Contributed by Rainer Ehling, MD*1, William Sterlacci, MD*2, Hans Maier, MD2, Thomas Berger, MD1
Departments of 1 Neurology and 2 Neuropathology, Medical University Innsbruck, Austria
* Both authors contributed equally to this work.
A 45-year-old man presented with left-sided hemihypesthesia, which remitted spontaneously within two months. 18 months later the same symptoms appeared again but were now aggravated by hemiparesis, dysarthria, ataxia and neurogenic bladder dysfunction, which finally led to pyelonephritis and acute renal failure. The patient's past medical, surgical and family history were all non-contributory. Cerebrospinal fluid (CSF) showed normal cell counts, glucose, protein, IgG index and no oligoclonal bands. Cytology was negative for malignant cells.
At disease onset, brain MRI demonstrated white matter abnormalities in the mesencephalon, pons and cerebellar peduncles, while other white matter areas were spared. Follow-up MRI 18 months later exhibited progression in the brainstem with mild mass effect. The lesions were hyperintense on proton density scans (Figure 1) and on T2-weighted images (Figure 2) but with inhomogeneous contrast-enhancment on T1-weighted images (Figure 3). An additional lesion was suspected in the cerebellar cortex. MR spectroscopy showed a decrease in N-acetylaspartate and a peak in choline. Positron emission tomography (PET) with 18-fluorodeoxyglucose (FDG) revealed intense lesion hypermetabolism (Figure 4).
H&E stained sections of the of the brainstem biopsy revealed white matter with abundant Rosenthal fibers and interjacent spindle-shaped and gemistocytic astrocytes, some with hyperchromatic and irregularly shaped nuclei (Figs. 5, 6). Some fragments contained large cells with similar nuclei displaced to the periphery. The glial origin of the conspicuous cells was identified by positive glial fibrillary acidic protein expression (Fig. 7). Immunocytochemistry using an antibody against myelin basic protein (MBP) detected focal loss of myelin (Figx. 8, 9), while axons were relatively preserved as shown by SMI-31 staining (Figs. 10, 11). Infiltrating microglial cells and CD8-positive T cells (Fig. 12) were sparse. Ki-67 proliferation index was lower than 2%.
The lesion was interpreted as an astrocytic tumor and because of the bizarre pleomorphic cells, a high-grade tumor was considered. Because of the intense infiltration of glial cells amidst Rosenthal fibers a second opinion by J. Hainfellner and H. Budka (Institute of Neurology, Medical University of Vienna, Austria) argued, that the sections are likely to be from the margin of a demyelinating lesion. However, an astrocytic tumor could finally not be ruled out.
CLINICAL HISTORY, CONTINUED
Lacking a definite histopathological diagnosis, the local interdisciplinary tumor board recommended treatment for the worst case scenario. Extended tumor field and total brain radiotherapy with a dosage of 54 Gray and concomitant temozolomide therapy was performed and led to a transient clinical and radiological stabilization of the disease until the patient suffered from acute renal failure. Shortly after having recovered from hemofiltration, the patient had respiratory and renal failure again and finally died of sepsis-associated multi-organ failure, three and a half years after disease onset.
POST MORTEM PATHOLOGY
White matter of the cerebellum and the brainstem contained lesions consisting of central amorphic necrosis without significant amounts of remaining myelin, as evidenced by MBP-staining (Fig. 13), or oligodendroglial cells. The lesions were surrounded by reactive astroglial cells with sometimes bizarre shapes and eccentric dark nuclei, along with infiltrating microglia and macrophages, including multinucleated forms (Figs. 14, 15, 16 and 17). Peripheral blood vessels displayed only rare CD4- and CD8-positive lymphocyte cuffs (Figs. 18, 19). Apart from the brainstem, a small focus of densely packed foamy macrophages was found near the posterior horn of the left ventricle.