Optic neuritis in neuromyelitis optica

Abstract

Neuromyelitis optica (NMO) is an autoimmune demyelinating disease associated with recurrent episodes of optic neuritis and transverse myelitis, often resulting in permanent blindness and/or paralysis. The discovery of autoantibodies (AQP4-IgG) that target aquaporin-4 (AQP4) has accelerated our understanding of the cellular mechanisms driving NMO pathogenesis. AQP4 is a bidirectional water channel expressed on the plasma membranes of astrocytes, retinal Müller cells, skeletal muscle, and some epithelial cells in kidney, lung and the gastrointestinal tract. AQP4 tetramers form regular supramolecular assemblies at the cell plasma membrane called orthogonal arrays of particles. The pathological features of NMO include perivascular deposition of immunoglobulin and activated complement, loss of astrocytic AQP4, inflammatory infiltration with granulocyte and macrophage accumulation, and demyelination with axon loss. Current evidence supports a causative role of AQP4-IgG in NMO, in which binding of AQP4-IgG to AQP4 orthogonal arrays on astrocytes initiates complement-dependent and antibody-dependent cell-mediated cytotoxicity and inflammation. Immunosuppression and plasma exchange are the mainstays of therapy for NMO optic neuritis. Novel therapeutics targeting specific steps in NMO pathogenesis are entering the development pipeline, including blockers of AQP4-IgG binding to AQP4 and inhibitors of granulocyte function. However, much work remains in understanding the unique susceptibility of the optic nerves in NMO, in developing animal models of NMO optic neuritis, and in improving therapies to preserve vision.

Clinicopathological features in anterior visual pathway in neuromyelitis optica

“…First, the long, thin cylindrical dimension of the optic nerves with the cul-de-sac anatomy of the subarachnoid space may cause unique cerebrospinal fluid (CSF) dynamics, including restricted diffusion of proinflammatory elements (eg, AQP4 antibodies), retained inflammation, and limited clearance of myelin and axonal debris, followed by enhanced NMOsd lesion formation. 28,29 We revealed prominent pathological meningeal thickening with inflammation (see Fig 4) and radiologically abnormal enhancement of the OPN pattern in NMOsd (see Fig 1). Inflammatory processes may contribute to the closing of the arachnoid apertures that drain CSF into the meningeal lymphatics, thus adding to CSF compartmentalization.…”

“…Finally, abundant large orthogonal arrays of particles (OAPs) in astrocytic endfeet of the optic nerves enhance binding of AQP4 antibodies and complement-dependent astrocyte damage. 28 These unique structures of the optic nerves may promote typical NMOsd lesions that show a pattern-specific loss of AQP4 with complement activation. Importantly, we demonstrated that severe and widespread neurodegeneration with aberrant accumulation of degenerative mitochondria and TRPM4 channels was evident in the optic nerves in NMOsd.…”

Retinal segmented layers with strong aquaporin-4 expression suffered more injuries in neuromyelitis optica spectrum disorders compared with optic neuritis with aquaporin-4 antibody seronegativity detected by optical coherence tomography

“…Neuromyelitis optica (NMO) and multiple sclerosis (MS) are autoimmune demyelination diseases that mainly affect the central nervous system (CNS)1 and optic neuritis (ON) is the most common initial manifestation of NMO and MS. Isolated ON with aquaporin-4 antibody (AQP4-Ab) seropositivity (AQP4-Ab+/ON) has a high risk of converting to definite NMO in clinical practice; therefore, AQP4-Ab+/ON is presumed to have a similar pathogenesis as definite NMO such that when AQP4-Ab binds to its receptors it causes complement deposition, which results in astrocyte injury and secondary axonal demyelination from oligodendrocyte injury 2 3. Therefore, AQP4-Ab+/ON is considered an early or limited type of NMO and has been named an NMO spectrum disorder (NMOSD).…”

Mimics and chameleons of optic neuritis

“…NMO is much less common than MS (perhaps 1% of optic neuritis is due to NMO)3 but their pathophysiology is significantly different 21. Unlike MS, NMO requires immunosuppressive therapy.…”