Contributed by Frauke Otto MD1, Eva Neuen-Jacob MD2, Gabriele Arendt MD1, Olaf Stüve MD PhD1,3 and Hans-Peter Hartung MD1
1Department of Neurology, Heinrich-Heine University, Düsseldorf, Germany
2Department of Neuropathology, Heinrich-Heine University, Düsseldorf, Germany
3Department of Neurology, University of Texas Southwestern Medical Center at Dallas VA, Dallas, TX , U.S.A.
A 69-year-old patient with a four-year history of CIDP was admitted for evaluation of further treatment options at a tertiary University hospital. Diagnostic criteria for CIDP established by the AAN were fulfilled . Six months prior to this admission, the patient had suffered from a granulocytic meningitis while he was treated with azathioprine and prednisolone . At that time, evaluation of his cerebrospinal fluid (CSF) revealed a pleocytosis of 1240 white blood cells (WBC)/µl. Immunosuppressive therapy was immediately suspended. The causative pathogen could not be identified, but the patient partially recovered after empiric antibiotic treatment with ceftriaxon and ampicillin. Residual neurological deficits included persisting mild cognitive impairment. At that time, a cranial computer tomography (CT) and a magnetic resonance imaging (MRI) scan of the brain were normal.
After 2 months of progressively worsening CIDP, treatment with mycophenolate mofetil was commenced but had to be stopped within 3 weeks because of gastrointestinal side effects. Azathioprine medication was re-instituted, and the total leukocyte count in the peripheral blood (PB) was in the range of 3600 - 4700 /µl.
The patient was re-admitted because of acute-onset confusion, cognitive decline, and increasing weakness. On physical examination, the patient displayed significant attention deficits, disorientation in time, dysarthrophonia, a mild flaccid tetraparesis, areflexia of the lower limbs, gait disturbance, distal symmetric hypo- and dysesthesia, right-sided hemiataxia and bradydysdiadochokinesia. A cranial CT scan showed no abnormalities (Figure 1). His total leukocyte count in the PB was 4100 /µl, and his lymphocyte count 600/µl. Plasma exchange and oral corticosteroids temporarily improved his sensorimotor symptoms and signs.
Following plasma exchange the patient developed diarrhoea, and his cognitive impairment continued to worsen. A brain MR scan showed bilateral periventricular edema with multiple gadolinium-enhancing T1 lesions in the periventricular parenchyma (Figure 2). CSF analysis revealed increased albumin and IgG in the absence of WBC. Candida albicans was detected in stool specimens. Despite intravenous antibiotic, antiviral and antifungal therapy as well as administration of intravenous immunoglobulins (IVIG), the patient further deteriorated clinically with right-sided hemiparesis and a Broca dysphasia. Polymerase chain reaction (PCR) of the CSF for Epstein-Barr virus (EBV) was positive, while no DNA copy numbers of Candida, Aspergillus, toxoplasma, and other neurotropic viruses, including VZV, HSV, CMV, HIV were detected. Despite supportive intensive care treatment the patient died within 4 weeks.
MICROSCOPIC EXAMINATION AND NEUROPATHOLOGIC FINDINGS
A stereotactic brain biopsy of affected white matter parenchyma revealed non-specific necrosis without evidence of malignant or inflammatory cellular infiltrates. Three tiny specimens with a total size of 0,5 x 0.5 x 0.5 mm were submitted for examination (Figure 3, expression of CD68).
An autopsy was performed and gross examination of the brain demonstrated a necrotizing mass lesion in the left cerebral hemisphere approaching the ependyma and infiltrating the corpus callosum mimicking a glioblastoma (Figure 4). Microscopic examination disclosed angiocentric pleomorphic infiltrates of lymphocytes, histiocytes, large CD20-positive cells resembling lymphoblasts, centroblasts, and scattered CD30-positive pleomorphic polynuclear Reed-Sternberg like cells (Figures 5 and 6). There was a high mitotic and proliferative activity (Figure 7). In addition, perifocal edema with marked glial fibrillary acid protein (GFAP)-positive reactive astrocytic gliosis was noted. The EBV antigen EBNA2 was detected immunohistochemically in the majority of CD20-positive cells (Figure 8).