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Toxoplasma Infection in Systemic Lupus Erythematosus Mimicking Lupus Cerebritis

      An opportunistic infection is a known, although underdiagnosed, complication of systemic lupus erythematosus (SLE). A 48-year-old woman with a recent diagnosis of SLE was admitted to the hospital because of a fever, confused state, and convulsive episode. Her symptoms were interpreted as being compatible with lupus cerebritis. Treatment with methylprednisolone resulted in a temporary improvement in the patient's condition. Nevertheless, during the next few weeks, her physical and mental condition deteriorated, and she died of massive pulmonary emboli. An autopsy revealed no signs of lupus cerebritis; however, disseminated cerebral toxoplasmosis was found. Cerebral toxoplasmosis is a rare complication of SLE that may be misdiagnosed as lupus cerebritis.
      CNS (central nervous system), CRP (C – reactive protein), CSF (cerebrospinal fluid), SLE (systemic lupus erythematosus)
      Opportunistic infections are common in patients with systemic lupus erythematosus (SLE) and are a major cause of death. Opportunistic infections involving the central nervous system (CNS) are uncommon, although Cryptococcus.
      • Mok CC
      • Lau CS
      • Yuen KY
      Cryptococcal meningitis presenting concurrently with systemic lupus erythematosus.
      • Huang J-L
      • Chou M-L
      • Hung L-J
      • Hsieh K-H
      Multiple cryptococ-cal brain abscesses in systemic lupus erythematosus [letter].
      Nocardia
      • Mok CC
      • Lau CS
      • Poon SP
      Primary nocardial meningitis in systemic lupus erythematosus.
      Listeria.
      • Kraus A
      • Cabral AR
      • Sifuentes-Osomio J
      • Alarcon-Segovia D
      Listeriosis in patients with connective tissue diseases.
      Neisseria meningitidis,
      • Fijen CA
      • Kuijpcr EJ
      • Tjia HG
      • Daha MR
      • Dankert J
      Complement deficiency predisposes for meningitis due to nongroupable menin-gococci and Neisseria-Kiated bacteria.
      and herpesvirus
      • Feinman MC
      • Friedberg MA
      • Schwartz JC
      • et al.
      Central nervous system herpesvinis infection in systemic lupus erythematosus: diagnosis by endoretinal biopsy.
      have been reported as CNS pathogens. Because brain vasculitis is extremely common in patients with SLE, distinguishing an infection of the eNS from vasculitis can be a diagnostic challenge. In such a case, misdiagnosis may be fatal.
      We describe a patient with SLE and CNS manifestations that were suspected to be part of the primary disease and were treated as such; however, at autopsy, they were found to be cerebral toxoplasmosis.

      Report Of Case

      A 48-year-old woman was referred to the hospital in January 1996 because of a high fever, confused state, and convulsive episode. At age 40 years, she had undergone a subtotal thyroidectomy because of a multinodular goiter. A month before the current hospitalization, she had been hospitalized elsewhere for peripheral edema, and nephrotic syndrome was diagnosed. Histologic findings were consistent with membranous glomerulonephritis, a manifestation of SLE. Methylprednisolone, 60 mg/d, was begun.
      On admission to our hospital, the patient had a fever (39.3°C), a resting pulse rate of l00/min, a few oral ulcers, and a facial butterfly rash. Initial assessment revealed an increased erythrocyte sedimentation rate, anemia (hemoglobin concentration, 8.9 g/dl.), and leukopenia (leukocyte count, 2.5 × l0
      • Castillo M
      /L). Results of kidney function tests were normal, and no proteinuria was noted. Antinuclear antibody was positive at a titer of 1–160, as was anti-double-stranded DNA.
      Computed tomography of the brain revealed mild dilatation of the lateral and third ventricles and small calcifications in the basal ganglia (Figure 1). Electroencephalography showed general irregular deceleration. The patient was treated with ciprofioxacin because of a suspected urinary tract infection. The diagnosis of SLE was confirmed on the basis of her having 6 of the 1982 revised criteria for the classification of SLE: malar rash, renal disease with heavy proteinuria, oral ulcers, leukopenia, high antinuclear antibody, and positive anti-double-stranded DNA.
      • Tan EM
      • Cohen AS
      • Fries JF
      • et al.
      The 1982 revised criteria for the classification of systemic lupus erythematosus.
      Because she was confused and had a convulsive event, lupus cerebritis was suspected, and the dose of methylprednisolone was increased. She had an uneventful recovery within a few days.
      Figure thumbnail gr1
      Figure 1Computed tomographic scan of the brain of a 48-yearold woman, demonstrating calcifications in the basal ganglia.
      A week later, the patient was referred to the hospital after another “convulsive event”; she was in a confused state and had a temperature of 37.8°C. A lumbar puncture was performed. Findings on a cerebrospinal fluid (CSF) examination were normal except for an increased protein level (150 mg/dL) and oligoclonal bands of γ-globulin. No bacteria were observed, and CSF cultures were negative. Findings on repeated electroencephalography and computed tomography of the brain were normal. Corticosteroid treatment was continued because lupus involvement of the CNS was assumed.
      During the next 2 weeks, the patient's fever disappeared, but her mental and physical condition deteriorated, with apathy and depression, until she became bedridden. Deep venous thrombosis developed in her left thigh, and she underwent complete anticoagulation. However, acute respiratory failure occurred and led to her sudden death.

      Pathologic Findings

      Pathologic examination revealed a massive pulmonary embolism that probably caused our patient's death. Although membranous glomerulonephritis was found, no signs of lupus cerebritis were detected.
      Sections of the brain disclosed numerous necroinflammatory foci within the basal ganglia and cerebral gray matter. These foci were remarkable for the presence of microcystic structures that were 18 to 40 μrn in diameter. The cysts were filled with minute round basophilic structures consistent with bradyzoites of Toxoplasma (Figure 2). Plasma cells and lymphocytes were observed surrounding the cysts, inflammatory cells, and macrophages. Blood vessels showed perivascular lymphoid infiltration, endothelial swelling, and thrombosis. Immunohistochemical staining for Toxoplasma was positive in the cysts, an outcome confirming the histological diagnosis (Figure 3).
      Figure thumbnail gr2
      Figure 2Brain tissue showing inflammatory cells and several cysts filled with Toxoplasma (hematoxylin-eosin, original magnification × 400).
      Figure thumbnail gr3
      Figure 3Immunohistochemical staining for Toxoplasma shows strong reactivity within parasitic cysts (immunoperoxidase stain, original magnification × 400).

      Discussion

      Toxoplasma gondii infection is a common disease worldwide. Acute infection in an immunocompetent host is usually asymptomatic.
      The 3 major pathologic patterns of cerebral toxoplasmosis are diffuse encephalopathy with or without seizures, meningoencephalitis, and singular or large progressive mass lesions.
      • Remington J
      • Desmonts G
      Toxoplasmosis.
      Increased protein and increased IgG levels in the CSF, as in our patient, are the most common abnormalities in toxoplasmosis of the CNS.
      In the current case, the 2 nonspecific clues for toxoplasmosis were calcifications in the basal ganglia and a positive serum C-reactive protein (CRP).
      • Mok CC
      • Lau CS
      • Yuen KY
      Cryptococcal meningitis presenting concurrently with systemic lupus erythematosus.
      Basal ganglia calcifications (Figure 1) could lead to suspected toxoplasmosis.
      • Remington J
      • Desmonts G
      Toxoplasmosis.
      • Castillo M
      • Chapman S
      • Nakielny R
      Other causes of basal ganglia calcifications include cytomegalovirus, rubella, herpes simplex, hypoparathyroidism, pseudohypoparathyroidism, pseudopseudohypoparathyroidism, Cockayne syndrome, Wilson disease, Fahr syndrome, anoxia, lead poisoning, carbon monoxide poisoning, and familial and idiopathic causes.
      • Chapman S
      • Nakielny R
      In toxoplasmosis, a contrast-enhanced computed tomographic scan usually shows solitary or multiple ring-enhancing lesions with peripheral edema,
      • Post MJ
      • Chan JC
      • Hensley GT
      • Hoffman TA
      • Moskowitz LB
      • Lippmann S
      Toxoplasma encephalitis in Haitian adults with acquired immunodeficiency syndrome: a clinical-pathologic-CT correlation.
      a pattern not found in our patient. Healed lesions show focal areas of malacia, which may calcify.
      • Castillo M
      The absence of any other lesions in the brain of our patient suggests that the calcifications were benign and were not related to toxoplasmosis. A quantitative serum CRP determination, probably with a finding of high levels, could be a clue for such a superinfection. Such CRP detection in serum during an acute phase of CNS infection is diagnostically important because a CRP increase suggests a purulent process
      • Przyjalkowski W
      • Lipowski D
      • Kolasa T
      • Issa E
      • Janeczko J
      C-reactive protein (CRP) and its significance in purulent meningitis [published correction appears in Neurol Neurochir Pot. 1996;30: 177).
      and may be used for determining optimal duration of antibiotic treatment of meningitis
      • Nouira S
      • Elatrous S
      • Mustapha R
      • et al.
      C-reactive protein in bacterial meningitis in adults.
      However, CRP levels in CSF are much more accurate. Stearman and Southgate
      • Stearman M
      • Soulhgate HJ
      The use of cytokine and C-rcaclivc protein measurements in cerebrospinal fluid during acute infective meningitis.
      reported that a CRP concentration of 100 ng/mL had a sensitivity of 87% for bacterial meningitis.
      The diagnosis of SLE was based on the 1982 revised criteria for the classification of SLE
      • Tan EM
      • Cohen AS
      • Fries JF
      • et al.
      The 1982 revised criteria for the classification of systemic lupus erythematosus.
      of which our patient had 6.
      CNS disease in SLE may be expressed either by organic psychosis or by seizures.
      • Rothfield NF
      Systemic lupus erythematosis: clinical aspects and treatment.
      • Feinglass EJ
      • Amett FC
      • Dorsch CA
      • Zizic TM
      • Stevens MB
      Neuropsychiatric manifestations of systemic lupus erythematosus: diagnosis, clinical spectrum, and relationship to other features of the disease.
      Scizures are usually of the grand mal type, but chorea, petit mal seizures, jacksonian epilepsy, and temporal lobe seizures may also occur, usually during the beginning of the acute stage. Organic syndromes are characterized by impairment of orientation and perception, loss of ability to calculate, memory loss, and psychosis. Our patient had general convulsions and signs of organic brain disease, both typical manifestations of lupus cerebritis; thus, we assumed that she had lupus cerebritis.
      In a study involving 37 patients with neural lupus, Feinglass et al
      • Mok CC
      • Lau CS
      • Yuen KY
      Cryptococcal meningitis presenting concurrently with systemic lupus erythematosus.
      detected CSF abnormalities in 32% of cases of neuropsychiatric illness. Demonstration of tachyzoites in tissue sections or smears of body fluids establishes the diagnosis of acute Toxoplasma infection.
      • Beaman MH
      • McCabe RE
      • Wong S-Y
      • Remington JS
      Toxoplasma gondii.
      Detecting tachyzoites in stained tissue sections is often difficult.
      • Beaman MH
      • McCabe RE
      • Wong S-Y
      • Remington JS
      Toxoplasma gondii.
      Fluorescent antibody staining may be a useful, although nonspecific, method.
      • Frenkel JK
      • Piekarski G
      The demonstration of toxoplasma and other organisms by Lmmunofluorescence: a pitfall [editorial].
      The peroxidase-antiperoxidase technique with the use of antisera to Toxoplasma has proved to be both sensitive and specific in revealing the organism in the CNS.
      • Frenkel JK
      • Piekarski G
      The demonstration of toxoplasma and other organisms by Lmmunofluorescence: a pitfall [editorial].
      Other methods for detecting Taxoplasma in body fluids or tissues include enzyme-linked immunosorbent assay, fluorescein-labeled monoclonal antibodies to Taxoplasma for touch preparations of specimens and rapid electron microscopy, polymerase chain reaction examination, and Wright-Giemsastained slides of sediment of CSF or smears of biopsy tissue.
      In the immunocompromised host, taxoplasmosis is an important cause of morbidity and mortality.
      • Conley FK
      • Jenkins KA
      • Remington JS
      Toxoplasma gondii infection of the central nervous system: use of the peroxidase-antiper-oxidase method to demonstrate toxoplasma in formalin fixed, paraffin embedded tissue sections.
      Few reports of taxoplasmosis complicating SLE have been reported in the medical literature, and this emphasizes the difficulty in establishing the diagnosis. Noel and associates
      • Noel I
      • Balfour AH
      • Wilcox MH
      Toxoplasma infection and systemic lupus erythematosus: analysis of the serological response by immunoblotting.
      found high titers of Taxoplasma antibodies to be more common in patients with SLE than in healthy control subjects, and therefore test results should be interpreted carefully.
      Wechsler and colleagues
      • Wechsler B
      • Le Thi Huong Du
      • Vignes B
      • Piette JC
      • Chomette G
      • Godeau P
      Toxoplasmosis and lupus: a review of die literature apropos of 4 cases [in French].
      described 4 cases of toxoplasmosis in patients with SLE. They also emphasized the diagnostic problems and recommended serologic analysis for taxoplasmosis before initiation of and during treatment with corticosteroids. Deleze et al
      • Deleze M
      • Mintz G
      • del Carmen Mejia M
      Toxoplasma gondii encephalitis in systemic lupus erythematosus: a neglected cause of treatable nervous system infection.
      described taxoplasmosis of the brain that resembled lupus cerebritis and thus created a diagnostic challenge in a patient with SLE.

      Conclusion

      The diagnosis of CNS infection in SLE may be difficult. A patient with SLE and neurologic manifestations is naturally suspected to have lupus cerebritis, especially when the primary symptoms are typical for SLE: psychosis and general convulsions. Nonetheless, a CNS infection must always be considered. Because laboratory diagnosis of lupus cerebritis is difficult and computed tomography is frequently nonspecific, other methods such as lumbar puncture should be performed when CNS symptoms are present. Magnetic resonance imaging is the most sensitive radiographic technique to detect changes of SLE and may be helpful in diagnosing lupus cerebritis Both lumbar puncture and magnetic resonance imaging, however, may fail to identify CNS infection in a patient with SLE. Because the clinical manifestations of Taxoplasma infection may be protean and nonspecific, it must be carefully considered in the differential diagnosis of lupus cerebritis. Either histological diagnosis or serologic tests for demonstration of Taxoplasma antigen or specific antibody in both blood and CSF should be performed when lupus cerebritis does not abate with conventional immunosuppressive therapy.

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