FINAL DIAGNOSIS: ACUTE DEMYELINATING DISEASE
The demyelinating diseases of the central nervous system are usually diagnosed on clinical findings. Unless progressive multifocal leukoencephalopathy is suspected, demyelinating diseases are often investigated without biopsy.
Histologically, primary demyelinating diseases are characterized by destruction of myelin with relative axonal preservation, and abundant foamy macrophages containing myelin debris and lipid droplets. The macrophages stain for class II major histocompatibility complex antigens (HLA-DR; Ia). Electron microscopy studies reveal that most myelin destruction appears to be mediated by macrophages. In addition, perivascular lymphocytic infiltrate and variable gliosis are also features of demyelinating disease. Demyelinating lesions of multiple sclerosis can be subdivided into active and inactive plaques. Active plaques are hypercellular lesions containing a relatively dense perivascular and parenchymal infiltrate of lymphocytes and macrophages, and scattered reactive astrocytes. The lymphocytes in these regions are mostly T cells. CD4-positive (helper) cells predominate in earlier lesions and the actively demyelinating regions of older lesions, while CD8- positive (suppressor/cytotoxic) cells are more numerous in less active regions. Inactive plaques are hypocellular and densely gliotic lesions showing a marked loss of oligodendrocytes. In current case, hypercellular histologic features, along with contrast enhanced radiologic findings, are consistent with an acute demyelinating disease. Demyelinating diseases of known etiology or that occur only in specific clinical contexts include progressive multifocal leukoencephalopathy, central pontine myelinolysis and multifocal necrotizing leukoencephalopathy. On the other hand, differential diagnoses of the idiopathic demyelinating diseases include multiple sclerosis, acute disseminated encephalomyelitis, inflammatory or infectious processes, metastatic neoplasms and gliomas.
Multiple sclerosis (MS) is the most common demyelinating disease of the central nervous system which is typically multifocal with lesions of different ages. It is the prototype inflammatory autoimmune disorder, and with a lifetime risk of one in 400, potentially the most common cause of neurological disability in young adults. MS should be differentiated from other disorders that may have similar histological appearance of the lesions.
Acute disseminated encephalomyelitis (ADEM) is an uncommon multifocal inflammatory demyelinating disease of the central nervous system. It results from a transient autoimmune response towards myelin or other self-antigens. ADEM has similar histological features with that in MS, but has a much favorable long-term outcome. Therefore, differentiation of ADEM from the first attack of MS is important from prognostic as well as therapeutic point of view.
Solitary lesions, not surprisingly, prompt consideration of aggressive glial neoplasia, whereas multifocal lesions suggest metastatic neoplasms or even cerebral parasitosis when lesions exhibit cystic characteristics on scan. Such demyelinating "pseudotumors" understandablely occasion neurosurgical intervention for purposes of definitive diagnosis. Demyelinating "pseudotumors" are non-neoplastic lesions most often misinterpreted on biopsy as gliomas, specifically as diffuse fibrillary astrocytomas or, rarely, as oligodendrogliomas. The reasons for misinterpreting demyelinating disease as a glioma may be due to cytologically atypical astrogliosis and the finding of scatted mitotic figures. If numerous lipid-laden macrophages are encountered within parenchyma and around vessels, a demyelinating disease should be considered. Also, appropriate special stains for myelin and axons are needed to confirm this impression. Diffuse infiltration by macrophages is so rarely a feature of the untreated glioma as to virtually exclude this diagnosis. The ready identification of such cells in smears, touch preparations, or tissue sections should suggest a non-neoplastic, necrotizing process or a selectively demyelinating disorder. Every precaution should be taken to avoid interpreting a demyelinating lesion as a glioma, since the treatment for glioma is so different from that for demyelination.
It is also very important to exclude any infectious etiology before making a diagnosis of demyelinating disease. If the lesion was induced by a virus, amphophilic inclusions may be found, particularly at the periphery of the lesion. Viral disorders known to cause demyelination are HIV, JC virus, cytomegalovirus, papovavirus and varicella zoster. In our case, immunohistochemical stains for varicella-zoster virus, herpes simplex virus and Toxoplasma were negative, as well as in situ hybridization for JC virus.
Taken together, a confident diagnosis of demyelinating disease can only be rendered following exclusion of infectious etiology, necro-inflammatory process, sarcoidosis, Wegener's granulomatosis, rheumatoid disease, metastatic neoplasms and primary central nervous system tumors.
Contributed by Yan Peng MD, PhD, Rafael Medina-Flores MD, Clayton Wiley MD, PhD