Histopathology 1987, 11, 1093-1099

Cerebral infarction due to systemic necrotizing
vasculitis in a patient with rheumatic heart disease,
subacute bacterial endocarditis and status
epilepticus
T.MIZUTAN1, K.YOSHIMURA, H.MATSUSHITA*,
R.SHIOZAWA & M.HARA*
Departments of Neurology and * Pathology, Toranomon Hospital and
Okinaka Memorial Institute for Medical Research, Tokyo, Japan
Accepted for publication 22 January 1987
MIZUTANIT., YOSHIMURA
K., MATSUSHITA
H., SHIOZAWA
R. & HARAM. (1987)
Hisfoprhology 11, 1093-1099
Cerebral infarction due to systemic necrotizing vasculitis in a patient with rheumatic
heart disease, subacute bacterial endocarditis and status epilepticus

Systemic necrotizing vasculitis involving cerebral blood vessels is described in a
30-year-old man with rheumatic heart disease and subacute bacterial endocarditis.
Fever, anaemia, splenomegaly and positive blood cultures for Gram-negative
bacteria were found on adniission. The fever resolved with antibiotic therapy on the
third hospital day but he then developed hemiplegia and multifocal seizures. The
seizures progressed to uncontrollable status epilepticus accompanied by congestive
heart failure and the patient died 20 d after admission. At autopsy, exudative and
necrotizing vasculitis involving medium- to small-sized arteries was seen in the brain,
the heart and the skeletal muscles. Rheumatic myocarditis and endocarditis and old
rheumatic mitral valve deformities were also present. In addition, verrucous
endocarditis in the mitral valve and Lohlein’s focal glomerulonephritis were noted.
We discuss the possible mechanism of the systemic necrotizing vasculitis in relation
to rheumatic fever.
Keywords: systemic necrotizing vasculitis, cerebral vasculitis, cerebral infarction,
rheumatic fever, status epilepticus

Introduction

Central nervous system complications are not uncommon in patients with rheumatic heart disease and subacute bacterial endocarditis (SBE) (Bruetsch 1944, 1971,
Siment 1969, Pruitt et al. 1978). However, neurological complications due to
Address for correspondence: Dr T.Mizutani, Department of Neurology, Nihon University School
of Medicine, 30-1 Ohyaguchi Kami-machi, Itasbashi-ku, Tokyo 173, Japan.

1093

1094 T.Mizutani et al.
systemic vasculitis involving the brain are unusual in such patients (Stehbens 1972,
Yates 1976). We report here a case of systemic exudative and necrotizing vasculitis
involving the brain in a patient with rheumatic heart disease and SBE who died of
status epilepticus and congestive heart failure.

Case report
A 30-year-old mentally-retarded man had exhibited persistent fever for 3 months

prior to the admission. On admission, the temperature was elevated at 39.0"C and
blood pressure was 142172 mmHg. He was alert, and had bilateral Babinski signs.
No other abnormalities were present on physical examination.
The laboratory data on admission were as follows: haemoglobin, 6.3 g/dl; white
blood cell count, 1 2 . 8 ~ 1 0 ~ 1with
1 8% stab forms, 84% neutrophils, 7% lymphocytes and 1% monocytes; platelets, 1 l O X 109/l; erythrocyte sedimentation rate, 53
mm/h; C-reactive protein, 6+; anti-streptolysin 0 titre, 1:256; rheumatoid factor,
+; hepatitis B antigen positive and hepatitis B antibody negative; urea nitrogen,
4.8 mmol/l; creatinine, 168 pmolll; fasting blood sugar, 14.5 mmol/l; and 37.5% of
y-globulin. Urinalysis revealed numerous red blood cells, 25-30 white blood
celldfield, 1.7g/l protein, and +++ test for sugar. X-rays of the chest and
abdomen indicated splenomegaly, and a scintigram showed moderate to marked
splenomegaly and mild hepatomegaly . An electrocardiogram was normal. Blood
cultures revealed Klebsiella oxytoca and urine cultures showed Klebsiella
aerogenes. The cerebrospinal fluid was mildly xanthochromic under normal
pressure with 57 white cells/mm3 including 38 neutrophils, 14 lymphocytes and 5
others; total protein was 0.7g/l, glucose was 6.0 mmol/l, and there were negative
cultures for bacteria and fungi. A computed tomographic scan of the head
indicated slight cerebral atrophy.
The patient was started on sulbenicillin disodium, cefazolin sodium and
gentamicin sulphate, and the fever resolved after 3 d. However, the patient then
developed generalized seizures followed by persistent right hemiplegia. Subsequently, frequent multifocal seizures occurred, leading to status epilepticus which
became uncontrollable, followed by pulmonary oedema; he remained afebrile but
died on the 20th d after admission.

+

Autopsy findings

There was marked fibrous thickening and adhesions of the mitral valve leaflets with
fusion and shortening of the chordae tendineae. Several verrucae measuring 0.5 cm
in diameter were present at the mitral leaflets on the side of the left atrium and on
the part of the chordae tendineae in the left ventricle. A Gram's stain failed to
demonstrate any bacteria in the thrombi vegetations infiltrated by numerous
neutrophils and lymphocytes. Exudative and necrotizing vasculitis was evident in
the small- and medium-sized branches of the coronary arteries with or without mild

Cerebral infarction due to necrotizing vasculitis 1095

Figure 1. Myocardium. a Acute exudative and necrotizing vasculitis without infiltration of inflammatory
cells in a medium-sized artery. H & E. X 170. b A micro-infarct infiltrated by lymphocytes and histiocytes
including occasional binucleated cells (arrow). H & E. X330.

infiltration of lymphocytes, plasma cells and histiocytes (Figure la). There was
fibrinoid degeneration of the collagen fibres and basophilic ground substance in the
perivascular area, accompanied by a mild infiltrate of lymphocytes, Anitschkow
cells and binucleated histiocytes. Typical Aschoff bodies were not present. Multiple
small foci of necrosis were noted in the myocardium, occasionally accompanied by
a mild inflammatory reaction which consisted of lymphocytes, histiocytes and
binucleated cells (Figure lb) . The skeletal muscles showed occasional necrotizing
vasculitis in the small- and medium-sized arteries (Figure 2).
The brain weighed 1200g. The major cerebral arteries did not show any
significant abnormalities. Numerous acute and recent infarcts measuring 0.2-0.5 cm
in diameter (Figure 3a) were scattered in the cerebrum and cerebellum. A few old
infarcts were also observed. Microscopic examination of the brain revealed diffuse
acute necrotizing vasculitis with fibrinoid necrosis and exudative changes in the
medium- and small-sized arteries of the subarachnoid space and the parenchyma of
the cerebrum and cerebellum (Figures 3b & 3c), often accompanied by a mild
mononuclear cell infiltration and focal subarachnoid haemorrhages in the vicinity

1096 T.Mizutani et al.

Figure 2. Necrotizing vasculitis with fibrinoid necrosis in a medium-sized artery of the skeletal muscle,
accompanied by lymphocytes and histiocytes. H & E. x 100.

Figure 3. Brain. a Small acute (single arrow) and recent (double arrow) infarcts in the cerebral cortex and
white matter. b Acute exudative and necrotizing vasculitis in a medium-sized artery of the subarachnoid
space in the cerebrum. H & E. ~ 6 6c .Acute exudative and necrotizing vasculitis in a small vessel of the
cerebellum accompanied by a recent infarct. H & E. X200. d Multinucleated giant cells in the cerebral
cortex. H & E. ~ 3 0 0 .

Cerebral infarction due to necrotizing vasculitis 1097
of the vasculitis. Multinucleated giant cells (Figure 3d) and focal phlebitis were
rarely present. The infarcts were accompanied by moderate numbers of macrophages, and frequent binucleated histiocytes with or without a mild degree of
reactive astrocytosis. Microabscesses were rarely ,seen.
Aneurysmal formation was not present on macroscopic or microscopic examinations throughout the body. Additional findings included splenic and pulmonary
infarcts, Lohlein’s focal glomerulonephritis and ground-glass hepatitis B antigenpositive hepatocytes without evidence of hepatitis consistent with a carrier state.

Discussion

The most prominent pathologic feature in this case was systemic necrotizing
vasculitis involving medium- and small-sized arteries. The lesions were at different
stages of development and were accompanied by infarcts infiltrated with binucleated histiocytes in both the heart and the brain.
The possible causes’of the vasculitis in the patient could be related to rheumatic
fever, subacute bacterial endocarditis, drugs , hepatitis B antigen, temporal
arteritis, granulomatous angiitis of the central nervous system and Takayasu’s
arteritis. However, the latter five causes of vasculitis are considered unlikely for
the following reasons. Drugs usually give rise to hypersensitivity vasculitis which
primarily involves small vessels without producing severe organ dysfunction
(Alarcon-Segovia 1977, Fauci 1979, Cupps & Fauci 1981). Hepatitis B antigenassociated vasculitis may cause the entire spectrum of vasculitis (Fauci 1979) and is
associated with evidence of an active hepatitis (Sergent, Lockshin & Christian
1976). The vasculitis in this case was of a necrotizing and exudative nature and not
granulomatous. These features are also not consistent with temporal arteritis
(Stehbens 1972). Absence of the involvement of the aorta and its main branches
makes Takayasu’s arteritis also unlikely (Stehbens 1972).
An association of SBE with a polyarteritis nodosa type of vasculitis has been
reported (Helpern & Trubeck 1933). The vasculitis ordinarily seen in infective
endocarditis, particularly of the subacute type, is hypersensitivity vasculitis as
observed in Osler’s node (Alarcon-Segovia 1977, Durack & Beeson 1978, Scheld
1984). In addition, our patient developed uncontrollable status epilepticus and
congestive heart failure after his SBE was treated. Such circumstantial evidence
would suggest that the SBE was a less likely cause of the vasculitis, although this
possibility cannot be ruled out.
The vasculitis did resemble pol yarteritis nodosa. However, against this diagnosis were the findings of prominent exudative changes in and around the vasculitis
(Scotti & Hackel 1985, Baggenstoss & Titus 1968), the perivascular fibrinoid
degeneration of collagen fibres, occasional to frequent binucleated histiocytes in
the infarcts of the myocardium (Scotti & Hackel 1985) and brain and the absence
of aneurysmal formation in the arteries (Von Glahn & Pappenheimer 1926,
Baggenstoss & Titus 1968). These features would suggest that the vasculitis was
more likely to represent rheumatic arteritis rather than classic polyarteritis nodosa.

1098 T.Mizutani et al.
However, typical Aschoff bodies were not present in our patient. Aschoff bodies
develop during the granulomatous phase of acute rheumatic fever and they are not
yet formed during the early exudative phase (Bloor 1978, Scotti & Hackel 1985).
Thus, an absence of Aschoff bodies does not exclude the possibility of a rheumatic
arteritis (Bruetsch 1971, Bloor 1978). We consider therefore that our patient was at
an early exudative phase of rheumatic fever and the systemic necrotizing vasculitis
observed here was probably related to recurrent rheumatic fever.
Rheumatic vasculitis usually involves small intramyocardial branches of the
coronary arteries (Bruetsch 1971, Scotti & Hackel 1985). More extensive necrotizing vasculitis resembling polyarteritis nodosa may occur in association with
rheumatic fever (Friedberg & Gross 1934, Bruetsch 1971, Scotti & Hackel 1985),
but involvement of the brain in such cases has not been recorded. The pathological
lesions observed in the brains of patients with rheumatic fever (apart from
embolism) consist of obliterative arteritis of small meningeal and cortical vessels
with micro-infarction and rheumatic meningoencephalitis (Winkleman & Eckel
1932, Bruetsch 1944, 1971, Denst & Neuburger 1948, Stehbens 1972, Yates 1976).
However, the obliterative arteritis could be interpreted as a nonspecific change
which may occur in various toxic-infective conditions (Winkleman & Eckel 1932,
Stehbens 1972, Yates 1976). The systemic necrotizing vasculitis as observed in our
patient is unusual and has not previously been documented (Stehbens 1972, Yates
1976).

Acknowledgements

The authors wish to thank Ms Tsune Akune for technical assistance and Ms
Sachiko Iguchi for secretarial assistance. The contents of this paper were presented
at the 9th Annual Meeting of the Japanese Stroke Society, Tokyo, Japan on 11
May 1984.
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