticular
formation, which includes the Darkshevich nucleus, the interstitial nucleus
of Cajal, the rostral interstitial nucleus of the medial longitudinal fasciculus,
and the posterior commissure.11-14
Lesions in any of these structures can produce VSO, especially at the thalamomesencephalic
junction, which is regarded as important in the studies of VSO with unilateral
lesions.13-14 GABAergic neurons
in the pars reticulata of the substantia nigra, which project to the tectum,
are usually severely involved in patients with idiopathic PSP.16
This is also thought to contribute to eye movement abnormalities, especially
impairment in saccadic eye movements.16 Yet,
mesencephalic and nigral pathologic features were absent in all patients.
Recent clinical-anatomical studies17-18
demonstrated that unilateral or bilateral thalamic lesions can cause VSO.
The location of the lesions in the present series of patients with vascular
PSP suggests that thalamic lesions may also produce VSO, possibly by interrupting
supranuclear vertical gaze pathways.
The pathophysiological conditions of postural instability are poorly
understood. It is generally thought that loss of postural reflex is related
to reciprocal connections among the cortex, basal ganglia, and thalamus.19-20 A study21
of patients who had experienced a stroke showed that the parietal-insular
cortex or adjacent structures, including the basal ganglia, may be crucial
in impaired postural balance. Multiple interruptions of the cortical-striatal-pallidal-nigral-thalamic-cortical
loops are most likely responsible for the presence of parkinsonism in our
series. Ischemic or degenerative destruction of multiple cortical, basal ganglia,
and thalamic structures may also be the correlate of the unresponsiveness
to high-dose levodopa therapy in those with vascular PSP and in those with
idiopathic PSP. These structures depend on numerous neurotransmitters and
are not limited to dopaminergic cell loss.
A diagnosis of PSP was reasonable in these patients if strict research
criteria were not used,3 because all patients
had VSO, parkinsonism, and frequent falls. Furthermore, there was never any
apparent episodic deterioration in their histories suggestive of isolated
or multiple infarcts. The reason for the lack of these episodes may have been
an absence of apparent plegia, sensory disturbances, or focal cortical signs.
On the other hand, none of the patients would have fulfilled the clinical
research criteria proposed by Litvan et al3
for possible or probable PSP because of the late onset of falls, asymmetric
signs, and neuroradiologic abnormalities.3
Winikates and Jankovic9 suggested that vascular
PSP should be differentiated from idiopathic PSP if the patient has a higher
degree of asymmetry, lower body involvement, evidence of corticospinal and
pseudobulbar signs, some neuroimaging evidence of vascular disease, and an
increased frequency of risk factors for strokes. Our study showed that, in
addition to asymmetry, frequent falls beginning 1 year after symptomatic onset
was a common feature in all 4 patients and may be another differentiating
feature. Magnetic resonance imaging is also important for detecting vascular
lesions, because thalamic and unilateral or bilateral striatal involvement,
which may be difficult to detect with computed tomographic scans, seems crucial
for the development of vascular PSP.
Baker et al15 demonstrated increased
frequency of a particular form of the extended haplotype (the H1
haplotype) in patients with PSP compared with normal control subjects, with
frequencies of 93.7% in those with PSP compared with 78.4% in controls. In
the present series of patients with vascular PSP, 3 of the 4 patients carried
an H2 haplotype, including 1 who was homozygous for H2, a rare occurrence
in the general population. These results raise the possibility that determination
of the haplotype may be an ancillary aid in the differential diagnosis
of vascular PSP, but a larger study is needed to confirm this observation.
AUTHOR INFORMATION
Accepted for publication March 8, 2002.
Author contributions: Study concept and design (Drs Josephs, Ishizawa, Tsuboi, and Dickson); acquisition
of data (Drs Josephs and Dickson and Ms Cookson);
analysis and interpretation of data (Dr Josephs);
drafting of the manuscript (Dr Josephs); critical
revision of the manuscript for important intellectual content (Drs Josephs, Ishizawa, Tsuboi, and Dickson and Ms Cookson); statistical
expertise (Dr Dickson); obtained funding (Dr Dickson); administrative, technical, and material support (Drs Josephs, Ishizawa, Tsuboi, and Dickson and Ms Cookson);
study supervision (Dr Dickson).
This study was supported by grants AG16574, AG17216, AG14449, AG03949,
and NS40256 from the National Institutes of Health, Bethesda, Md; the Mayo
Foundation, Rochester, Minn; the State of Florida Alzheimer Disease Initiative,
Gainesville; and the Society for Progressive Supranuclear Palsy, Baltimore,
Md.
We thank Peter Davies, PhD, Albert Einstein College of Medicine, Bronx,
NY, for providing the phosphorylated monoclonal antibodies (CP13 or
PHF1).
Corresponding author and reprints: Dennis W. Dickson, MD, Department
of Pathology (Neuropathology), Mayo Clinic, 4500 San Pablo Rd, Jacksonville,
FL 32224 (e-mail: dickson.dennis{at}mayo.edu).
From the Departments of Neurology (Drs Josephs and Tsuboi) and Pathology
(Neuropathology) (Drs Ishizawa and Dickson and Ms Cookson), Mayo Clinic, Jacksonville,
Fla.
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