M. Wiedmann et al. Severe lupus erythematosus VASA 2004; 33:242–246 Departments of 1Internal Medicine II (Gastroenterology), 2IV (Rheumatology), and 3I (Medical ICU), Center of Internal Medicine, University of Leipzig, Leipzig, Germany ${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/0301-1526.33.4.242 - Tuesday, July 03, 2018 8:35:55 PM - Technische Universität München IP Address:129.187.254.46 A severe case of systemic lupus erythematosus with cerebral involvement Summary Zusammenfassung We describe an 18-year-old girl who presented with severe systemic lupus erythematosus with multiple organ involvement. The disease was further complicated by recurrent seizures and intracerebral left parieto-occipital bleeding that required neurosurgical treatment. Postoperative rebleeding occurred due to disseminated intravascular coagulation and platelet dysfunction. Catastrophic antiphospholipid syndrome was suspected, but could not be confirmed during follow-up. Additional treatment with plasmapheresis and intravenous pulse cyclophosphamide in combination with corticosteroids was started. Liquor drainage via a ventriculo-peritoneal (vp)-shunt was necessary because of a hydrocephalus malresorptivus. The patient’s recovery was slow and incomplete (cachexia and amaurosis persisted). Follow-up was further complicated by an intraperitoneal vp-shunt cyst, which was initially treated conservatively, but finally had to be revised operatively. Ein schwerer Fall eines systemischen Lupus erythematodes mit zerebralem Befall Wir beschreiben den Fall einer 18-jährigen Patientin mit schwerem systemischem Lupus erythematodes mit Multiorganbeteiligung. Die Erkrankung war weiterhin durch wiederholte zerebrale Krampfanfälle und eine intrazerebrale, linksseitig lokalisierte, parieto-okzipitale Blutung kompliziert, die eine neurochirurgische Behandlung erforderte. Postoperativ trat wegen einer disseminierten intravaskulären Koagulation und einer Thrombozytendysfunktion eine erneute Blutung auf. Ein katastrophales Antiphospholipidsyndrom wurde vermutet, konnte aber nicht bestätigt werden. Eine zusätzliche Therapie mit Plasmapherese und intravenöser Zyklophosphamidpulstherapie in Kombination mit Kortikosteroiden wurde begonnen. Eine Liquordrainage mittels ventrikulo-peritonealem (vp)-Shunt wurde wegen eines Hydrocephalus malresorptivus erforderlich. Die Genesung der Patientin verlief nur sehr langsam und inkomplett (eine Kachexie und Amaurose persistierten). Der weitere Verlauf wurde zusätzlich verkompliziert durch eine intraperitoneale vp-Shunt Zyste, die zunächst konservativ behandelt wurde, aber letztendlich einer operativen Revision bedurfte. Key words Systemic lupus erythematosus, antiphospholipid syndrome, vasculitis Introduction Systemic lupus erythematosus (SLE) is a disease of unknown origin in which tissue damage is induced by pathogenic autoantibodies and immune complexes. The incidence of SLE is rising over the past four decades [16]. Its prevalence in Northern Europe and the United States is about 40 per 100,000 population, commonly affecting women of childbearing age [10]. Patients with both SLE and antiphospholipid antibodies may develop “antiphospholipid syndrome” in 50 to 70% after 20 years of follow-up. There is an association between antiphospholipid antibodies and a syndrome of hypercoagulability [2, 13]. Although venous thrombosis is the most common manifestation of this syndrome, arterial thromboses can also occur and most commonly manifest with features consistent with ischemia or infarction [2, 4, 18]. In addition, DIC, which is not a feature of primary or sec242 Submitted 27. 3. 2004 / Accepted after revision 29. 5. 2004 DOI 10.1024/0301-1526.33.4.242 ondary antiphospholipid syndrome, occurs in approximately 25% of patients with catastrophic antiphospholipid syndrome, which is defined as the clinical involvement of at least three different organ systems over a period of days or weeks with histopathological evidence of multiple occlusions of large or small vessels [3]. The brain is the most common site for arterial thromboses in antiphospholipid syndrome and also affected in 56% of all catastrophic antiphospholipid syndromes. Although antiphospholipid syndrome and catastrophic antiphospholipid syndrome are therefore important causes of brain infarction in patients with SLE, the differential diagnosis of SLE vasculitis has to be considered [19]. As our case report demonstrates, the differentiation between the three entities is often difficult in an acute clinical setting. Abbreviations: BMI, body mass index; DIC, disseminated intravascular coagulation; ICP, intracranial pressure; ICU, intensive care unit; IVCYC, intravenous pulse cyclophosphamide; SLE, systemic lupus erythematosus © by Verlag Hans Huber, Hogrefe AG, Bern 2004 M. Wiedmann1,W. Seidel2, L. Mende3, S. Petros3 and L. Engelmann3 M. Wiedmann et al. Severe lupus erythematosus ${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/0301-1526.33.4.242 - Tuesday, July 03, 2018 8:35:55 PM - Technische Universität München IP Address:129.187.254.46 Case report In April 2002, an 18-year-old girl was referred to the department of Hematology of our university hospital for a suspected lymphoma. The patient complained of fatigue, malaise and fever for four weeks. Past medical, social and family history were unremarkable. On admission, the girl was alert and oriented, but in a reduced general (Karnofsky 70%) and nutritional state (BMI 18.3). She was pale, and bilateral basal pulmonary rales as well as hepatosplenomegaly were detected on clinical examination. The remaining physical examination including neurological status was unremarkable. A CT scan demonstrated an intraabdominal tumour, hepatosplenomegaly, pericardial and left pleural effusion, and unclear infiltration in the left lower lobe of the lung. Initial routine blood chemistry was normal apart from mild anemia (hemoglobin of 8.5 g/dl [normal 11.7–15.5]), thrombocytopenia (117×109/l [normal 150–300]), and hypoproteinemia (62.2 g/l [normal 66–87]), as well as a slight elevation of ASAT, GGT, LDH, and CK. CRP was 109.7 mg/l (normal < 5). A bone marrow biopsy showed a hypercellular marrow with increased granulo- and megakaryopoesis, a slight plasmocytosis, but no sign of lymphoma. Cells were positive for CD20 in 10%, negative for CD30, and positive for CD3 in 3% by immunhistochemistry. Bronchoscopy, bronchial lavage and pleural fluid analyses were negative. The patient was transferred to the department of Surgery for explorative minilaparotomy the second day after admission. This revealed an unclear retroperitoneal process with enlarged lymph nodes of up to 3 cm diameter. Lymph node histology showed a moderate inflammation and sinus histiocytosis. Peritoneal biopsy showed proliferation of mesothelial cells, fibrin deposits, calcifications and giant cell reaction. There was no sign of malignancy or granulomatous inflammation reaction. On the first postoperative day the general condition of the patient rapidly deteriorated with dyspnea, somnolence and tachycardia. She was transferred to the ICU (intensive care unit) and an VASA 2004; 33:242–246 intravenous therapy with ciprofloxacin and methylprednisolone was started. Initial ANA-titer was 1:10240 and anti-dsDNA-titer > 2000 U/ml (Table I). Together with a proteinuria of 0.75 g/l, five of the eleven criteria for the diagnosis of SLE were fulfilled. This was consistent with a reduced level of C3 and C4 complement. A pericardial effusion (600 ml) had to be drained and antimicrobial treatment was extended with piperacillin, beta-lactamase inhibitor, and difluconazole. Low-dose low molecular weight heparin was also started. The patient reported pain in her knee, finger, and elbow joints. During the afternoon of the same day she developed several grand mal seizures requiring sedation, intubation and mechanical ventilation. Valproic acid and diazepam were started. In addition, 800 mg cyclophosphamide was administered i.v. because neurologic manifestation of SLE was suspected. CT scan and MRI of the brain were unremarkable (Fig. 1A). Two days later the patient could be extubated. A skin biopsy showed superficial und deep perivascular dermatitis with linear deposits of IgA and IgM at the basal membrane including several blood vessels. Based on these findings SLE vasculitis was considered very likely. A control CT scan of the thorax depicted a regression of the pulmonary infiltrate and the pleural effusion. Anticardiolipin antibodies were 35 GPL/ml for IgG (normal < 12) and 7.3 MPL/ml for IgM (normal < 6) with a negative lupus anticoagulant (Table I). The next day, the patient developed anisocoria and Cheyne Stokes breathing pattern. Because of retention of secretion, reintubation was required. Cerebrospinal fluid (CSF) analysis was normal, but a repeat CT scan revealed a left-sided cerebral mass bleeding (Fig. 1B). A craniotomy was carried out, with removal of hematoma and insertion of an intracranial pressure (ICP) probe. Antifibrinolytic treatment was started due to DIC-associated wound bleeding. Flow cytometry for GMP-140 (p-selectin) expression showed reduced platelet activation after stimulation with ADP and TRAP-6. Microbiological investigation of tracheal secretion revealed enterococcus faecium, which was managed accordingly. Thirteen days after the operation, the patient could be weaned off the Table I: Antibody screening during the course of disease. Antibodies ANA Anti-dsDNA (IU/ml) Anticardiolipin (IgG/IgM) Lupus Anticoagulant Anti-Ro (SSA) Anti-La (SSB) Anti-RNP Anti-Sm (IU/ml) Anti-Jo-1 Anti-Scl-70 Anticentromere Antihistone Antinucleosome c-ANCA x-ANCA p-ANCA Anti-β-2-glycoprotein I Date (2002) April May June September November 1:10240 12100 positive negative positive positive positive 760 negative negative borderline 1:1280 5175 negative 1:320 109 negative negative positive negative positive 169 negative negative positive negative 1:1280 negative 1:640 negative positive negative positive 433 negative negative negative positive positive negative negative negative negative negative negative negative negative negative negative negative negative positive negative negative negative negative negative negative negative negative 243 ${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/0301-1526.33.4.242 - Tuesday, July 03, 2018 8:35:55 PM - Technische Universität München IP Address:129.187.254.46 M. Wiedmann et al. Severe lupus erythematosus 244 VASA 2004; 33:242–246 A A B B Fig. 1: CT scans of the brain. On the third day after admission to ICU the patient developed several grand mal seizures, but CT of the brain was unremarkable (A). Three days later a repeat scan revealed a left-sided parieto-occipital cerebral mass bleeding (B). Fig. 2: CT scans of the brain and thorax 24 days after the initial operation or 4 days after wound revision, respectively. New hypodense bilateral frontal and parieto-occipital lesions appeared causing a shift of the middle line to the left (A). Massive confluent interstitial infiltrations of both lungs excluding the periphery (B). ventilator and steroids were tapered off. A repeat skin biopsy proved SLE vasculitis. A right sided incomplete paresis, sensoric and motoric aphasia, and blurred vision, with the visual field limited to the left side, persisted. On the 20th postoperative day, surgical wound revision was required due to a subgaleal liquor deposit. The next day, the patient became unconscious, combined with another grand mal seizure, with the need for reintubation and mechanical ventilation. A CT scan of the brain revealed new hypodense bilateral frontal and parieto-occipital lesions (Fig. 2A). Massive confluent interstitial infiltrations of both lungs excluding the periphery were detected on CT scan of the lungs (Fig. 2B). This was interpreted as a progressive SLE, so that plasmapheresis (3×) and intraveneous pulse cyclophosphamide (IVCYC) in combination with corticosteroids were initiated and an ICP probe reinserted. The patient could be weaned off the respirator two days later, but a new minor right frontal cerebral bleeding (2.7 × 2.7 cm) was detected (Fig. 3B). Because it was not progressive, no further neurosurgical intervention was deemed necessary. A new subgaleal liquor deposit was also drained the same day. Another two days later, ICP probe could be removed and the liquor fistula was treated by lumbar liquor drainage for a total of seven days (Fig. 3A). The patient was then transferred to a general ward where phenprocoumon therapy was initiated and continued until antiphospholipid and catastrophic antiphospholipid syndromes were ruled out. She stayed there for another five weeks receiving two more cycles of IVCYC (intravenous pulse cyclophosphamide). ${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/0301-1526.33.4.242 - Tuesday, July 03, 2018 8:35:55 PM - Technische Universität München IP Address:129.187.254.46 M. Wiedmann et al. Severe lupus erythematosus A dura plastic and reimplantation of the skull bone were carried out. Ventriculo-peritoneal (vp)-shunt had to be installed due to a hydrocephalus malresorptivus. Because of recurrent epileptic attacks, valproic acid dose was increased and phenytoin added to the regimen. The patient`s further recovery was slow and incomplete, complicated by an intraperitoneal vp-shunt cyst (15.6 × 7.9 cm), which was initially treated conservatively, but finally had to be revised operatively in October 2003. Cachexia and amaurosis persisted. The patient was put on a regimen of IVCYC every month, and prednisolone dose was reduced to 5 mg per day. A B Fig 3: CT scans of the brain 39 days after the initial operation or 19 days after wound revision, respectively. Although a left occipital subgaleal liquor deposit was treated locally and drained for a total of seven days with a lumbar access, it was still present (A). Panel (B) depicts the remnants of a minor right frontal cerebral bleeding (2.7 × 2.7 cm) which had first occurred 6 days after wound revision. VASA 2004; 33:242–246 Discussion A 1999 consensus document has defined the neurological and psychiatric manifestations of SLE [1], which include a plethora of syndromes. Our patient suffered grand mal seizures and intracerebral bleeding. Seizures of any type occur in about 20% of patients during the course of disease. Focal brain infarctions and intracerebral bleeding are less frequent manifestations. The left parieto-occipital infarction that had occurred in our patient, followed by DICassociated wound bleeding after craniotomy, was first interpreted as part of a catastrophic antiphospholipid syndrome. Although anticardiolipin antibodies were initially positive, control evaluations were negative (Table I), so that the criterion for the diagnosis of antiphospholipid syndrome was not fulfilled [11]. Lupus anticoagulant was always negative. In addition, a test for β-2-glycoprotein I antibodies (Table I), which are currently not included in the laboratory criteria for antiphospholipid syndrome, was also negative. As a differential diagnosis, lupus vasculitis is described in up to 56% of patients with SLE [6]. In our patient, skin biopsies were indicative of this manifestation. However, there was no definite proof for the involvement of the intracerebral blood vessels. Smith et al. described two patients who developed a fatal neurological involvement with perivascular hemorrhages in one case [15]. Brain stem infarction [17] as well as cerebral infarction and hemorrhage [9] are also reported in the literature. Only ten randomised controlled trials on the treatment of complicated SLE have been published during the last 5 years, most of which included small numbers of patients [14]. The treatment of cerebral lupus is empiric due to a lack of randomized studies. High doses of glucocorticoids are rated beneficial for severly disabling manifestations of SLE. Cyclophosphamide in combination with glucocorticoids is probably beneficial in controlling the active disease, reducing the rate of recurrences and steroid requirements [7]. Intravenous pulse doses (10 to 15 mg/kg) once every 4 weeks have less urinary bladder toxicity than daily doses. In addition, although not proven, plasmapheresis might be beneficial in patients with acute life-threatening disease, for which high-dose immunosuppressive therapy may not be possible, or as an adjunct in patients not responding to conventional therapy [12]. Rather than the unselective removal of plasma, adsorption procedures allow the selective or specific removal of immunoglobulins, which seems to be a more reasonable approach especially in lupus nephritis. Plasmapheresis was used in our patient since her condition worsened dramatically 21 days after the initial neurosurgical operation. This was interpreted as progressive SLE and a more intense treatment regimen was considered necessary. Mycophenolate mofetil may be a promising alternative in patients who do not respond to high doses of cyclophosphamide or azathioprine [5]. Immunoablative therapy with and without autologous marrow stem-cell transplantation and some recently developed monoclonal antibodies such as anti-CD40L, anti-CD154 or anti-IL-10, or other molecules such as LJP394 may prove useful in the near future [8, 14]. Anticoagulation is mandatory for prevention of thrombotic complications. Several authors recommend oral anticoagulation with a tar- 245 M. Wiedmann et al. Severe lupus erythematosus ${protocol}://econtent.hogrefe.com/doi/pdf/10.1024/0301-1526.33.4.242 - Tuesday, July 03, 2018 8:35:55 PM - Technische Universität München IP Address:129.187.254.46 get international normalized ratio (INR) of 3–3.5, especially if antiphospholipid syndrome is suspected. In addition, infections are the leading cause of morbidity and mortality in patients with SLE. Meticulous exclusion of infection is mandatory, because this may masquerade as exacerbation of the underlying disease. 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Large vessel vasculitis of the central nervous system in systemic lupus erythematosus: report and review of the literature. J Rheumatol 1991; 18: 748–51. Marcus Wiedmann, M.D., Department of Internal Medicine II, University of Leipzig, Philipp-Rosenthal-Str. 27, 04103 Leipzig, Germany E-mail: wiedm@medizin.uni-leipzig.de 246