A 54-year-old patient with systemic lupus erythematosus (SLE) presented with headache and confusion for 2 days.
History of the present illness
A 54-year-old woman was admitted to our hospital because of headache and confusion for 2 days. Her family reported that she had been feeling drowsy with slow speech and difficulty walking for one week. The headache was diffuse, dull, and constant, and associated with excessive sleepiness. The patient had longstanding SLE for 30 years, manifested by photosensitivity, arthralgias, membranous nephritis, hemolytic anemia, ischemic colitis, and positive antinuclear antibody (1:2,560 homogeneous pattern), anti–double-stranded DNA antibody (45 IU/ml, low positive), and anti-RNP antibody. Complement levels (C3 and C4) had been within normal range on repeated testing.
Past medical history and medications
Besides SLE, the patient had a history of avascular necrosis of both hips and had undergone bilateral hip replacement. For exacerbations of SLE in the past, she had been receiving dosages of prednisone ranging from 5 to 60 mg/day. She was started on mycophenolate mofetil 5 years ago following her most recent episode of hemolytic anemia and ischemic colitis, and prednisone was successfully tapered down to 5 mg/day. Her current immunosuppressive drug regimen was prednisone (5 mg/day), mycophenolate mofetil (1,000 mg/day), and hydroxychloroquine (400 mg/day).
Social and family history
The patient lived with her daughter and worked as an office secretary. She did not smoke tobacco or drink alcohol. Her family history was negative for any autoimmune disease.
Review of systems
There was no history of recent travel, trauma, or sick contact. Her family denied any recent events such as fever, chills, rash, alopecia, focal weakness, vision change, gastrointestinal or genitourinary disturbance, or cough or shortness of breath.
On admission, her vital signs were as follows: blood pressure of 124/56 mm Hg, heart rate of 68, respiration rate of 16, and temperature of 36.5°C. Oxygen saturation was 98% at room air. Physical examination did not reveal a rash or active synovitis. The patient was drowsy with slow, low volume speech, and oriented to person only. Neurologic status was difficult to assess because she could not remain awake for more than a few seconds at a time. Muscle tone was normal but deep tendon reflexes were diffusely brisk and the patient had poor coordination. Fundoscopy showed blunting of the optic disk margins bilaterally.
Laboratory and radiologic evaluation
Laboratory data showed a normal white cell count (6.7 × 1,000/c.mm) without lymphopenia. Other than low serum potassium (2.9 mmoles/liter) and calcium (8.1 mg/dl) levels, the metabolic profile was normal and tests of coagulation were normal. Serum complement (C3 and C4) and anti-DNA antibodies were within normal limits. A chest radiograph was normal. Computed tomography (CT) of the brain showed a large midline cerebellar hemorrhage with intraventricular extension and early hydrocephalus due to mass effect on the fourth ventricle (Figure 1). An emergent angiogram of the brain showed no evidence of aneurysm.
Surgery and postoperative course
The patient underwent surgery; a left suboccipital craniotomy was performed followed by cerebellar hematoma evacuation and placement of a right ventricular drainage catheter. The patient did well postoperatively, her mental status improved, and she was successfully extubated 4 days after surgery. During this period, her immunosuppressive regimen was discontinued. On postoperative day 7, the patient developed high-grade fevers up to 105°F with an altered mental status and abdominal distension. Blood, urine, and stool cultures were obtained and broad spectrum antibiotics were initiated. A chest radiograph was normal.
The patient is a 54-year-old woman with SLE and cerebellar hemorrhage requiring surgical evacuation who developed postoperative fever while off her immune suppression.
SLE exacerbation and neuropsychiatric SLE
Since the patient was taken off of her immune suppression during the perioperative period, we strongly considered the possibility of SLE exacerbation. She also had a history of ischemic colitis that could account for the abdominal distension and fever. Central nervous system (CNS) involvement can occur as a complication of SLE. Up to 18–67% of SLE patients can have CNS involvement or neuropsychiatric SLE (NPSLE) (1, 2). CNS manifestations are varied and can include psychosis, mood disorders, seizures, acute confusional states, stroke, migraine, chorea, aseptic meningitis, transverse myelopathy, as well as subtle cognitive impairment (3). There are no specific laboratory or magnetic resonance imaging (MRI) findings for NPSLE (4). MRI findings of the brain may be normal despite overt neuropsychiatric symptoms (5). Cerebrospinal fluid (CSF) analyses may show mild lymphocytic pleocytosis, raised protein levels, and IgG indices, as well as oligoclonal bands in 25–50% of cases (6). In up to 81% of the cases, NPSLE may occur without systemic SLE activity (2), often leading to a delayed diagnosis.
Patients with SLE also have an increased susceptibility to infection with many pathogens because of their intrinsic defects in immunity and the use of immunosuppression (7). Complement deficiency in lupus may contribute to immune defects, with a particular risk for developing serious infections with encapsulated organisms such as Streptococcus pneumoniae and Neisseria meningitidis (8). Viral (human immunodeficiency virus, cytomegalovirus, and herpes simplex virus) and parasitic infections must be considered and carefully excluded as well. Not uncommonly, rheumatologists face a diagnostic dilemma where it is difficult to distinguish NPSLE from an infectious complication of therapy.
Although rare in SLE, CNS vasculitis can occur in 25–75% of patients with various connective tissue disorders (9). In our patient, CNS vasculitis could have accounted for the altered mental status and cerebellar hemorrhage. However, the patient's angiogram did not support this diagnosis or a ruptured aneurysm and she clearly improved postoperatively before declining again.
FURTHER DIAGNOSTIC EVALUATION
The patient's hematocrit level dropped from 37.1% to 24.4% over 3 days. Laboratory data were consistent with hemolytic anemia with a positive direct Coombs' test, high lactate dehydrogenase, and low haptoglobin; she also had guaiac-positive stools. CT of the brain showed stable postoperative changes. CT of the abdomen showed colitis, possibly ischemic, most prominent in the cecum. Blood, urine, and stool cultures were negative. Lumbar puncture was performed that revealed xanthochromia, protein 72 gm/dl, glucose 72 mg/dl (serum glucose 145), and 222 nucleated cells (71% neutrophils, 18% lymphocytes, and 8% monocytes). A Gram stain of the CSF showed weakly acid-fast, Gram-positive branching, filamentous bacilli consistent with Nocardia asteroides, and this was later confirmed by culture report.
A subsequent MRI of the brain revealed faint frontal and temporal ring-enhancing lesions consistent with CNS nocardiosis (Figure 2). A partial ring-enhancing lesion was also noted in the cerebellum (Figure 3) at the site of the cerebellar hemorrhage seen on the CT of the brain at the time of admission. Intravenous trimethoprim/sulfamethoxazole (TMP/SMX) and methylprednisolone were simultaneously started to treat the CNS infection and lupus exacerbation manifested by hemolytic anemia and colitis. The patient showed remarkable improvement in the next few days and was discharged on oral TMP/SMX and a prednisone taper.
We present here an unusual case of a patient with SLE who developed CNS nocardiosis secondary to chronic immunosuppression followed by life-threatening features of SLE exacerbation on withdrawal of immunosuppression. This case therefore reminds us that all immunosuppressed SLE patients should be constantly monitored for infection; however, withdrawing immunosuppression in the face of a serious infection can be dangerous as well as it often precipitates a flare of SLE, as in our patient.
Nocardia was first described by Nocard in 1889. Nocardia comprises a group of gram-positive, weakly acid-fast, nonmotile, aerobic bacteria that form branching filaments that may fragment into rods or coccoid elements (10). Nocardiosis is a rare infection caused by strict aerobic actinomycetes of the Nocardia genus present in the soil that are not commensal organisms in animals or humans (11). Although there are a number of Nocardia species, only a few cause disease in humans, specifically N asteroides, N brasiliensis, N otitidiscaviarum (caviae), N transvalensis, N farcinica, and N nova. N asteroides accounts for the majority of all nocardial infection (12).
Nocardiosis has become a significant opportunistic infection in the last 2 decades due to the increase in the number of immunocompromised patients that has occurred with advances in organ transplantation and cancer chemotherapy, and the emergence of the acquired immunodeficiency syndrome (AIDS) (13). CNS involvement constitutes the most severe form of nocardiosis, and it typically presents as a brain abscess (13). CNS nocardiosis has been described in patients with SLE (10) and those receiving corticosteroid treatment (14). To our knowledge, no other case of CNS nocardiosis has been previously reported that presented with cerebellar hemorrhage in a patient with SLE. Justiniano et al reported a case of CNS nocardiosis in a patient with SLE following immune suppression for lupus nephritis (15). The diagnosis was delayed for several months and the patient developed ring-enhancing brain lesions; however, the patient was successfully treated. In our case, the presentation was much more acute due to the cerebellar hemorrhage leading to a prompt diagnosis.
Nocardiosis usually arises from direct inoculation of the skin or soft tissues or by inhalation. Nocardia are facultative intracellular pathogens that interfere with oxidative killing mechanisms and fusion of phagosomes and lysosomes, and block phagosomal acidification after being taken up by phagocytes (16). The host's defenses against nocardial infection rely on the integrity of neutrophil, monocyte, and lymphocyte functions (16). Impaired cell-mediated immunity such as that caused by corticosteroids and other immunosuppressive therapy or AIDS is an important risk factor for nocardiosis. Abnormal monocyte or neutrophil functions such as defective phagocytosis and free-radical generation also predispose to nocardial infection (17).
Because tropism for the cerebral tissue has been observed experimentally with Nocardia (18), seeding of the CNS may follow hematogenous spread from any focus. N asteroides is responsible for approximately 80% of noncutaneous invasive disease and for most systemic and CNS involvement (16). In cerebral nocardiosis, coexisting nocardial infection outside the CNS occurs in up to 71% of patients (19). In our case, Nocardia was not isolated from any other site, although the primary source of infection was presumably by inhalation.
Upon review of the current literature on nocardiosis and SLE, we found several case reports and case series describing the typical features and presentation of these patients. Pneumonia, nodules, and abscesses have all been described in patients with pulmonary involvement with subsequent hematologic dissemination to the CNS, skin, and subcutaneous tissues (20). CNS nocardiosis typically presents with a brain abscess, and patients with this infection have symptoms such as headache, confusion, fever, and seizures (4). Mok et al studied 215 patients with SLE and found 6 cases of nocardiosis, giving an incidence of ∼2.8%. All except one were caused by N asteroides. The lung was the commonest site of involvement (81%), followed by the CNS (13%). The mortality was high (35%), especially when the CNS was involved (75%) (10). Another survey of 36 cases of nocardial bacteremia by Kontoyiannis et al showed a mortality of 50%, rising to 85% in the severely immunocompromised (21). Involvement of 2 or more contiguous organs also carries a worse prognosis (22).
Definitive diagnosis of Nocardia infection relies on isolating and identifying the organism from biologic specimens, such as the CSF in our case. An aggressive diagnostic approach including bronchopulmonary lavage, lung biopsy, and aspiration of abscesses may be needed, depending on the site of infection. Diagnosis of nocardiosis in SLE patients can be difficult for several reasons: first, clinical features of nocardiosis may resemble clinical manifestations of SLE (23), such as in our case where the patient's altered mental status was attributed to NPSLE. Second, the clinical presentation may become atypical after initial treatment with nonspecific antibiotics, which may have some activity against the organism. Lastly, the in vitro growth of Nocardia is slow and usually takes weeks (24), and a routine Gram smear may miss the organism. These problems often lead to delayed diagnosis and contribute to increased mortality (10).
Antibiotic therapy of nocardiosis is based on empirical recommendations due to poor correlation between the in vitro and clinical efficacy of antibiotics and the absence of controlled clinical trials (25). The use of antibiotics and surgical drainage of abscesses are the mainstays of treatment. Treatment decisions are often complicated due to the fact that many SLE patients have active disease requiring augmented doses of steroids, which can worsen and prolong the infection (10). First-line treatment usually consists of TMP/SMX (26) because its pharmacokinetics allow good CSF penetration (25). The imipenem-amikacin combination and linezolid (27) also appear to be clinically effective regardless of the species responsible (25, 26). Antibiotics must be continued for 3–12 months, depending on the severity of the clinical features. Surgery, especially for drainage of an abscess, is sometimes indicated (11). In the present case, TMP/SMX was continued for 12 months and prednisone was quickly tapered down to 5 mg/day. Subsequent MRI of the brain showed resolution of the multiple ring-enhancing lesions. Due to the need for long-term immunosuppression, the patient remains on low-dose TMP/SMX prophylaxis based on current recommendations (28).
CNS nocardiosis can present with headache, confusion, and seizures due to one or more brain abscesses. We report here the first case of CNS nocardiosis that presented with cerebellar hemorrhage in a patient with SLE. Rheumatologists should keep the possibility of infection with Nocardia in mind in SLE patients with neurologic symptoms. Although rare, CNS nocardiosis is associated with high mortality and requires early diagnosis and institution of appropriate therapy. An aggressive multidisciplinary diagnostic and therapeutic approach comprising rheumatology, neurosurgery, and infectious disease services is often required. TMP/SMX is the drug of choice, but other antibiotic combination regimens may be effective. Whenever possible, immune suppression should be minimized and long-term prophylaxis should be considered for this serious infection.
CNS nocardiosis presenting as cerebellar hemorrhage and concomitant SLE exacerbation.
All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Ranganathan had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Study conception and design. Bashir, Ranganathan.
Acquisition of data. Bashir, Ranganathan.
Analysis and interpretation of data. Bashir, Ranganathan.