Central Nervous System Brucellosis Granuloma and White Matter Disease in Immunocompromised Patient

Brucellosis is a multisystem zoonotic disease. We report an unusual case of neurobrucellosis with seizures in an immunocompromised patient in Saudi Arabia who underwent renal transplantation. Magnetic resonance imaging of the brain showed diffuse white matter lesions. Serum and cerebrospinal fluid were positive for Brucella sp. Granuloma was detected in a brain biopsy specimen.


The Study
The patient was a 46-year-old Saudi woman who had chronic hepatitis C, end-stage renal disease of undetermined etiology, and a renal transplant in 1993. She reported a 5-month history of headaches and seizures. Seizures were usually preceded by epigastric pain and a sensation of nausea for few seconds, followed by left arm posturing and loss of consciousness. She did not have fever, weight loss, or joint pain. She lived in a rural area, was involved in animal husbandry, and consumed unpasteurized milk products. Her husband had been treated for brucellosis. Her medications included mycophenolate mofetil (500 mg 2×/d since 1993), prednisone (5 mg 1×/d since 1993), levetiracetam (500 mg 2×/d for 5 mo), and phenytoin (200 mg every night for 1 mo).
Neurologic examination showed left homonymous hemianopia, increased deep tendon reflexes in the left hemibody, and the Babinski sign on the left hallux. Initial laboratory test results, including those for complete blood count, erythrocyte sedimentation rate, C-reactive protein, and liver and renal profiles, were within references ranges. An electroencephalogram showed sharp waves over the right temporal region and continuous slow activity over the right temporooccipital region. Magnetic resonance imaging (MRI) of the brain showed diffuse T2/fluid-attenuated inversion recovery hyperintense white matter lesions involving the right frontal, parietal and temporal lobes ( Figure 1). No appreciable mass effect or enhancement after administration of gadolinium was observed. Positive emission tomography of the brain showed hypometabolic cerebral activity involving a large area of right cerebral hemisphere. Magnetic resonance spectroscopy shows a low peak of n-acetyl aspartate (2.2 ppm).

Results
A brain biopsy specimen of cerebral cortex and superficial white matter showed a moderate lymphoplasmacytic and focally histiocytic infiltrate that involved deep cortex, white matter, and leptomeninges. The histiocytic component formed small epithelioid granulomas that were nonnecrotizing. The inflammatory reaction, including granulomas, was mainly perivascular with some angiocentric patterns and focal parenchymal involvement. The white matter portion was heavily infiltrated by macrophages. Reactive astrogliosis was prominent. There were no morphologic signs of a specific etiology: no viral inclusions, and staining results microorganisms (AFB, fungi, Epstein-Barr virus, and JC polyomavirus) were negative ( Figure 2). A gram stain was initially negative for bacteria. At day 5, Brucella spp. were isolated from brain biopsy specimens. An antibiogram showed that the Brucella sp. was sensitive to gentamicin, streptomycin, tetracycline, trimethoprim/ sulfamethoxazole, and rifampin.
Three months later, repeat MRI of the brain showed decreased T2 hyperintensity associated with volume loss  and ex vacuo dilatation of the subjacent right lateral ventricle. We did not observe any appreciable new lesions.
After 6 months of follow-up, her headaches had resolved. However, she continued to have auras without major seizures.

Conclusions
Neurobrucellosis can affect the central or peripheral nervous systems and lead to diverse clinical syndromes (4). Diagnosis of neurobrucellosis depends on clinical manifestations, CSF findings suggestive of pinocytosis, high protein levels, low or standard glucose levels, and a positive antibody titer for Brucella spp. Although the patient had mild pleocytosis with a predominance of lymphocytes and high antibody titers against Brucella spp. in CSF, the CSF protein level was within the reference range. Antibodies against Brucella spp. in CSF are usually an indication of neurobrucellosis. However, low levels of antibodies might not be detected by SAT. In suspicious cases in which the SAT result is negative, SAT and a Coombs test, ELISA, and PCR are helpful in making a diagnosis.
77The clinical−radiologic correlation for neurobrucellosis ranges from uneventful results for imaging studies, despite positive clinical findings, to imaging abnormalities (3). Neurobrucellosis with a focal brain mass has been rarely observed in imaging studies (7,8).
Radiologic results in this case suggested an infectious disease, autoimmune disease, or malignancy in an immunocompromised patient. Because we deemed it necessary to exclude other conditions, such as progressive multifocal leukoencephalopathy or lymphoma, we performed a brain biopsy. The diagnosis was established by detecting antibodies against a Brucella sp. in serum and CSF and confirmed by isolation of a Brucella sp. from brain tissue.
We found that the patient had epilepsy and extensive white matter changes secondary to brucellosis. She continued to have auras without major seizures. MRI of the brain showed abnormal results (prominent white matter disease and focal encephalomalacia). Inflammation can cause permanent cellular biochemical dysfunction, which can lead to electrically irritable tissue and parenchymal damage despite successful treatment. This finding might explain the persistency of brain lesion. Appropriate antimicrobial therapy can eliminate the infection.
Longitudinal studies of white matter hyperintensities caused by vascular, noninfectious, infectious, and inflammatory conditions showed white matter hyperintensities over time despite effective treatment. Fincham et al. reported that white matter changes in neurobrucellosis were sequelae of demyelination, as confirmed by the pathologic analysis (9). We believe that unresolved white matter hyperintensities in this patient were a sequela of the inflammatory process. A case report documented similar clinical features in a patient with seizures caused by chronic neurobrucellosis for 2.5 years (10).
Granuloma is a pathogenesis of epilepsy (11). Solitary cysticercus granuloma and calcified lesion are 2 common neuroimaging abnormalities in patients with epilepsy. Treatment for underlying cysticercosis does not cure epilepsy (12). Seizures associated with central nervous system tuberculomas are often resolved after successful treatment (13). The underlying pathogenesis for relapsing epilepsy in neurocysticercosis is probably related to abnormal neurons and their arrangement within calcified nodules (13). The epilepsy prognosis for neurobrucellosis is probably similar to that for central nervous system neurocysticercosis (13).
A perivascular nonnecrotizing granuloma is a histopathologic feature of neurobrucellosis. Neurocellosis granuloma is a pathogenesis of refractory epilepsy. Our findings indicate the need for suspecting neurobrucellosis as a cause of epilepsy and white matter disease in immunocompromised patients in disease-endemic areas.