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

Cerebral occlusive vasculopathy in systemiclupus erythematosus and speculation on the partplayed by complement

Ali Hammad, Yoshiaki Tsukada, Nelson Torre

AbstractA 35 year old woman with systemic lupuserythematosus and hypocomplementenaemiapresented with new onset seizures and sub-sequently died. At necropsy, widespreadmicroinfarctions of the cerebral cortex were

found to be predominantly due to the forma-tion of leucoaggregates within small bloodvessels without any vasculitis.

Despite recent advances in the understanding ofthe pathophysiology of systemic lupus ery-

thematosus (SLE), the pathogenesis of some

complications of SLE remains enigmatic and, insome instances, more than one mechanism maybe responsible for a similar complication.Considerable controversy surrounds the patho-genesis of central nervous system disease inSLE. 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 ofMedicine,Sisters ofCharity Hospital,State University ofNew York at Buffalo,New York, USAA HammadN TorreDepartment ofPathology,Sisters ofCharity Hospital,State Universityof New Yorkat Buffalo,New York, USAY TsukadaCorrespondence to:Dr Nelson Torre,Department of Medicine,Sisters ofCharity Hospital,2157 Main Street,Buffalo, NY 14214, USA.Accepted for publication16 July 1991

Case reportA 35 year old woman with a history of SLE was

admitted to the Sisters of Charity Hospital withrapidly progressive shortness of breath.

She had been in good health until three years

before this admission when she was admitted tohospital for polyarthritis. Pertinent laboratorydata at that time were as follows: haemoglobin101 g/l, packed cell volume 30 3, platelets135 x 109/1, microscopic haematuria, 2+proteinuria, positive antinuclear antibodyscreen (titre 280, homogeneous), positive anti-bodies to double stranded DNA (titre 1/320),total complement 22% of reference (normal51-150%), C3 0-29 g/l (normal 0-7-1-76 g/l), C40*05 g/l (normal 0- 18-0-45 g/l). Serum electro-lytes, blood urea nitrogen, and creatinine were

normal. Rheumatoid factor and anticardiolipinantibodies were absent. A diagnosis of SLE was

made.The patient also developed immune thrombo-

cytopenia and her platelet counts reached aminimum of 39x 109/l. High dose prednisoneresulted 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 pro-

liferative glomerulonephritis. Proteinuria was

quantified at 2-2 g/day. She continued to havelow C3 and C4 levels and developed a vasculiticrash on her hands and feet. She was then treatedwith azathioprine and prednisone for approxi-mately seven months with improvement.Subsequently, she developed maxillary sinusitis

requiring admission to hospital and treatmentwith antibiotics. At that time, azathioprine wasstopped and prednisone was decreased to20 mg/day. Two months before this admissionshe developed a Mycobacterium chelonei infectionof the skin of the left upper arm and wasadmitted to the hospital for intravenous treat-ment with antibiotics. At the time of thisadmission she was receiving prednisone(20 mg/day).On examination she was alert and oriented

but obviously dyspneic. Vital signs wereas follqws: blood pressure 150/70 mmHg,temperature 37°C, pulse 120 beats/minute,respiratory rate 32 breaths/minute. Jugularvenous distention was noted. An S4 gallop washeard. Her lungs were clear and her abdomenwas normal. No focal neurological deficits werenoted. Serum sodium, potassium and glucosewere normal. Creatinine was 240 [imol/l andlactate dehydrogenase was 1488 U/1. Liverenzymes were normal. Her white blood cellcount was 12 7 x 109/l, haemoglobin was 100 g/l,packed cell volume was 31. Urine analysisshowed a specific gravity of 1 023, pH 5,protein 3+, red blood cell count 10-20/highpowered field, white blood cell count 2-5/highpowered field, bacteria 1+, and no leucocyteesterase or glucose. The coagulation profile wasnormal. Blood, urine, and sputum specimenswere obtained for culture. An electrocardio-gram showed sinus tachycardia with a non-specific ST abnormality. Echocardiographyshowed diffuse hypokinesis, a left ventricularejection fraction of 25-30%, and a moderatesized thrombus in the left ventricle. Shortlyafter presentation, she developed intermittenttonic clonic seizure activity. Intravenousheparin for possible cerebral emboli and highdose parenteral corticosteroids for possiblevasculitis were begun. She developed cardiacarrest from which she was promptly andsuccessfully resuscitated, but she then remainedcomatose and hypotensive. Arterial blood gasdeterminations showed a severe and persistentmetabolic acidosis. Empirical treatment withantibiotics was begun with cefoxitin, amikacin,and erythromycin. A computed tomographyscan of the brain showed multiple corticalinfarctions without intracranial haemorrhage.The patient then developed acute renal failurewith anuria. She finally succumbed to hermultisystem disease less than 48 hours afteradmission. Cultures of blood, urine, andsputum remained negative.

At necropsy, anasarca was noted. The heartshowed concentric hypertrophy but no muralthrombus was found. The lungs showed severe

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Systemic occlusive vasculopathy inSLE51

passive congestion. No vasculitis was found inthe heart or the lungs. The kidneys wereshrunken and showed se'vere glomeruloscierosisand crescentic glomerulonephritis. The patho-logy of the brain was important. Multiple smallcortical infarctions were seen scattered through-out the cerebral hemispheres (fig 1). Microscopicexamination showed these infarctions to be oneto two days old with acute ischaemic changes ofthe neurones and polymorphonuclear infil-tration. A few older microscopic infarcts werepresent. The vessels in the areas of infarctionwere normal in appearance and free of anyvasculitic process. A main pathological processappeared to be occlusion of these small vesselsby aggregates of leucocytes (fig 2). Occlusion ofsmall vascular lumens by fibrin thrombi was

Figure I Photograph of the frontal lobe of the cei

showing multiple recent cortical infarcts.

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0

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.................. ArJ

Figure 2 Occlusion ofsmall blood vessels with leucocyte aggregates, and neuronesanoxic changes (haematoxylin and eosin stain).

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 Virchow-Robin spaces filled with4eucocytes, representingextension of leucocytes from the subarachnoidspace (fig 4).

rebrum

DiscussionThe clinical manifestations of central nervoussystem disease in SLE are protean. Theyinclude seizures, cranial nerve disorders, hemi-paresis, paraparesis, peripheral neuropathy,

*movement disorders, meningeal signs, andautonomic disorders.' Psychiatric manifes-tations and disorders of mental functions arealso well described.2 The pathogenesis of centralnervous system disease in SLE, however,

.......remains ill defined. In one necropsy series,the major neuropathological findings includedvasculopathy, infarction, haemorrhage, andinfection.3 Vasculopathy was found in 65% ofthe studied cases and was further-subclassifiedas vascular hyalination, perivascular inflam-mation, endothelial proliferation, thrombosis,

* and, rarely, vasculitis. Antiphospholipid anti-bodies, which may be present in up to 44% ofpatients with SLE, have also been associatedwith an increased propensity towards throm-bosi. Complement probably has an importantpart to play in vascular injury in SLE. The role

wihaue of immune complexes in complement activationis well established. Autoantibodies against

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Hammad, Tsukada, Torre

nuclear antigens, especially double strandedDNA, result in the formation of immunecomplexes that deposit within the walls of smallvessels and activate complement at the site ofdeposition.5 Nevertheless, some lupus patientshave small vessel occlusive disease without anyevidence of immune complex deposition. Thiscould be explained on the basis of intravascularactivation of complement via the alternativepathway as a cause of activation and aggregationof inflammatory cells in SLE.b

In 1988 Hopkins et al 7 reported two patientswho died during an acute lupus flare and, atnecropsy, were found to have cerebral andintestinal infarctions. Microscopy failed to showany fibrin thrombi or vasculitis. Many vessels,however, were found to be occluded by aggre-gates of neutrophils. They suggested thatcirculating anaphylatoxins, C3a and C5a,products ofintravascularcomplement activation,may result in occlusive vasculopathy by aggre-gation of leucocytes and platelets in a mannersimilar to the endotoxin induced Shwartzmanreaction.8 These leucothrombi can result fromthe increased adhesiveness of the polymor-phonuclear cells to the subendothelial surface ofsmall vessels. Such increased adhesiveness hasbeen induced in vitro by lipopolysaccharide,interleukin 1, and tumour necrosis factor.9Cytokines, such as interleukin 1 and tumournecrosis factor, and bacterial endotoxin lipo-polysaccharide can induce the formation ofpolypeptide endothelial leucocyte adhesionmolecules (ELAM 1) on the surface of culturedhuman endothelial cells.'0 Theoretically, inSLE, in addition to interleukin 1 and tumournecrosis factor, complement split products,immune complexes, and anticardiolipin anti-bodies may be responsible for such an increasein vascular adhesiveness.7

In the patient reported here, we were able toshow a good correlation between clinical signs(seizures and coma) and pathological findings(diffuse cortical infarcts of various ages). Micro-scopically, the predominant lesion was that ofocclusive vasculopathy due to aggregation of

leucocytes within vessels subtending infarctions(fig 2). The patient had low CH50, C3, and C4levels throughout the course of her illness. Thisprobably represented continually active diseaseand ongoing complement activation with in-flammation. Complement activation productsand endogenous mediators of inflammationcould have resulted in increased adhesiveness ofthe cerebral vascular endothelium by inductionof ELAM-1 like molecules with subsequentleucothrombus formation leading to cerebralinfarction. It is noteworthy that anticardiolipinantibodies were absent in this patient.We have thus reported a patient with SLE

with major central nervous system diseaseresulting in death. The pathological findingssuggest that the mechanism of infarction wasrelated to leucothrombus formation. Furtherstudies are needed to elucidate the pathogeneticmechanism involved.

1 Johnson R T, Richardson E P. The neurological manifestationsot systemic lupus erythematosus. Medicine(Baltimore) 1968;47: 347-69.

2 Feinglass E J, Arnett F C, Dorsch C A, Zizic T M, StevensM B. Neuropsychiatric manifestations of systemic lupuserythematosus: diagnosis, clinical spectrum, and relation-ship to other features of the disease. Medicine (Baltimore)1976; 55: 323-39.

3 Ellis S G, Verity M A. Central nervous system involvement insystemic lupus erythematosus: a review of neuropathologicfindings in 57 cases, 1956-1977. Semin Arthritis Rheum1979; 8: 212-21.

4 Love P E, Santoro S A. Antiphospholipid antibodies:anticardiolipin and the lupus anticoagulant in systemiclupus erythematosus (SLE) and in non-SLE disorders. AnnIntern Med 1990; 112: 682-98.

5 Fauci T Y, Haynes B F, Katz P. The spectrum of vasculitis.Ann Intern Med 1978; 89: 660-76.

6 Abramson S B, Weissmann G. Complement split productsand the pathogenesis of SLE. Hosp Prac [OfQ 1988; 15:45-56.

7 Hopkins P, Belmont H M, Buyon J, Philips M, WeissmannG, Abramson S B. Increased levels ofplasma anaphylatoxinsin systemic lupus erythematosus predict flares of thedisease and may elicit vascular injury in lupus cerebritis.Arthritis Rheum 1988; 31: 632-41.

8 Shwartzman G. Phenomenon of local tissue reactivity. NewYork: Paul Hoeber, 1937.

9 Pohlman T H, Stanness K A, Beatty P G, Ochs H D, HarlanJ M. An endothelial cell surface factor(s) induced in vitroby lipopolysaccharide, interleukin 1, and tumor necrosisfactor alpha increases neutrophil adherence by a CDwl8-dependent mechanism. J Immunol 1986; 136: 4548-53.

10 Bevilacqua M P, Pober J S, Mendrick D A, Cotran R S,GimbroneMA Jr. Identification ofan inducible endothelial-leukocyte adhesion molecule. Proc Natl Acad Sci USA1987; 84: 9238-42.

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