Immunopathogenesis and Neuropathology

The exact pathophysiology of ADEM remains only partially understood, and the issue becomes more complicated when neurologists review the potential relationship between ADEM and MS as why most patients with ADEM will not progress to clinically definite MS. Most experts concur that ADEM is an immune-mediated disease and the similarities between ADEM and experimental allergic encephalomyelitis also raise interesting questions about ADEM being an autoimmune condition (RRERRRRR) [8-11].

Presently, the prevailing hypotheses about the pathophysiology of ADEM include “molecular mimicry theory versus inflammatory theory,” and both share the fundamental tenet that the patient’s immune system has been exposed to an antigenic challenge (viral or bacterial antigens) and this in turn precipitates a massive immune response which clinically manifests as ADEM. Based on the molecular mimicry hypothesis, certain CNS molecules such as myelin basic protein, proteolipid protein, and myelin oligodendrocyte protein share certain structural features with antigenic infrastructure and determinants of invading microorganism, and as a result the provoked immune response, particularly antiviral or antibacterial antibodies, cross- reacts with some or all of the abovementioned CNS natural molecules, and this translates into a formidable autoimmune response and initiation of ADEM. Of note, viruses implicated in ADEM include influenza virus, enterovirus, measles, mumps, rubella, VZV, EBV, CMV, HSV, hepatitis A, and coxsackievirus. Bacteria linked to pathophysiology of ADEM are Mycoplasma pneumoniae, Borrelia burgdorferi, Leptospira, and group A beta-hemolytic streptococcus [12]. In addition, potent antimyelin basic protein antibodies have been detected in patients with post-vaccinial ADEM after being vaccinated with Semple rabies vaccine [13, 14].

According to the inflammatory hypothesis of ADEM, the patient’s CNS is injured secondary to the offensive viral infection. As a result of this and due to disruption of the blood-brain barrier, CNS antigens such as myelin-based epitopes are released into the peripheral circulation [9]. The released antigens are exposed to the T lymphocytes which in turn cause a new cascade of inflammation targeted against the patient’s CNS. This infection-based hypothesis originates from another animal model of inflammatory demyelination, Theiler murine encephalomyelitis virus (TMEV), which generates a two-stage disease: the initial CNS viral infection followed by a second autoimmune response with more destruction to the patient’s CNS. A number of chemokines and cytokines such as IL-6 and TNF-a have been proposed in pathophysiology of ADEM; however, Based on their analysis Franciotta et al. [15] analyzed the cytokine and chemo- kine profile in the CSF of patients with ADEM versus MS and noticed that compared to healthy controls, CSF of patients with ADEM contained significantly higher levels of chemokines with attractant/activating properties toward neutrophils (CXCL1 and CXCL7), monocytes/T lymphocytes (CCL3 and CCL5), Th1 lymphocytes (CXCL10), and Th2 lymphocytes (CCL1, CCL22, CCL17). Based on their analysis, they noticed that within the CSF, mean levels of CXCL7, CCL1, CCL22, and CCL17 were more elevated in patients with ADEM than those with MS. The CSF levels of CCL11 were lower in MS patients than those with ADEM. The authors concluded that increased expression of chemokines active on neutrophils and Th2 lymphocytes can separate ADEM from MS.

The most salient and the neuropathological hallmark of ADEM (which is also recognized as perivenous encephalomyelitis) is the presence of peri-venular (perivenous) inflammation with penetration and presence of macrophages and areas of demyelination which affect various and large areas of cerebral hemispheres, brain stem, cerebellum, subcortical gray matter, and spinal cord in a sleeve like fashion. While perivenous inflammatory demyelination also occurs in the context of MS, demyelination in MS consists more obviously of confluent layers of macrophages mixed with reactive astrocytes. In ADEM, it is presumed that such immune cell-mediated inflammatory demyelination stems from or is triggered by infection or immunization. Other less common abnormalities consist of the presence of lymphocytes and neutrophils outside the Virchow-Robin space, infiltration of the vascular wall by the inflammatory cells, perivascular edema, and swelling of the endothelium. Chronologically, ADEM lesions appear to be of similar oldness and more prominently affect the small vessels of the white matter; however, they also affect the deeper layers of the cerebral cortex, thalami, hypothalamus, and basal ganglia as well as the vessels in walls of the lateral and third ventricle. Interestingly, the neuropathology of ADEM shares certain similarities with monophasic EAE.

Regarding AHLE, influenza, HSV, mycoplasma pneumonia, and EBV have been reported to precede the condition. It is hypothesized that AHLE results from direct viral neuro-invasion, neurotoxin production, and immune-mediated demyelination. Pathologically it consists of deep white matter fine vacuolation, perivascular demy- elination associated with areas of ring and ball hemorrhages, and fibrinoid vascular necrosis along with neutrophil and monocyte infiltrates [16]. Although nonspecific, when incorporated with in the clinical context, AHLE diagnosis can be made.

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