2020 NPA-01

This case was originally published in 2020. The information provided in this case was accurate and correct at the time of initial program release. Any changes in terminology since the time of initial publication may not be reflected in this case.

The patient is a 46-year-old right-handed woman with no significant past medical history. She had been in her usual state of good health until two days prior to admission when she noted the gradual onset of left leg weakness. She attributed this to fatigue and went to bed. The next morning her leg had not improved, and she found her left arm was weak. During the day she rested, but her symptoms did not improve. After another night of sleep, she awoke unable to walk due to profound left leg weakness. She was taken to the hospital where an MRI was obtained (Image A and Image B). She was admitted and started on dexamethasone and antiseizure medication. An extensive medical workup did not reveal a clear diagnosis. Three days after admission a needle biopsy of a brain lesion was performed.

Tissue Site
Right frontoparietal lobe mass

The whole slide image provided is an H&E-stained slide of the brain from a needle biopsy.

The lesion in this case is extensive and caused acute, progressive neurological problems. MRI (Image A and Image B) shows a large, heterogeneously-enhancing abnormality in the right centrum semiovale and right corpus callosum which is hypointense on T1 and hyperintense on T2 imaging. Some mass effect but no herniation is noted. These findings are not specific for a single entity and could be consistent with neoplasm, infection, or demyelination.

The biopsy is typical of an active inflammatory demyelinating lesion. It exhibits an inflammatory process with a relatively sharp border (Image C) and is characterized by extensive infiltration of the brain parenchyma by foamy macrophages (Image D and Image E). Lymphocytes are noted in the parenchyma and in perivascular areas (Image E). A GFAP stain reveals parenchymal gliosis in the lesion (Image F). While not prominent in this case, astrocytes in acute demyelinating lesions can exhibit nuclear atypia and contain “granular mitoses,” so-called Creutzfeldt astrocytes. A CD68 stain highlights characteristic macrophage infiltration and microglial activation in the lesion, while adjacent tissue is relatively unaffected (Image G). In this case a CD4 stain reveals darkly-staining helper T-cells and the less intensely-staining, activated, foamy macrophages (Image H). In acute demyelination, a CD3 stain (not shown) demonstrates T-cells scattered through the lesion and in perivascular areas; a CD8 stain (not shown) also shows cytotoxic T-cells. Labelling for CD138 reveals the presence of plasma cells in the lesion (Image I), which are often clustered in perivascular areas. The key diagnostic feature of active inflammatory demyelinating lesions is seen in the Luxol fast blue stain (here without counterstain) which reveals near-complete myelin loss in the area of inflammation with a sharp edge separating demyelinated from unaffected parenchyma (Image J). Staining for neurofilament shows relative preservation of axons in the demyelinated area but also demonstrates axonal spheroids, attesting to some acute axonal injury (Image K). Histochemical stains for infectious agents (not shown) are negative.

The differential diagnosis of demyelinating lesions such as this can be complex. Primary glial neoplasm must be excluded. It is relatively easy here since there are no cells in the lesion that suggest a glial neoplasm. While macrophages can be seen in gliomas, it is rare to have so many. In demyelination due to progressive multifocal leukoencephalopathy there are diagnostic nuclear inclusions in enlarged oligodendrocytes seen at the edge of the lesion which are not present in this case. Steroid-treated lymphoma can present a diagnostic challenge for neuropathologists; however, in such cases there are most often degenerating cells or cellular debris, and myelin loss is not present. Patchy myelin loss can be seen in treated lymphomas but tends to have indistinct borders, and in the absence of immature lymphoid elements excluding treated lymphoma can be difficult. The presence of plasma cells and absence of necrotic cells and debris weigh against treated lymphoma. B-cell markers may be useful for identifying small numbers of residual lymphoma cells. Distinguishing an acute cerebral infarct from a demyelinating lesion can be difficult. Both may contain large numbers of foamy macrophages and scattered leukocytes. Extensive, sharply-demarcated demyelination is usually not seen, and damage to axons is much more severe in infarcts. Moreover, as in this case, the pace of the clinical onset, the area involved not corresponding to a specific vascular territory, and the presence of a chronic inflammatory infiltrate with selective myelin loss, make demyelination the most likely diagnosis. Finally, infection should be ruled out in suspected active inflammatory demyelinating lesions.

The terminology of active inflammatory demyelinating conditions is complex and can be confusing. Kepes initially defined an entity that has come to be termed “tumefactive multiple sclerosis (MS).” It presents precipitously, may have one or more large lesions, and may exhibit tumor-like mass effects. Histologically, there are no distinct features that separate this entity from other demyelinating disorders. In the case presented here, there is no indication that the patient has multiple sclerosis (MS) or any of its usual variants. It is best to avoid diagnosing these active inflammatory demyelinating lesions using the term “MS” since that disease has a more ominous and chronic prognosis than this entity. While statistics vary, some cases like this progress to MS; others are a monophasic event that can extensively resolve. Similarly, it is not accurate to term this type of condition as acute disseminated encephalomyelitis (ADEM). ADEM and its variants typically involve the central nervous system much more extensively, frequently follow viral infection, and show distinctive perivenular demyelination. In cases such as the one illustrated here, it is best to diagnose an active inflammatory demyelinating lesion and omit any reference to MS or ADEM unless the clinical and imaging studies support such a specific diagnosis. This patient has regained much of her neurological function, and she has no new symptoms. By MRI, the inflammation has abated, and there are no new lesions.

• The differential diagnosis in cases of active inflammatory demyelination can be challenging.
• The histological features of active inflammatory demyelinating lesions are not clearly distinct from some other demyelinating diseases.
• Luxol fast blue staining can be useful in demonstrating demyelination.
• While there is relative axonal sparing in active inflammatory demyelinating lesions when compared to infarcts, there is still significant axonal damage.
• It is best to omit any reference to MS or ADEM in making the diagnosis.
• The future neurological course of patients with active inflammatory demyelinating lesions is unpredictable.

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