ltal. J. Neurol. Sci. 13.'135-140,

1992

Slowly progressive familial dementia
with recurrent strokes and white
matter hypodensities on CT scan
Salvi F.*, Michelucci R.*, Plasmati R.*, Parmeggiani L.*, Zonari P.*, Mascalchi M.**, Tassinari C.A.*
* Clinica Neurologica Universith di Bologna, Ospedale Bellaria, Bologna
** Dipartimento di Scienze Neurologiche, Universith di Firenze

We describe 2 normotensive sisters presenting slowly progressive dementia associated with acute or subacute focal neurological symptoms, unilateral or bilateral
motor signs, and dysarthria. Theirfather, who died in the seventh decade, had a
similar clinical picture. Computerized axial tomography (CT) scan of the head
showed symmetrical hypodensities in the periventricular white matter and mild to
moderate hydrocephalus. In these patients a diagnosis of Binswanger's disease
was based on the clinical features supported by white matter changes on CTscan.
Our study suggests" that genetic factors may play a role in the etiology of Binswanger's disease.

Key Words: Hereditary cerebrovascular disease -- Binswanger disease -- vascular dementia

Introduction
Vascular dementias (multi-infarct dementia, lacunar state, cerebral amyloid angiopathy, subcortical arteriosclerotic encephalopathy or Binswanger disease) usually occur sporadically in elderly hypertensive patients. However, rare instances of pathologically confirmed hereditary
multi-infarct dementia and Binswanger disease
(BD) in young and normotensive cases have been
reported [9-19-23-24]. The present study describes a family in which two normotensive siblings had clinical and radiological features consistent with the diagnosis of BD and the father of
the probands also had chronic vascular dementia.

ed members: two of them are sisters (cases II- 1
and II-5) who have been extensively studied clinically and radiologically, and the other is their father (case I-l) whose clinical history was obtained from past medical records and interviews
with other family members. All patients had similar symptoms and the course of the disease
showed relatively little variations from one case
to another.

Case reports

The pedigree of the family we studied is shown in
Fig. 1. The genealogical tree includes three affect-

Case I-1 was first admitted to the Institute of
Clinical Neurology, Bologna, in 1966 at age 61
with a 24-hours history of headache, vomiting,
dysarthria, right hemiparesis, and urinary incontinence. Neurological examination was unremarkable except for a mild right hemiparesis, increased tendon reflex on the right side, and a
right extensor plantar response. He partially recovered from the deficits over a 3-week period. In

Received 20 September 1990- Accepted 28 February 1991

13 5

Materials

The Italian Journal of Neurological Sciences

Fig. 1. Family pedigree.

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1967 he presented another acute episode of headache, vertigo, and marked dysarthria, from which
he totally recovered.
During the following four years, his mental status
progressively deteriorated and revealed a particularly severe amnesia, disorientation in time and
space, abulia, and dysphoria. In 1971 he was
readmitted to the hospital because of history of

gait disturbance with frequent falls and urinary
incontinence that developed over a 2-week period.
On neurological examination, he had evidence of
dementia and bilateral pyramidal signs in the upper and lower extremities. In 1974, the patient
died from circulatory shock at age 69. An autopsy
was not performed.

Fig. 2. Case 11-1. CTscan o f the brain at the age o f 38 (2A) and 42 (2B). Periventricular white matter lucencies increased in size over time. A t 42 a marked ventricular enlargement is present.
136

Salvi F.: Familial dementia with recurrent strokes

Fig. 3 Case II-5. CT images at the age of 49. White
matter hypodensities around thefrontal horn of the
lateral ventricles.
Case II- 1 was a 38-year-old woman who was first
seen in May 1983 because of a 6-month history of
rapidly progressive dementia. There was no past
medical history of arterial hypertension or cardiovascular disease. On admission, mental status
examination revealed a severe recent memory
loss and a disorientation to time, space, and person.
Neurological examination was unremarkable
except for a vertical nystagmus. Blood pressure
was normal. Routine hematological and biochemical tests were normal and serology for
syphilis was negative. Serum and urine aminoacids, urinary mucopolysaccharides and oligosaccharides and determination of the activity of lysosomal enzymes in the white cells were normal.
The following tests were normal: electrocardiogram (ECG), electroencephalogram (EEG),
electromyogram (EMG), and duplex ultrasonographic scanning of the carotid and vertebral arteries. Computerized tomography (CT) scan of
the head showed a mild ventricular dilatation
and diffuse, symmetrical hypodensities in the
white matter of both hemispheres mainly localized in the frontal and occipital periventricular
areas (Fig. 2A). An isotope cisternogram was
normal. During the following 8 months, she presented a progressive deterioration of mental
functions. On readmission to the hospital in February 1984, blood pressure was occasionally

mildly elevated with recordings up to 175/95
mmHg. On examination, she had a mild right hemiparesis and frontal lobe symptoms characterized by a marked apathy, dysphoria, bulimia,
and urinary incontinence. CT scan of the head
showed an extension of the white matter hypodense areas. On May 1985, she was seen at the
outpatient clinic because of a progressive onset
of left hemiparesis, which recovered partially
over a 1-month period. In the following months,
she gradually developed gait impairment with
frequent falls. She also had dysphagia, dysarthria, urinary incontinence, and episodes of
pathological crying and laughing. On admission
in January 1987, she was mute and could follow
only simple commands. On examination, a vertical nystagmus and bilateral pyramidal signs were
noted and she was totally unable to walk. A third
CT scan of the head revealed further enlargement of the ventricles (Fig. 2B). Over the following 8 months, there was some improvement of
the pseudobulbar and pyramidal signs but the intellectual impairment remained unchanged. The
patient died from pneumonia in July 1988 at the
age 43. Permission for autopsy was refused.
Case II-5 was a 49-year-old woman who was first
admitted to the hospital in June 1986 because of
an acute onset of dysarthria and left hemiparesis.
Blood pressure was normal. Head CT scan revealed white matter hypodensities in the frontal
periventricular region (Fig. 3). Her symptoms
partially improved within a few days. In December 1986, the patient was readmitted because of
mood changes and intellectual deterioration. On
mental examination, she was disoriented to time,
space, and person and she had memory deficits.
Neurological examination showed that she had
dysphoria, dysarthria hypomimia, and brisk
deep tendon reflexes but her gait was normal.
Routine hematological and biochemical tests
were normal and serology for syphilis was negative. Serum and urine aminoacids, urinary mucopolysaccharides and oligosaccharides, leukocyte
arylsulfatase. A level, and determination of lysosomal activity in the white blood cells were normal. Screening for serum transthyretin (TFR)
protein according to a previously described technique [1] was negative. The following tests were
also normal: ECG, EMG, and duplex ultrasonographic scanning of the carotid and vertebral arteries. The EEG showed an excess oftheta activity over the frontal and temporal regions bilaterally. A second CT scan of the head revealed an increase in the periventricular white matter
hypodensities. Nuclear magnetic resonance
(NMR) imaging showed signal hyperintensity of
almost the entire cerebral white matter on T2
weighted images (Fig. 4A). Small areas of lucency lacunae were also evident in the basal ganglia
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The Italian Journal of Neurological Sciences

Fig. 4 Case 11-5. NMR of the head at the age of 50. T2 weighted images. Diffuse involvement of the white
matter (4.4) associated with areas of increased signal in the basal ganglia (4B).

and thalamus (Fig. 4B). An isotope cisternogram
was normal. Over the following year, she showed
slight progression of the intellectual impairment.
Discussion

A clinical picture of slowly evolving dementia occurring in adult patients and associated with recurrent stroke-like episodes, subacute accumulation of focal deficits, dysarthria and deterioration
of gait and sphincter control - - as encountered in
our cases -- clearly Suggests the diagnosis of vascular dementia. This term is currently used to
designate a few clinical entities with distinctive
pathological findings, such as multi-infarct dementia (MID), lacunar state, and subcortical arteriosclerotic encephalopathy or Binswanger disease (BD) [2, 4, 5, 6, 15, 16, 17, 21, 37]. In the present study pathological verification was not
available and, therefore, no definite proof of any
of these entities was reached. BD seemed however the most probable diagnosis owing to the neuroradiological findings of diffuse periventricular
white matter involvement and subcortical lacunae, as previously stressed in DB by several investigators [5, 14, 18, 20, 22, 26].
A variety of different conditions with similar CT
findings (such as normal pressure hydrocepha138

lus, chronic progressive multiple sclerosis, leukodystrophies, cerebral edema, watershed cerebral
infarction in the distribution of the carotid arteries, progressive multifocal leukoencephalopathy,
acute disseminated encephalomyelitis, metho=
trexate white matter necrosis, and hypertensive
encephalopathy) were excluded in our cases because of different clinical pictures and negative
complementary laboratory findings. Two main
features in our patients are quite unusual in vascular dementia and warrant special emphasis:
the familial occurrence and the absence of hypertensions. Maeda et al. [19] first published the
cases of two young normotensive Japanese
brothers with autopsy proven BD. Since then,
two further pairs of siblings with verified BD
were described by Friedland et al. [9] and two
large families with so-called "hereditary M I D "
were extensively reported by Sourander and Walider [24] and Sonninen and Savontaus [23]. All
these cases have common clinical features, including young age at onset and absence of arterial hypertension. The familial occurrence of vascular dementia, as observed in our cases, calls for
differential diagnosis from hereditary cerebral
amyloid angiopathies. These include a form with
recurrent cerebral hemorrhages, mainly described in Iceland [7, 8, 11, 12, 13], and also a variety defined under the heading of"familial ocu-

Salvi F.: Familial dementia with recurrent strokes

loleptomeningeal amyloidosis" [10] with associated TI'R accumulation [25]. In our patients cerebral hemorrhages were not detected and T r R
serum typing was negative. In summary, we report 3 members of a family who had a vascular
dementia and whose clinical and radiological
features resembled BD. Our findings along with

scattered reports of similar families in the literature [9, 19, 23, 24], suggest that the role of genetic
factors in vascular dementias may be more important than previously recognized. The absence
of hypertension and early age at onset in patients
with suspected vascular dementia should warrant further family inquiry.

Sommario

Descriviamo due giovani sorelle normotese affette da demenza lentamente progressiva associata a sintomi
neurologici focali ad insorgenza sia acuta che subacuta. Un quadro clinico simile era presente nel padre deceduto all'etil di 70 anni.
La TAC cranica mostrava nelle due pazienti ipodensiM simmetriche della sostanza bianca perventricolare
con idrocefalo moderato.
In questi pazienti una diagnosi di malattia di Binswanger f u fatta in base al quadro clinico ed alle lesioni riscontrate alia TA C. 11,nostro studio dimostra la possibiliti~ che fattori genetici siano responsabili di alcune
forme di malattia di Binswanger soprattutto in pazienti normotesi, giovani e senza fattori di rischio per malattie cerebrovascolari.
Address reprint requests to:
Dr. Fabrizio Salvi
Divisione di Neurologia
Ospedale Bellaria
Via Altura 3 - 40139 Bologna
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