Primary cerebral lymphoma presenting as diffuse leukoencephalopathy

Primary central nervous system lymphoma (PCNSL) is a late complication of HIV infection occurring mainly when the CD4 T count cells is less than 50 cells/mm3 [1]. Conflicting data concerning incidence trends since the widespread use of combined therapies suggest that PCNSL will remain a major complication in HIV-infected patients [1]. In a large autopsy series the frequency of PCNSL was approximately 6% of patients, and has not changed from 1984 to 1999 [2]. PCNSL commonly presents with mental status changes, headache, seizures, or neurological deficits in the setting of focal ring-enhancing, often periventricular, masses [3–5]. From a diagnostic viewpoint, the problem is that magnetic resonance imaging (MRI) findings in PCNSL overlap with those of other intracranial mass lesions in HIV-infected patients. We report on a patient with a good immunovirological status and histologically confirmed PCNSL, whose clinical and radiological appearance was most likely a progressive leukoencephalopathy, indistinguishable from HIV-associated encephalopathy, progressive multifocal leukoencephalopathy or another demyelinating process, toxic or metabolic abnormalities. Case report A 45-year-old woman infected by HIV-1 through blood transfusion in 1984 was only discovered to be seropositive in 1995, with a CD4 cell count of 9 cells/mm3. A bitherapy including protease inhibitors (lamivudine and nelfinavir) was started on May 1996, with a good and sustained immunovirological response. Since January 2000 the CD4 cell count had varied from 400 to 500 cells/mm3 and the plasma viral load varied between 100 and 300 copies/ml. In May 2001 she complained of an unsteady gait and dysarthria that spontaneously recovered within 2 weeks. The CD4 cell count was 492 cells/mm3 (29% total lymphocytes). Brain MRI disclosed bilateral symmetrical hyperintense lesions localized in the white matter on T2-weighted and FLAIR images, without oedema, mass effect and enhancement (Fig. 1). Chest radiograph, haematological and biochemical tests with serum lacticodeshydrogenase and electrophoresis were unrevealing. The cerebrospinal fluid (CSF) contained 47 cells/mm3 (97% lymphocytes), 110 mg/dl protein, and normal glucose. α-IFN, polymerase chain reaction (PCR) for Epstein–Barr virus (EBV), varicella zoster virus, herpes simplex virus, cytomegalovirus, JC virus and cytological analysis were negative. A second CSF analysis performed 9 days later showed only 10 mononuclear cells/mm3 and normal proteinorachia. Cultures and PCR for herpes viruses and Mycobacterium tuberculosis were negative. A common viral meningitis was hypothesized and the patient was discharged without treatment. On October 2001, she presented with choreoathetoïd movements of both upper limbs. She had never used neuroleptics or illicit drugs. Brain MRI disclosed an extension of the white matter lesions. A third CSF analysis showed no cells, normal protein and glucose concentrations. PCR for herpes viruses, including EBV and human herpesvirus 6 were still negative. MRI of the spinal cord was normal. A right frontal biopsy was then performed. A immunoblastic lymphoma (group 9 REAL classification) EBV positive was identified. As no evidence of systemic lymphoma could be demonstrated, chemotherapy combining cyclophosphamide–hydroxydaunomycin–oncovin–prednisone and methotrexate (3 g/m2) was started and after five cycles within a 9-month period the neurological examination was normal, and brain MRI showed a marked regression of the white matter lesions (Fig. 1).Fig. 1.: Magnetic resonance imaging FLAIR axial images. (a) Diffuse and bilateral high-intensity signal of the white matter before chemotherapy; (b) after chemotherapy.Our patient presented with evolving, non-enhancing cerebral white matter lesions consistent with a progressive leukoencephalopathy, whose cause eluded diagnosis despite multiple clinical, laboratory, and imaging studies. Leukoencephalopathy in HIV-infected individuals principally results from HIV, immune, opportunistic, or drug-based mechanisms. The good immune status, the negativity of three consecutive CSF PCR EBV and the lack of radiological evidence for PCNSL could have delayed the correct diagnosis and jeopardized the patient's condition. The need to identify any treatable cause in HIV-infected patients with CNS lesions led to the brain biopsy [6]. The typical MRI appearance of PCNSL is single or multiple demarcated lesions, surrounded by a small rim of oedema, with little mass effect on the adjacent structures and an enhancement pattern that range from 92 to 100% [4,5]. Few reports have described atypical MRI: non-enhancing focal process [3,7] or diffuse bilateral leukoencephalopathy as in our patient [3]. Diffuse non-enhancing lymphomatous invasion, without discrete tumour-like lesions on MRI, is very rare in immunocompetent individuals [8–11], but has only been reported once in HIV infection [3]. Enhancement is presumed to be caused by the breakdown of the blood–brain barrier at the site of tumour invasion of vessels [7]. The lack of parenchymal enhancement on MRI suggests that lymphoma was diffusely infiltrative without significant disruption of the blood–brain barrier [11]. In our case lymphomatous cells lay relatively sparsely in the brain, without forming tumour nodules. Despite recent advances in neuroimaging and PCR, the diagnosis of HIV-associated neurological complications remains a challenge, notably in patients with good immunovirological status. Awareness that PCNSL can present as a non-enhancing infiltrative lesion may shorten the interval between the onset of clinical symptoms and diagnosis. When tests prove inconclusive, brain biopsy remains the last resort diagnostic procedure [6].