Annals of the Rheumatic Diseases 1992; 51: 550-552

550

Cerebral occlusive vasculopathy in systemic
lupus erythematosus and speculation on the part
played by complement
Ali Hammad, Yoshiaki Tsukada, Nelson Torre

Abstract
A 35 year old woman with systemic lupus
erythematosus and hypocomplementenaemia
presented with new onset seizures and subsequently died. At necropsy, widespread
microinfarctions of the cerebral cortex were
found to be predominantly due to the formation of leucoaggregates within small blood
vessels without any vasculitis.

Despite recent advances in the understanding of
the pathophysiology of systemic lupus erythematosus (SLE), the pathogenesis of some
complications of SLE remains enigmatic and, in
some instances, more than one mechanism may
be responsible for a similar complication.
Considerable controversy surrounds the pathogenesis of central nervous system disease in
SLE. We report here an unusual case in an
attempt to explain a mechanism that may play a
part in central nervous system disease in SLE.

Department of
Medicine,
Sisters of
Charity Hospital,
State University of
New York at Buffalo,
New York, USA
A Hammad
N Torre
Department of
Pathology,
Sisters of
Charity Hospital,
State University
of New York
at Buffalo,
New York, USA
Y Tsukada
Correspondence to:
Dr Nelson Torre,
Department of Medicine,
Sisters of

Charity Hospital,
2157 Main Street,
Buffalo, NY 14214, USA.
Accepted for publication
16 July 1991

Case report
A 35 year old woman with a history of SLE was
admitted to the Sisters of Charity Hospital with
rapidly progressive shortness of breath.
She had been in good health until three years
before this admission when she was admitted to
hospital for polyarthritis. Pertinent laboratory
data at that time were as follows: haemoglobin
101 g/l, packed cell volume 30 3, platelets
135 x 109/1, microscopic haematuria, 2+
proteinuria, positive antinuclear antibody
screen (titre 280, homogeneous), positive antibodies to double stranded DNA (titre 1/320),
total complement 22% of reference (normal
51-150%), C3 0-29 g/l (normal 0-7-1-76 g/l), C4
0*05 g/l (normal 0- 18-0-45 g/l). Serum electrolytes, blood urea nitrogen, and creatinine were
normal. Rheumatoid factor and anticardiolipin
antibodies were absent. A diagnosis of SLE was
made.
The patient also developed immune thrombocytopenia and her platelet counts reached a
minimum of 39x 109/l. High dose prednisone
resulted in an amelioration of symptoms and an
increase of the platelet count to normal levels.
A renal biopsy, performed two months later,
showed a mild and sparse sclerosing and proliferative glomerulonephritis. Proteinuria was
quantified at 2-2 g/day. She continued to have
low C3 and C4 levels and developed a vasculitic
rash on her hands and feet. She was then treated
with azathioprine and prednisone for approximately seven months with improvement.
Subsequently, she developed maxillary sinusitis

requiring admission to hospital and treatment
with antibiotics. At that time, azathioprine was
stopped and prednisone was decreased to
20 mg/day. Two months before this admission
she developed a Mycobacterium chelonei infection
of the skin of the left upper arm and was
admitted to the hospital for intravenous treatment with antibiotics. At the time of this
admission she was receiving prednisone
(20 mg/day).
On examination she was alert and oriented
but obviously dyspneic. Vital signs were
as follqws: blood pressure 150/70 mmHg,
temperature 37°C, pulse 120 beats/minute,
respiratory rate 32 breaths/minute. Jugular
venous distention was noted. An S4 gallop was
heard. Her lungs were clear and her abdomen
was normal. No focal neurological deficits were
noted. Serum sodium, potassium and glucose
were normal. Creatinine was 240 [imol/l and
lactate dehydrogenase was 1488 U/1. Liver
enzymes were normal. Her white blood cell
count was 12 7 x 109/l, haemoglobin was 100 g/l,
packed cell volume was 31. Urine analysis
showed a specific gravity of 1 023, pH 5,
protein 3+, red blood cell count 10-20/high
powered field, white blood cell count 2-5/high
powered field, bacteria 1+, and no leucocyte
esterase or glucose. The coagulation profile was
normal. Blood, urine, and sputum specimens
were obtained for culture. An electrocardiogram showed sinus tachycardia with a nonspecific ST abnormality. Echocardiography
showed diffuse hypokinesis, a left ventricular
ejection fraction of 25-30%, and a moderate
sized thrombus in the left ventricle. Shortly
after presentation, she developed intermittent
tonic clonic seizure activity. Intravenous
heparin for possible cerebral emboli and high
dose parenteral corticosteroids for possible
vasculitis were begun. She developed cardiac
arrest from which she was promptly and
successfully resuscitated, but she then remained
comatose and hypotensive. Arterial blood gas
determinations showed a severe and persistent
metabolic acidosis. Empirical treatment with
antibiotics was begun with cefoxitin, amikacin,
and erythromycin. A computed tomography
scan of the brain showed multiple cortical
infarctions without intracranial haemorrhage.
The patient then developed acute renal failure
with anuria. She finally succumbed to her
multisystem disease less than 48 hours after
admission. Cultures of blood, urine, and
sputum remained negative.
At necropsy, anasarca was noted. The heart
showed concentric hypertrophy but no mural
thrombus was found. The lungs showed severe

551
Systemic occlusive vasculopathy in SLE51

passive congestion. No vasculitis was found in
the heart or the lungs. The kidneys were
shrunken and showed se'vere glomeruloscierosis
and crescentic glomerulonephritis. The pathology of the brain was important. Multiple small
cortical infarctions were seen scattered throughout the cerebral hemispheres (fig 1). Microscopic
examination showed these infarctions to be one
to two days old with acute ischaemic changes of
the neurones and polymorphonuclear infiltration. A few older microscopic infarcts were
present. The vessels in the areas of infarction
were normal in appearance and free of any
vasculitic process. A main pathological process
appeared to be occlusion of these small vessels
by aggregates of leucocytes (fig 2). Occlusion of
small vascular lumens by fibrin thrombi was

Figure 3 Fibrin microthrombus within a small blood vessel
(haematoxylin and eosin stain).

Fi'gure 4 Leucocytes in a Virchowv-Robi'n space
(haematoxyli'n and eosi'n stai'n).

~' rare (fig 3). A few small vessels showed VirchowRobin spaces filled with4eucocytes, representing
extension of leucocytes from the subarachnoid
space (fig 4).
I Photograph of the frontal lobe of the cei rebrum
showing multiple recent cortical infarcts.

Figure

40.
.....

0

..........

Discussion
The clinical manifestations of central nervous
system disease in SLE are protean. They
include seizures, cranial nerve disorders, hemiparesis, paraparesis, peripheral neuropathy,
*movement disorders, meningeal signs, and
autonomic disorders.' Psychiatric manifestations and disorders of mental functions are
also well described.2 The pathogenesis of central
nervous system disease in SLE, however,
remains ill defined. In one necropsy series,
the major neuropathological findings included
vasculopathy, infarction, haemorrhage, and
infection.3 Vasculopathy was found in 65% of
the studied cases and was further-subclassified
as vascular hyalination, perivascular inflammation, endothelial proliferation, thrombosis,
* and, rarely, vasculitis. Antiphospholipid antibodies, which may be present in up to 44% of
patients with SLE, have also been associated
with an increased propensity towards thrombosi. Complement probably has an important
part to play in vascular injury in SLE. The role
wihaue of immune complexes in complement activation
is well established. Autoantibodies against

.......

Ar

..................

J

vessels with leucocyte aggregates, and neurones
Figure 2 Occlusion of small blood
anoxic changes (haematoxylin and eosin stain).

552

Hammad, Tsukada, Torre

nuclear antigens, especially double stranded
DNA, result in the formation of immune
complexes that deposit within the walls of small
vessels and activate complement at the site of
deposition.5 Nevertheless, some lupus patients
have small vessel occlusive disease without any
evidence of immune complex deposition. This
could be explained on the basis of intravascular
activation of complement via the alternative
pathway as a cause of activation and aggregation
of inflammatory cells in SLE.b
In 1988 Hopkins et al 7 reported two patients
who died during an acute lupus flare and, at
necropsy, were found to have cerebral and
intestinal infarctions. Microscopy failed to show
any fibrin thrombi or vasculitis. Many vessels,
however, were found to be occluded by aggregates of neutrophils. They suggested that
circulating anaphylatoxins, C3a and C5a,
products of intravascular complement activation,
may result in occlusive vasculopathy by aggregation of leucocytes and platelets in a manner
similar to the endotoxin induced Shwartzman
reaction.8 These leucothrombi can result from
the increased adhesiveness of the polymorphonuclear cells to the subendothelial surface of
small vessels. Such increased adhesiveness has
been induced in vitro by lipopolysaccharide,
interleukin 1, and tumour necrosis factor.9
Cytokines, such as interleukin 1 and tumour
necrosis factor, and bacterial endotoxin lipopolysaccharide can induce the formation of
polypeptide endothelial leucocyte adhesion
molecules (ELAM 1) on the surface of cultured
human endothelial cells.'0 Theoretically, in
SLE, in addition to interleukin 1 and tumour
necrosis factor, complement split products,
immune complexes, and anticardiolipin antibodies may be responsible for such an increase
in vascular adhesiveness.7
In the patient reported here, we were able to
show a good correlation between clinical signs
(seizures and coma) and pathological findings
(diffuse cortical infarcts of various ages). Microscopically, the predominant lesion was that of
occlusive vasculopathy due to aggregation of

leucocytes within vessels subtending infarctions
(fig 2). The patient had low CH50, C3, and C4
levels throughout the course of her illness. This
probably represented continually active disease
and ongoing complement activation with inflammation. Complement activation products
and endogenous mediators of inflammation
could have resulted in increased adhesiveness of
the cerebral vascular endothelium by induction
of ELAM-1 like molecules with subsequent
leucothrombus formation leading to cerebral
infarction. It is noteworthy that anticardiolipin
antibodies were absent in this patient.
We have thus reported a patient with SLE
with major central nervous system disease
resulting in death. The pathological findings
suggest that the mechanism of infarction was
related to leucothrombus formation. Further
studies are needed to elucidate the pathogenetic
mechanism involved.
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ot systemic lupus erythematosus. Medicine(Baltimore) 1968;
47: 347-69.
2 Feinglass E J, Arnett F C, Dorsch C A, Zizic T M, Stevens
M B. Neuropsychiatric manifestations of systemic lupus
erythematosus: diagnosis, clinical spectrum, and relationship to other features of the disease. Medicine (Baltimore)
1976; 55: 323-39.
3 Ellis S G, Verity M A. Central nervous system involvement in
systemic lupus erythematosus: a review of neuropathologic
findings in 57 cases, 1956-1977. Semin Arthritis Rheum
1979; 8: 212-21.
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