(Stroke. 1997;28:965-969.)
© 1997 American Heart Association, Inc.
Articles |
Neurological Signs and Frontal White Matter Lesions in Vascular Parkinsonism
A Clinicopathologic Study
From the Department of Neurology, Tokyo Metropolitan Geriatric Hospital, Japan.
Correspondence to Hiroshi Yamanouchi, MD, Department of Neurology, Tokyo Metropolitan Geriatric Hospital, 35-2 Sakaecho, Itabashiku, Tokyo 173, Japan.
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Abstract |
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Background and Purpose The clinical characteristics and the pathological lesions of so-called vascular parkinsonism (VP) are still debatable. The purpose of this study was to define the core signs and symptoms and assess the cerebrovascular lesions in pathologically confirmed VP.
Methods In the present study, VP was defined as the presence of parkinsonism and pathological evidence of cerebrovascular lesions but no depigmentation or Lewy bodies at the substantia nigra. We compared the clinical signs and symptoms of 24 VP patients with those of 30 age-matched patients with pathologically confirmed Parkinson's disease. We compared the brain pathology in VP patients with that in 22 age-matched patients with Binswanger's disease (BD) who had no parkinsonism according to clinical records.
Results VP was characterized clinically by a short-stepped or frozen gait, lead-pipe rigidity, absence of resting tremor, and negative response to levodopa. Half or more of VP patients demonstrated pyramidal tract signs and pseudobulbar palsies. There was no significant difference in the extent of vascular lesions at the basal ganglia between patients with VP and with BD without parkinsonism. The extent of frontal white matter pallor tended to be less broad in VP than in BD without parkinsonism. In VP patients, the number of oligodendrocytes in the frontal white matter was significantly less than that in age-matched normal control subjects and significantly more than in those with BD.
Conclusions The core signs and symptoms of autopsy-proved VP differ from those of typical Parkinson's disease, and most VP patients had diffuse cerebral white matter lesions as well as basal ganglia lesions. VP might be related to frontal white matter lesions.
Key Words: Binswanger's disease • cerebral disorders • Parkinson's disease • white matter
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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A variety of insults to the brain can induce parkinsonism. A proposal concerning the cerebrovascular etiology has been made,1 but some doubts remain because of the lack of pathologically confirmed cases with adequate clinical correlations.2 3 Critchley1 defined arteriosclerotic parkinsonism as being characterized by rigidity, masked face, and short-stepped gait and speculated that multiple vascular lesions of the basal ganglia were related to the core symptoms. However, he provided no neuropathological evidence. On the other hand, parkinsonism is sometimes observed in patients with BD, in which there are widespread lesions in the white matter. The clinicopathologic entity of VP remains debatable. Because diagnostic criteria for VP have not yet been established, we defined our criteria for VP in the present study. On the basis of this definition of VP, we investigated the clinical and neuropathologic characteristics of VP in autopsy cases.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We defined parkinsonism by the presence of at least two of the following four symptoms: tremor, rigidity, bradykinesia, and gait disorders (including short-stepped gait, frozen gait, or festination). We defined VP as follows: (1) parkinsonism, (2) evidence of cerebrovascular lesions, (3) no depigmentation or Lewy bodies in the substantia nigra, (4) exclusion of other degenerative diseases that can induce parkinsonism, (5) exclusion of marked hydrocephalus, and (6) no administration of drugs that can induce parkinsonism. We defined PD as follows: (1) parkinsonism, (2) pathological confirmation of depigmentation and Lewy bodies in the substantia nigra, (3) exclusion of other degenerative diseases that can induce parkinsonism, and (4) no administration of drugs that can cause parkinsonism. A diagnosis of BD was based on diffuse pallor in the cerebral white matter on myelin staining associated with multiple small infarctions and severe atherosclerosis and arteriosclerosis in the cerebral arteries in patients with vascular dementia.
On the basis of our clinicopathologic criteria for VP, we examined 24 patients with VP among autopsy cases at the Tokyo Metropolitan Geriatric Hospital. The cases included 17 men and 7 women aged 70 to 92 years with a mean±SD age of 80.0±6.1 years at autopsy. Nineteen of the 24 patients had a history of hypertension; there was no exact information about history of hypertension for the others. Signs and symptoms on clinical records were compared with those in 30 age-matched patients with PD, including 16 men and 14 women aged 72 to 92 years (mean age of 80.4±5.6 years). Vascular lesions in the cerebral white matter and deep structure in VP were compared with those in 22 age-matched patients with BD without parkinsonism (mean age of 80.1±5.0 years [range, 73 to 88 years] at autopsy). Eighteen of the BD patients had a history of hypertension; there was no exact information about history of hypertension for 4. Fourteen patients (64%) had been bedridden, 13 (59%) showed hemiparesis, and 6 (27%) showed akinetic mutism.
Microscopic examinations were made using 10-µm-thick sections stained
with Klüver-Barrera's method and hematoxylin-eosin. Sections
were stained with Bodian's silver impregnation as needed. We counted
the number of pigmented and nonpigmented neurons with nucleoli in the
substantia nigra. We examined the extent of vascular lesions in the
caudate nucleus, putamen, and globus pallidus, in which coronal
sections at the level of the mammillary body were used for evaluation,
and the thalamus at the level of the red nuclei. We classified the
extent of the vascular lesions into the following five groups: vascular
lesions occupying more than 1/3 of the structure, from 1/3 to 1/5, from
1/5 to 1/10, less than 1/10, and no lesion. We evaluated the extent of
white matter pallor on myelin-stained coronal sections of the anterior
portion and at the level of the mammillary body in the frontal lobe. We
counted the numbers of oligodendrocytes and astrocytes in the frontal
white matter as indicators of the severity of white matter
damage.4 Macrophages, microglia with oval or
spindle-shaped nuclei, and vessel-wall cells were excluded. All other
cells with clear, focused, round nuclei were counted in the sum of
oligodendrocytes and astrocytes. Cells with small, solid, and round
nuclei were considered to be oligodendrocytes.4 The
numbers of oligodendrocytes and astrocytes in VP were compared with
those in patients with BD without parkinsonism and in age-matched
normal control subjects (22 patients; mean age, 80.4±5.1 years; range,
68 to 88 years). Statistical analysis was performed with
Student's t test and the 
2 test.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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As the initial symptom, tremor was observed in only 1 of the VP patients (4%) and 14 of the PD patients (47%). This difference was significant at P<.001. A short-stepped gait or frozen gait was observed in 15 of the VP patients (63%) and 12 of the PD patients (40%) as the first symptom. During the clinical course, tremors were present in 4 of the VP patients (17%), with resting tremor in 1 and action tremor in 3. Among the PD patients, 22 (73%) had tremor, with resting tremor in 20 (67%). The incidence of tremor or resting tremor was significantly less in VP (P<.001) than in PD. Limb rigidity was observed in 23 of the VP patients (96%) and 29 of the PD patients (97%). Cog-wheel rigidity was found in only 7 VP patients (29%) but in 22 PD patients (73%) (P<.01). Right-left asymmetry of limb rigidity was observed in only 5 VP patients (21%) but in 17 PD patients (57%) (P<.05). All VP patients had gait disorders, usually short-stepped gait, with frozen gait in 5 (21%). Twenty-three PD patients (77%) showed gait disturbances, with frozen gait in 9 (30%). Bradykinesia was recorded in 17 VP patients (71%) and 25 PD patients (83%). This difference was not statistically significant. Dementia was observed in 17 VP patients (71%) and 13 PD patients (43%) (P<.05).
Nine VP patients (38%) had hemiparesis, and 15 (63%) had
pyramidal tract signs. No hemiparesis or
pyramidal tract signs were observed with PD. Pseudobulbar
palsies were found in 13 VP patients (54%). Eight PD patients (27%)
had dysphagia or dysarthria, considered to be swallowing and speech
muscle dysfunctions due to PD itself. The initial responses to
anti-Parkinson drugs were rated as no response, insufficient response
(improvement less than about 50% of the degree of symptoms), and good
response (improvement greater than 50% of the degree of symptoms).
Among 15 patients with VP who received anti-Parkinson drugs (13
levodopa, 2 others), none showed a good response; 3 showed an
insufficient but transient response, while the remaining 12 showed no
response. Among 29 PD patients who received anti-Parkinson drugs (25
levodopa, 4 others), 18 showed a good response, while 9 showed an
insufficient response, including 5 patients who did not receive
sufficient maintenance doses because of adverse reactions; 2
patients showed no clear response to drug treatment
(Table
).
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The mean±SD number of pigmented neurons in the substantia nigra was
168±60 in VP patients, 178±50 in those with BD without parkinsonism,
and 185±59 in age-matched normal control subjects. The number of cells
did not differ significantly among these three groups. The sum of
pigmented and nonpigmented neurons in the substantia nigra was 194±64,
205±49, and 212±36, respectively, with no significant difference
among the three groups. In 30 PD patients, the number of pigmented
neurons at the substantia nigra was 57±29, and the sum of pigmented
and nonpigmented neurons was 90±36. These neurons in PD were
significantly less than those in VP, in BD without parkinsonism, and in
age-matched normal control (P<.001). From 2 to 12 Lewy
bodies were observed at the substantia nigra of PD patients, with a
mean number of 5.4±2.8 per slice. The extent of vascular lesions in
the caudate nucleus, putamen, globus pallidus, and thalamus did not
differ significantly between VP and BD without parkinsonism. Most cases
of VP and BD without parkinsonism showed vascular lesions extending
throughout less than one third of the basal ganglia structure (Fig 1). Pallor area occupying more than two thirds of the
anterior portion of the frontal white matter was observed in 15 VP
patients (62.5%) and in 18 BD patients (81.8%). At the level of the
mammillary body, the same finding was observed in 9 VP patients
(37.5%) and 18 BD patients (81.8%) (P<.005). The pallor
area in the occipital lobe was also less widespread in VP than in BD
(Fig 2). Fig 3 shows the frontal white
matter pallor in a VP patient. The sum of oligodendrocytes and
astrocytes in a 0.20-mm2 area in the anterior portion of
the frontal white matter was 279±39 in normal control subjects,
194±48 in VP patients, and 147±35 in those with BD without
parkinsonism. The number of these cells was significantly less in VP
than in normal control (P<.001) and significantly more than
in BD without parkinsonism (P<.001). The number of
oligodendrocytes was 136±20 in normal control, 86±27 in VP, and
60±17 in BD without parkinsonism, significantly less in VP than in
normal control (P<.001) and significantly more than in BD
without parkinsonism (P<.001) (Fig 4).
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Among 30 PD patients, 1 died of massive thalamic hemorrhage and 1 had fresh multiple cortical infarctions associated with disseminated intravascular coagulation syndrome. In the remaining 28 cases, lacunar infarctions at the basal ganglia were found in 4, small infarctions in the cerebral white matter in 2, small putaminal hemorrhage in 1, lacunar infarction at the thalamus in 1, occipital cortical infarction in 1, and no cerebrovascular lesion in 19.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The clinical entity known as VP is still debatable. In 1929, Critchley1 defined "arteriosclerotic parkinsonism," the symptoms of which were rigidity, masked face, and a short-stepped gait in an elderly hypertensive person. He classified other subtypes of arteriosclerotic parkinsonism: parkinsonism associated with pseudobulbar palsy, parkinsonism with dementia, parkinsonism with pyra-midal tract signs, and parkinsonism with cerebellar ataxia. He speculated that multiple vascular lesions in the basal ganglia, as described earlier,5 must have an etiologic connection to the core neurological symptoms of arteriosclerotic parkinsonism. However, he presented no case material of his own of any neuropathologic examinations. Others disagreed with his opinions because of the high frequency of the characteristic vascular lesions in patients without clinical signs of parkinsonism.2 3 Jellinger6 indicated that about 6% of 400 parkinsonism cases in an autopsy series could be classified as having disease of vascular origin, showing multi-infarct atrophy, hypertensive or Binswanger-type encephalopathy, and multiple vascular lesions in the basal ganglia and brain stem, with no or only mild degenerative nigral damage. However, he provided no clinical definition of parkinsonism. His report lacked exact information about the location and extent of vascular lesions. Furthermore, most of his VP cases showed neuronal loss in the substantia nigra, and 9.3% of the cases had Lewy bodies in the substantia nigra. His diagnosis of VP is not precise.6
Because there are no established diagnostic criteria for VP at present, we defined the clinicopathologic entity of VP. In the present study, most neuropathologically confirmed VP patients showed a short-stepped gait, lead-pipe rigidity, symmetry of rigidity, absence of resting tremor, and a negative response to anti-Parkinson drugs. Half or more of the VP patients had pseudobulbar palsies and pyramidal tract signs. The present data on neurological features were based on the clinical records, not on the prospective follow-up observations. Thus, we do not have chronologically perfect information. Within the restriction of methodology in the present study, the clinical features of VP at the onset and at the clinical examination during long-term courses were similar to those described by Critchley and others1 7 8 but different from the typical clinical features in pathologically confirmed PD, which is characterized by cog-wheel rigidity, asymmetry of rigidity, frequent resting tremor, good response to anti-Parkinson drugs, and the absence of pyramidal tract signs.9 Core neurological signs and symptoms in VP are considered to be different from those in typical PD, although some patients with histologically confirmed PD can show atypical clinical features.9 10 11 Murrow et al12 reported an autopsy case with a clinical syndrome indistinguishable from PD in which postmortem examination revealed extensive lacunar infarctions of the basal ganglia without evidence of coexistent PD. However, in that case, sections of the substantia nigra showed an average of one neuron with a Lewy body, and those of the locus ceruleus showed an average of two to three intraneuronal Lewy bodies per section. On the basis of our diagnostic criteria for VP, that case must be excluded from the VP classification because of the evidence of Lewy bodies. This might be a case with coexistence of PD and VP. Hughes et al9 11 recorded coexistent cerebrovascular lesions, especially striatal lacunar infarctions in PD patients. In the present study, some PD patients had coexistent vascular lesions in the basal ganglia and in the cerebral white matter, but all these lesions were small in size. Tolosa and Santamaria7 reported the parkinsonian syndrome in 3 patients with CT evidence of basal ganglia infarcts. However, the clinical picture in these cases improved spontaneously. This suggests that basal ganglia lesions can induce parkinsonism only transiently and do not contribute to lasting parkinsonism. Mark et al13 showed three cases of autopsy-proved BD presenting as levodopa-responsive parkinsonism. Parkinsonism in these cases improved initially, after the treatment with levodopa, but afterward developed worsening symptoms despite continued treatment with levodopa.
Good preservation of pigmented neurons in the substantia nigra in VP suggests that the substantia nigra does not contribute to the core symptoms in VP. We investigated not only the presence or absence of vascular lesions but also the total extent of lesions in the basal ganglia because the structure of the neighboring small infarctions or hemorrhages was usually well preserved. Microscopic examination revealed that the extent of vascular lesions in the basal ganglia in VP is not different from that in BD without parkinsonism. Furthermore, most cases of both BD without parkinsonism and VP had vascular lesions covering less than one third of the structure.
Thompson and Marsden14 evaluated the disordered gaits of 12 hypertensive patients suspected of having BD because of typical low-density periventricular cerebral white matter changes on CT scans. Five of the 12 were thought by physicians to have parkinsonism. All had severe walking disturbances, and some could not walk because of poor standing balance and magnetic apraxic feet. Thompson and Marsden surmised that periventricular low density on CT might signify damage to the white matter tracts connecting the basal ganglia and cerebellum with supplementary motor areas in the frontal lobes. The abnormal gait would consequently result from a disruption of these pathways to the lower limbs (lower-half parkinsonism). Fitzgerald and Jankovic15 compared LBP patients with those having more typical generalized PD. Multiple subcortical white matter lesions were seen on MRI scans in 7 of 8 LBP patients and in 4 of 8 typical PD patients. The authors thought that LBP might result from chronic subcortical ischemia secondary to hypertensive vascular disease and that some LBP patients might have had BD. Recently, Zijlmans et al16 reported that patients with suspected VP had more subcortical lesions on MRI than those with PD or hypertension and that there were two types of VP: one had an acute onset and lesions located in the subcortical gray nuclei; the other had an insidious onset and lesions diffusely distributed in the white matter. However, none of these changes seen on MRI was confirmed by postmortem examination.
Dubinsky and Jankovic17 reported that about one third of progressive supranuclear palsy patients or those with supranuclear palsy–like conditions have CT or MRI evidence of a multi-infarct state. Abnormal MRI scans showed periventricular white matter high-intensity signals and multiple discrete areas in the brain stem and basal ganglia, compatible with small infarctions. However, because CT and MRI white matter abnormalities are frequently found in hypertensive elderly patients, these changes are often a nonspecific marker for age or hypertension rather than an indicator for BD. The exact significance of subcortical white matter abnormalities on MRI remains controversial. The many studies of white matter abnormalities on CT and MRI scans in the elderly have failed to reach a consensus.18 19 20 21
On the other hand, parkinsonism can sometimes be observed in patients with pathologically confirmed BD.22 23 24 In an electron microscopic study, Yamanouchi et al25 indicated that the number of nerve fibers is decreased in the frontal white matter in BD. The pallor of the frontal white matter observed in BD and VP probably results from a loss of nerve fibers. Yamanouchi4 revealed a loss of oligodendrocytes in the frontal white matter in BD to a level about half that of age-matched normal control subjects. Oligodendrocyte loss might not only be a pathogenetic factor for nerve fiber loss in BD but also an indicator of the severity of white matter damage. In the present study, the extent of vascular lesions in the basal ganglia was essentially almost equal between VP and BD without parkinsonism, and the frontal white matter lesions were less widespread and less severe in VP than in BD without parkinsonism. Severe damage to the frontal lobe can induce abulia and/or a bedridden state. The poor activity in daily living associated with the bedridden state, hemiparesis, or akinetic mutism, which are frequently observed in BD patients without parkinsonism, might mask parkinsonism (especially the gait disorders) because of the inability to walk. Although the neuropathologic difference between BD with and without parkinsonism remains obscure, most VP can be a pathologically mild type of BD or of BD in which parkinsonism is not conspicuous, or BD patients without parkinsonism on the clinical records might have had parkinsonism temporarily during their lifetime.
We could not find definite confirmation to deny the hypothesis that basal ganglia lesions are the main cause of parkinsonism.1 However, lacunar infarctions in the basal ganglia can be sometimes observed in patients without parkinsonism, even in neurologically asymptomatic cases.
From widespread lesions in the frontal white matter and relatively slight lesions in the basal ganglia, we speculate that VP can be more closely related to frontal white matter lesions than to basal ganglia lesions. Further studies are necessary to confirm this conclusively.
NPH can cause parkinsonism, dementia, incontinence, and gait disorders.26 Koto et al27 reported an NPH syndrome possibly related to hypertensive and arteriosclerotic vasculopathy. NPH has been shown in some cases of pathologically confirmed BD.21 25 Some clinical overlap between BD and NPH can exist, although the role of widespread white matter lesions in causing hydrocephalus is not clear. We excluded patients with marked hydrocephalus from this study because of a lack of radioisotope cisternographic examination in VP patients. Nevertheless, it cannot be ruled out completely that NPH might have coexisted in some cases of VP. Further studies are necessary to determine whether widespread white matter lesions can contribute to the dynamic state of cerebrospinal fluid circulation.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This work was supported in part by a grant (94A2408) from the Japanese Ministry of Health and Welfare and by a grant (Dementia in the Elderly) from the Tokyo Metropolitan Institute of Gerontology (Japan). We thank Dr T. Mizutani, Division of Neuropathology, Tokyo Metropolitan Institute of Gerontology, for helpful advice.
Received December 13, 1996; accepted February 12, 1997.
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