Presence of six different lesion types suggests diverse mechanisms of tissue injury in neuromyelitis optica

Abstract

Neuromyelitis optica (NMO) is an autoimmune disease targeting aquaporin 4 (AQP4), localized mainly at the astrocytic foot processes. Loss of AQP4 and glial fibrillary acidic protein (GFAP) was reported, but the pathological significance of astrocytopathy is still controversial. Here we show that active lesions in NMO display a wide spectrum of pathology even within a single tissue block of an individual patient. We have distinguished six different lesion types. The first reflects complement deposition at the surface of astrocytes, associated with granulocyte infiltration and astrocyte necrosis and followed by demyelination, global tissue destruction and the formation of cystic, necrotic lesions (lesion type 2). Such destructive lesions lead to Wallerian degeneration in lesion-related tracts (lesion type 3). Around active NMO lesions AQP4 may selectively be lost in the absence of aquaporin 1 (AQP1) loss or other structural damage (lesion type 4). Another pattern is characterized by clasmatodendrosis of astrocytes, defined by cytoplasmic swelling and vacuolation, beading and dissolution of their processes and nuclear alterations resembling apoptosis, which was associated with internalization of AQP4 and AQP1 and astrocyte apoptosis in the absence of complement activation. Such lesions give rise to extensive astrocyte loss, which may occur in part in the absence of any other tissue injury, such as demyelination or axonal degeneration (lesion type 5). Finally, lesions with a variable degree of astrocyte clasmatodendrosis are found, which show plaque-like primary demyelination that is associated with oligodendrocyte apoptosis, but with preservation of axons (lesion type 6). In active multiple sclerosis (MS) lesions astrocytes reveal changes of reactive protoplasmatic or fibrillary gliosis. Only in a subset of lesions, in patients with aggressive disease, loss of AQP4 is observed in the initial stage of their formation, which is associated with retraction of astrocyte processes in the absence of complement deposition, granulocyte infiltration or loss of AQP1 or astrocytes. Our data underline the primary assault of astrocytes in NMO lesions, but also indicate that different mechanisms of tissue injury operate in parallel in the same patient and even within the same lesion.Electronic supplementary materialThe online version of this article (doi:10.1007/s00401-013-1116-7) contains supplementary material, which is available to authorized users.

Inflammatory demyelination without astrocyte loss in MOG antibody–positive NMOSD

“…3 Histopathology of active lesions from AQP4-seropositive patients with NMO showed inflammatory infiltrate with reduction or loss of GFAP-positive astrocytes, or astrocyte cytologic abnormalities. 5 In contrast, our patient's brain lesion demonstrated active inflammatory demyelination, with relative preservation of GFAP-positive astrocytes within and surrounding the lesion. This is consistent with a report of a MOG-seropositive patient with NMO with CSF biomarkers during an acute attack showing markedly elevated levels of myelin basic protein, but undetectable GFAP.…”

Immunopathophysiology of pediatric CNS inflammatory demyelinating diseases

“…In contrast to MS lesions, NMO lesions show dystrophic astrocytes associated with perivascular deposition of IgG and complement and a striking loss of AQP4 extending beyond the area of demyelination. 15,16 In general, NMO lesions are more destructive than MS lesions, leading to extensive loss of axons and oligodendrocytes.…”

Uhthoff's Phenomenon in Multiple Sclerosis and Neuromyelitis Optica

“…Initially, the presence of necrotic lesions but not demyelination was considered to be the main feature of the pathology of NMO, which is unlikely to block conduction. However, recent studies have detected demyelinating lesions in NMO [2]. We compared the incidence and neurological symptoms of Uhthoff's phenomenon between MS and NMO patients.…”