626

Subcortical Arteriosclerotic Encephalopathy
(Binswanger's Disease)
A Vascular Etiology of Dementia
PETER C. BURGER, M.D.,

J. GORDON BURCH, M.D.,

AND ULF KUNZE,

M.D.

Downloaded from http://ahajournals.org by on April 10, 2024

SUMMARY A 51-year-old man with moderate intermittent hypertension had a rapidly progressive, profound dementia in the absence
of significant localizing neurological signs. Postmortem examination
disclosed the vascular alterations and diffuse white matter degenera-

tion which characterize subcortical arteriosclerotic encephalopathy
(SAE) or Binswanger's disease. The case underscores the need to
consider vascular disease as an etiology of dementia — even in the
absence of focal neurological deficit.

BEDSIDE CONSIDERATION of cerebrovascular disease
as an etiology of dementia has been deemphasized somewhat
in recent years in favor of disorders such as Alzheimer's disease, slow virus infections, and normal pressure hydrocephalus. Cerebrovascular disease, nevertheless, is common
and may be responsible for clinical conditions in which
dementia is a leading aspect. Vascular dementias are usually
engendered by extensive cortical softenings,1' * but on occasion are derived from the diffuse white matter degeneration
of subcortical arteriosclerotic encephalopathy (SAE) or
Binswanger's disease.3"12 This report documents the clinical
and pathological features of a patient with this unusual
cerebrovascular disorder, and emphasizes that vascular disease must be included in the differential diagnosis of dementia, even in the absence of localizing neurological signs.

logical deficits. The opening pressure at lumbar puncture
was 160 mm H2O and the CSF protein was 57 mg/dl. An extensive investigation was undertaken to elucidate the
etiology of the patient's dementia. Negative examinations
included the following: chest x-ray, ECG, blood and CSF
chemistries, urine porphyrin screen, bone marrow aspirate,
gastric aspirate for pH and cytology, LE prep and antinuclear factor, toxic screen for hypnotic and tranquilizing
agents, upper GI series, barium enema, intravenous
pyelography, liver scan, skull x-ray, two brain scans, and
CSF studies for serologic evidence of fungi and viruses,
cytological abnormalities, and the presence of infectious
agents. Sequential EEGs revealed diffuse deterioration of
the background activity (fig. 1), while radioactive serum
albumin (RISA) cisternography showed ventricular reflux,
delayed clearance, and absence of sagittal activity after
24 and 48 hours (fig. 2). Pneumoencephalography demonstrated marked ventricular dilatation and minimal freeconvexity air (fig. 3). There were minor irregularities of
the siphon and proximal anterior cerebral arteries on left
carotid arteriography, but the study was otherwise unremarkable. Repeated CSF drainage by lumbar puncture
appeared to improve the patient's condition somewhat,
although there was no further improvement after the insertion of a ventriculovenous shunt. The opening pressures at
the time of these taps were within normal limits. Light and
electron microscopic examination of a cortical biopsy containing gray matter and 1 mm of subcortical white matter
from the right parieto-occipital region revealed no abnormalities of the parenchyma or vasculature.
The patient's blood pressure was intermittently elevated
during the first two hospitalizations with diastolic recordings
up to 150 mm Hg, although there were no clinical or radiographical manifestations of hypertensive disease or
historical documentation of hypertension. Serial serum electrolytes were normal. The plasma renin level was low, while
vanilmandelic acid and catecholamine determinations were
normal. The patient's hypertension was initially treated with
alpha-methyldopa while hydrochlorothiazide alone later
provided adequate control.
During the two months following discharge there was a
progressive deterioration as the patient became incontinent
and increasingly dependent on others for his daily care.
On his third admission in August, 1972, he was completely disoriented, mumbled incoherently in a low voice,
and exhibited frontal release signs, ataxia, bilateral plantar
extensor responses, and a mild left hemiparesis. Concern

Case Presentation
Clinical History
A 51-year-old man (accountant) was hospitalized at the
Durham Veterans Administration Hospital on six occasions
in one year because of progressive dementia.
The patient's initial neurological difficulties were noted by
his wife in June, 1971, as the gradual onset of personality
change characterized by apathy, easy fatigability, decreased
recent and remote memory, and difficulty in business
judgments. These mental aberrations were reported to be accompanied by episodic ataxia, intermittent dysarthria,
deterioration of handwriting, and decreased right-sided
coordination. Two hospitalizations at other institutions
revealed a left frontal slow-wave EEG focus, an elevated
CSF protein (65 mg/dl), and unremarkable left carotid
arteriography.
At the patient's first Durham VA hospitalization in
March, 1972, a state of psychomotor retardation was
noticed and, although there were positive snout and suck
reflexes, the clinical impression was depression as supported
by psychological testing. A lumbar tap was unremarkable;
the opening pressure was 150 mm H2O.
The patient's second admission seven days later was
prompted by a 48-hour period of confusion, incontinence,
ataxia, and agitated delirium with disorientation and incoherent speech. There were no focal or lateralizing neuroFrom the Department of Pathology, and Division of Neurology, Duke
University Medical Center, Durham, North Carolina 27710; and Plk
Reichenau Post Fach 3000, Germany.

SUBCORTICAL ARTERIOSCLEROTIC ENCEPHALOPATHY/Surger et al.

4-4-72

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12-4-72

627

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FIGURE 1. Serial EEGs depict a progressive deterioration of the background activity and, in the last tracing in March, 1973, the appearance
of triphasic potentials. All tracings were obtained with a 16-channel Grass Model VI calibrated at SO microvolts/7.5 mm.

that the patient's deterioration was due to shunt malfunction
prompted efforts at ventricular tapping which were unsuccessful. A CO2 pneumoencephalogram demonstrated
normal ventricular size (fig. 3), although a midline shift from
right to left was present. A right carotid arteriogram disclosed a 1.5-cm peripheral veneer compatible with a subdural hemorrhage. Following evacuation of the hematoma,
the hemiparesis cleared and the patient was discharged,
although there had been no improvement in his mental
status.
Several subsequent short hospitalizations were necessitated by a subdural empyema at the site of the
craniotomy which was treated successfully by drainage and
antibiotics. During the last months of his life the patient had
myoclonic jerks, mutism, and lethargy. An EEG revealed
triphasic waves with progression of the background
deterioration when compared with previous recordings 3 and
11 months earlier (fig. 1). Marked obtundation and bilateral
bronchopneumonia immediately preceded his death in
March, 1973. Permission for autopsy was limited to the
brain.
Autopsy Findings
The 1,320-gm brain was not atrophic. A plastic shunt tube
terminated in the body of the right lateral ventricle. A firm,

flat, fibrotic mass 1.5 cm in thickness tenaciously adhered to
the dura over the right frontal lobe. There was moderate to
severe atherosclerosis of the large vessels at the base of the
brain, as well as the more peripheral branches of the middle
cerebral arteries emerging from the sylvian fissures and in
the pericallosal branches of the anterior cerebral arteries
(fig. 4). A 2.0 X 3.0 X 2.0 cm cystic infarct was positioned
in the right frontal lobe and a similar lesion was superficially
situated in the left parietal lobe.
Coronal sections revealed that, with the exception of the
two infarcts and the cavity at the biopsy site in the right occipital lobe, the cortical ribbon was of normal thickness,
configuration, and color throughout. The ventricles were of
normal size. Lacunar infarcts were scattered throughout the
basal ganglia, internal capsules, corpus callosum, cerebral
hemispheric white matter, pons, and cerebellum (fig. 4).
Microscopically, the flat mass over the right frontal lobe
was composed of dense fibrous tissue containing scattered
foci of chronic inflammatory cells and was consistent with
an organized subdural empyema. The lacunar infarcts were
variable in age —' most were old but a few were recent.
Marked vascular changes were present throughout the
brain. The large vessels at the base as well as the more
peripheral vessels over the convexities were atherosclerotic
(fig. 4), while the intraparenchymal arteries of the basal

STROKE

ANTERIOR VIEW

VOL. 7, No. 6, NOVEMBER-DECEMBER 1976

R. LAT. VIEW

24 HR.

48 HR.

FIGURE 2. A RISA cisternogram in April, 1972, shows ventricular reflux, delayed clearance, and absence
of sagittal activity at 24 and 48 hours.
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ganglia, centrum semiovale, cerebellum, and pontine base
were hyalinized and contained intramural deposition of lipid
(lipohyalinosis) (fig. 5). Arterioles demonstrated focal
medial thickening and hyalinization (fig. 6). In the pons, this
hyalinization of small arterioles was often brightly
eosinophilic and surrounded by a collar of necrotic

parenchyma (fig. 7). Veins showed slight fibrous thickening.
Widely scattered small petechiae dotted the centrum
semiovale and brain stem. There was no evidence of a
vasculitis.
A most striking change affecting the parenchyma of the
brain was the bilateral presence of large confluent areas of

FIGURE 3. In a pneumoencephalogram from April, 1972 (left), there is diffuse ventricular enlargement and very little free-convexity air. In
August, 1972 (right), the ventricles are of normal size and displaced to the left by a right subdural hematoma.

SUBCORTICAL ARTERIOSCLEROTIC ENCEPHALOPATHY/flurger et al.

FIGURE 4. /I whole mount histological section at the level of the
optic chiasm reveals a diffuse pallor of the centrum semiovale which
spares the subcortical arcuate zone. The cortex is intact; lacunar infarcts are scattered throughout the basal ganglia, the deep white
matter, the internal capsules and the corpus callosum. There is
marked atherosclerosis of the basilar vessels as well as the
peripheral anterior and middle cerebral arteries. Hematoxylin and
eosin/luxol fast blue, X 1.4.

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white matter pallor in the centrum semiovale and cerebellar
white matter and brain stem (fig. 4). The intensity of this
alteration varied somewhat from area to area and consistently spared the cerebral subcortical arcuate fibers (figs.
4 and 8). In the least involved regions there was simply a
decreased density of axons and their myelin sheaths and a
prominence of reactive astrocytes, while in more advanced
areas a further decrease in axon density was accompanied by
the presence of small, clear, empty spaces. In the most
severely involved zones there was a loose meshwork of
widely separated myelinated fibers enmeshed in a matrix of
granular eosinophilic material (fig. 9). Fragmenting axis
cylinders and degenerating myelin were both present, but
comparison of adjacent sections stained for myelin
(H&E/LFB) and axis cylinders (Holmes) suggested a
greater loss of myelin than axis cylinders. This apparent
preferential loss of myelin could also be appreciated in
H&E/LFB sections where large demyelinated axons were
observed (fig. 9). Scattered small cystic areas of frank infarction were noted which merged focally with the more
diffuse form of tissue loss. For the most part it was not possible to correlate a specific local vascular alteration with the
presence or absence of the diffuse white matter loss.
The diffuse white matter disease was reflected distally as
Wallerian pallor of the internal capsules, cerebral peduncles,
pontine base, and medullary pyramids. With the exception
of the old parietal and frontal infarcts, the cerebral and
cerebellar cortices were conspicuously intact (fig. 8).
Bielschowsky stains on sections of the frontal and hippocampal cortices revealed a few senile plaques but no
neurofibrillary change, granulovacuolar degeneration, Pick
bodies, or cortical status spongiosus.

629

FIGURE 5. An artery in the caudate nucleus shows the medial
thickening and deposition of a bubbly lipid characteristic of
lipohyalinosis. Hematoxylin and eosin/luxol fast blue, X 70.

vascular alterations of severe atherosclerosis, lipohyalinosis, and arterial and arteriolar hypertrophy and
hyalinization. It is unlikely that the senile plaques, which
have been encountered in other cases of SAE,10 contributed
significantly to the patient's dementia as they were few in
number and not associated with either neurofibrillary
change or granulovacuolar degeneration.
The present case is one of the more thoroughly clinically
studied examples of SAE and is a dramatic example of the
progressive dementia in this disorder. The age of onset (49
years) is atypical, as most cases have presented between 55
and 70 years of age.3'8 The neurological examination
revealed only transient, mild, focal lateralizing findings
which contrasted with the striking evidence of diffuse
cerebral dysfunction including disturbances of emotion and
memory, disorders of gait and speech, snout and suck reflexes, incontinence, and finally a state of akinetic mutism with
generalized increase in muscle tone. The patient's
progressive deterioration could be correlated with changes in
serial EEG tracings which showed progressive deterioration

Discussion

The diagnosis of SAE or Binswanger's disease in this
patient rests on the association of hypertension and dementia with a diffuse white matter degeneration accompanied by

FIGURE 6. An arteriole in the centrum semiovale is markedly
thickened. The white matter is pale and contains small cystic spaces
and reactive astrocytes. Hematoxylin and eosin/luxol fast blue,
X225.

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VOL. 7, No. 6, NOVEMBER-DECEMBER

1976

m

FIGURE 7. Two small arterioles in the pons are hyalinized and
brightly eosinophilic. Unlike the other vascular alterations, this
change was usually associated with a well-defined local breakdown
of myelin and axis cylinders. Here, the vessels are surrounded by a
zone of pallor which contains many macrophages. Hematoxylin and
eosin/luxol fast blue, X 225.

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of the background with increasing irregular slow wave activity. In the last months of life, infrequent myoclonic jerks,
primarily of truncal musculature, were seen, but could not
be correlated with EEG activity. In addition to the diffuse
slowing which has been documented in other reports,6' 9~12
this patient manifested triphasic waves which, in company
with myoclonic jerks, drew attention to the possibility of
Jakob-Creutzfeldt disease.
The patient had labile hypertension without systemic
manifestations. In most case descriptions of SAE, severe
hypertension has been documented, but there has been no
reported beneficial effect on the progression of the illness
with antihypertensive therapy, and no explanation why
hypertension expresses itself in this unique fashion in a small
group of cases. Cerebral angiography in our patient showed
mild arteriosclerotic changes in the large basal vessels, but
other large and small vessels were unremarkable. In two

FIGURE 8. A section from the left parietal lobe emphasizes the
preservation of the cortex and subcortical arcuate fibers, and, at the
far left, the pallor of the deep white matter. Hematoxylin and
eosin/luxol fast blue, X 25.

FIGURE 9. A hemaloxylin and eosin/luxol fast blue preparation
reveals a large axon (arrows) that has lost its myelin sheath. X 300.

previously reported cases of SAE, cerebral angiography was
unremarkable.9'12
An informative aspect of the present case was the evaluation by pneumoencephalography and radioactive serum
albumin (RISA) cisternography. Both studies demonstrated
changes compatible with normal pressure hydrocephalus
(NPH) (figs. 2 and 3), although such alterations are increasingly recognized as nonspecific.13 Because the patient's
clinical picture was consistent with the NPH syndrome, and
because repeated lumbar punctures led to an apparent improvement in clinical status, shunting seemed indicated.
Following a ventriculovenous shunt,- the ventricular size
returned to normal (fig. 3), but unfortunately did not alter
the progression of the patient's dementia. The abnormal
RISA study and the effect of the shunt in reducing ventricular size, the latter finding confirmed at postmortem examination, document an abnormality in CSF dynamics,
although this did not appear to contribute significantly to the
clinical symptomatology as it is presumed to do in the NPH
syndrome.
In light of the cortical preservation, dementia is one of the
most curious facets of SAE and is usually attributed to the
white matter lesions. The pathogenesis of this white matter
disease has been difficult to explain. Ischemia secondary to
the usually severe cerebrovascular disease is an obvious candidate, and is incriminated in our case by the gradations
between the diffuse form of white matter degeneration and
the frankly infarctive cystic foci. Some authors, however,
feel that the severe vascular changes are independent or
secondary alterations," and it remains to be explained why
ischemia's effect should be so largely directed at the white
matter.
One explanation utilizes the concept that the parenchyma
supplied by the most distal branches of the major cerebral
vessels is the most susceptible to a reduction in cerebral
bloodflow.This "watershed" or "borderzone" phenomenon
is usually most apparent in the setting of severe hypotension
as parasagittal infarcts which straddle the terminal distributions of the anterior and middle cerebral arteries, but
has also been advocated for the white matter degeneration in
SAE.8-1S
In the present case the white matter lesions were ubiq-

SUBCORTICAL ARTERIOSCLEROTIC ENCEPHALOPATHY/flurgev et al.

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uitous and clearly exceeded the watershed regions, but certainly could have begun there. In a sense, one might consider
the entire centrum semiovale as a watershed zone, as the
supplying vessels are most distal from the large arteries in
the subarachnoid space. Cerebral blood flow studies in
baboons confirm this precarious supply to the white matter
by the demonstration that progressive reduction of arterial
pressure can produce a state of zero blood flow in the centrum semiovale at a time when the cortical gray matter is
still being perfused.18 Experimental hypotension in dogs, furthermore, in some animals, produces selective necrosis of
the cerebral white matter."
A modification of this approach has suggested that the
long perforating vessels which supply the centrum semiovale
overreact to the hypertension to become fibrotic, dilated,
and unable to shield the more distal white matter
vasculature from the effects of the elevated pressure. It is
further postulated that this situation is aggravated by a
shunting of blood from the cortex.6
Others have noted that the deep cerebral white matter
forms an anatomic unit distinct from the cortex because of
the former's drainage into the deep or galenic system of
veins. These authors have suggested that congestion and
stasis within these veins, secondary to right-sided heart
failure, are pathogenetic factors in the white matter
degeneration of SAE. 16 ' 18
Still others have implicated cerebral edema, since it occurs in the brains of hypertensives and shows a similar distribution (deep white matter with sparing of the gray matter
and subcortical arcuate zone) as that of the white matter
degeneration of SAE. 14 ' 19 The apparent combination of
edema (induced by hypoxia) and ischemia has been
associated in some patients with cerebral lesions positioned
predominantly in the white matter. 20 ' 21
Whatever its pathogenesis, SAE remains a curious expression of hypertension and cerebrovascular disease which
appears unpredictably among the population of hypertensive individuals. The present case underscores the importance of its consideration in the genesis of dementia, even in
the presence of normal arteriography and in the absence of
sustained hypertension and significant
localizing
neurological signs. It also indicates that altered CSF
dynamics identical to those of the normal pressure hydrocephalus syndrome may occur in disease states in which
shunting is ineffective in altering the progression of the
dementia.

631

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