Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system (CNS) characterized by severe and recurrent episodes of optic neuritis and longitudinally extensive transverse myelitis. Brain lesions usually, but not always, develop later in the disease.1
Patients who have NMOSD, an astrocytopathic disease, present with a variety of tissue lesions. Astrocytes support and protect neurons; they are important in the formation of the blood-brain barrier and in CNS homeostasis. When activated, astrocytes synthesize all the components of the complement system.2 Various mechanisms have been proposed as the cause of astrocyte destruction,3-5 and many studies have described the consequent damage observed in patients. An important limitation of these studies is that they relied on the use of diagnostic criteria formulated in 2006, which did not account for water channel protein aquaporin-4 (AQP4) seronegativity.5
Pathology of NMOSD Lesions
Investigators have classified 82 NMOSD lesions into 4 distinct types: early active demyelinating, late active demyelinating, remyelinating, and inactive demyelinated.6 Early active demyelinating lesions are characterized by a diffuse infiltration of immunoreactive macrophages. Late active demyelinating lesions show extensive myelin degradation. Remyelinating lesions have thin myelin sheaths, whereas inactive demyelinating lesions show complete demyelination.6
Active NMOSD lesions have been described with features of granulocyte infiltration, inflammation, microglial activation, and complement activation with vascular fibrosis—evidence of a pathogenic role of the humoral immunity.6 Activation of the terminal lytic complement complex is confirmed by the presence of an epitope of complement C9, C9neo, in different lesions.5 C9neo activation and immunoglobulin deposition are found at the endfeet of astrocytes surrounding blood vessels. The targeted antigen has been confirmed to be AQP4, which accumulates in the endfeet of astrocytes.2
Active lesions can be further categorized into 6 types, according to the level of immune infiltration and tissue damage. In type 1 lesions, astrocytes are significantly damaged or partially covered with activated complement. The tissue is heavily infiltrated with granulocytes, and necrotic astrocytes are present. Oligodendrocytes are lost, and active demyelination can be observed.3 Type 2 lesions show fluid-filled cysts, in addition to macrophage infiltration and AQP4 loss.3 Type 3 lesions are typically lesions of the white matter of the spinal cord, characterized by myelin loss and gliosis. Complete loss of AQP4 is found in type 4 lesions. Mild to moderate perivascular infiltration can also be seen. Type 5 lesions are characterized by an infiltrate of T cells and macrophages, as well as astrocytes with enlarged perinuclear cytoplasm.3 Cellular infiltration is also present in type 6 lesions; however, complete demyelination and significant loss of axons and oligodendrocytes are the hallmarks of these lesions.3
Localization of NMOSD lesions
The preferential locations of NMOSD lesions are the optic nerves and spinal cord. Lesions of the optic nerves are located mostly in the posterior regions, involving the optic chiasm. Swollen and damaged axons are observed. Anterior lesions can also be detected; these may be caused by infiltration of the pial septa after microglial activation. Optic nerve damage can occur directly through AQP4-immunoglobulin G interaction.5 Lesions in the spinal cord can exhibit necrosis, edema, and microcystic alterations as a consequence of the demyelination process.5
NMOSD can also affect areas of the brain where significant amounts of AQP4 protein are found. Lesions within the brain surround the third and fourth ventricles and the cerebral aqueduct, affecting the thalamus, hypothalamus, and anterior border of the mid brain.5 These are called periependymal lesions, and dorsal brain stem involvement causing area postrema syndrome is common in patients with NMOSD. Dorsal brain stem lesions show loss of AQP4 reactivity, with microglia activation and complement deposition in the astrocytes. Infiltration of immune cells, such as T cells, B cells, plasma cells, and eosinophils, is also observed.5
1. Neuromyelitis optica spectrum disorder. National Organization for Rare Disorders (NORD). Accessed October 24, 2021.
2. Lucchinetti CF, Guo Y, Popescu BF, Fujihara K, Itoyama Y, Misu T. The pathology of an autoimmune astrocytopathy: lessons learned from neuromyelitis optica. Brain Pathol. 2014;24(1):83-97. doi:10.1111/bpa.12099
3. Misu T, Höftberger R, Fujihara K, et al. Presence of six different lesion types suggests diverse mechanisms of tissue injury in neuromyelitis optica. Acta Neuropathol. 2013;125(6):815-827. doi:10.1007/s00401-013-1116-7
4. Takai Y, Misu T, Suzuki H, et al. Staging of astrocytopathy and complement activation in neuromyelitis optica spectrum disorders. Brain. 2021;144(8):2401-2415. doi:10.1093/brain/awab102
5. Ramakrishnan P, Nagarajan D. Neuromyelitis optica spectrum disorder: an overview. Acta Neurobiol Exp (Wars). 2020;80(3):256-272. PMID: 32990284
6. Lucchinetti CF, Mandler RN, McGavern D, et al. A role for humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica. Brain. 2002;125(Pt 7):1450-1461. doi:10.1093/brain/awf151
Reviewed by Harshi Dhingra, MD, on 10/25/2021.
Reviewed by Harshi Dhingra, MD, on 10/25/2021.