Neuromyelitis optica spectrum disorders: from pathophysiology to therapeutic strategies

AbstractNeuromyelitis optica (NMO) is a chronic inflammatory autoimmune disease of the central nervous system (CNS) characterized by acute optic neuritis (ON) and transverse myelitis (TM). NMO is caused by a pathogenic serum IgG antibody against the water channel aquoporin 4 (AQP4) in the majority of patients. AQP4-antibody (AQP4-ab) presence is highly specific, and differentiates NMO from multiple sclerosis. It binds to AQP4 channels on astrocytes, triggering activation of the classical complement cascade, causing granulocyte, eosinophil, and lymphocyte infiltration, culminating in injury first to astrocyte, then oligodendrocytes followed by demyelination and neuronal loss. NMO spectrum disorder (NMOSD) has recently been defined and stratified based on AQP4-ab serology status. Most NMOSD patients experience severe relapses leading to permanent neurologic disability, making suppression of relapse frequency and severity, the primary objective in disease management. The most common treatments used for relapses are steroids and plasma exchange.Currently, long-term NMOSD relapse prevention includes off-label use of immunosuppressants, particularly rituximab. In the last 2 years however, three pivotal clinical trials have expanded the spectrum of drugs available for NMOSD patients. Phase III studies have shown significant relapse reduction compared to placebo in AQP4-ab-positive patients treated with satralizumab, an interleukin-6 receptor (IL-6R) inhibitor, inebilizumab, an antibody against CD19+ B cells; and eculizumab, an antibody blocking the C5 component of complement. In light of the new evidence on NMOSD pathophysiology and of preliminary results from ongoing trials with new drugs, we present this descriptive review, highlighting promising treatment modalities as well as auspicious preclinical and clinical studies.

Download Full-text

Eculizumab in the treatment of neuromyelitis optica spectrum disorder

Immunotherapy ◽

10.2217/imt-2020-0163 ◽

2020 ◽

Vol 12 (14) ◽

pp. 1053-1066

Author(s):

Katrin Giglhuber ◽

Achim Berthele

Keyword(s):

Neuromyelitis Optica ◽

Controlled Trial ◽

Water Channel ◽

Spectrum Disorder ◽

Phase Iii ◽

Neuromyelitis Optica Spectrum Disorder ◽

Humanized Monoclonal Antibody ◽

The Complement System ◽

Terminal Complement ◽

Aqp4 Antibody

Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune disease of the CNS which is distinct from multiple sclerosis and typically presents with a relapsing course of optic neuritis, myelitis and midline brain inflammatory lesions. In at least two-thirds of cases, antibodies against the water channel AQP4 can be found, which lead to an antibody-mediated activation of the complement system with consecutive damage to neuronal structures. Eculizumab, a humanized monoclonal antibody against the terminal complement component 5, was shown to significantly reduce the risk of NMOSD relapse in a Phase III placebo-controlled trial. Based on this, eculizumab (Soliris®) was the first drug to be formally approved for the treatment of anti-AQP4-antibody positive NMOSD in 2019.

Download Full-text

Neuromyelitis Optica

10.1093/med/9780199937837.003.0088 ◽

2017 ◽

Cited By ~ 1

Author(s):

Teri L. Schreiner ◽

Jeffrey L. Bennett

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Central Nervous System ◽

Nervous System ◽

Optic Neuritis ◽

Neuromyelitis Optica ◽

Water Channel ◽

Transverse Myelitis ◽

Inflammatory Disorder ◽

The Central Nervous System

Neuromyelitis optica (NMO), or Devic’s disease is an inflammatory disorder of the central nervous system that preferentially affects the optic nerves and spinal cord. Initially considered a variant of multiple sclerosis (MS), NMO is now clearly recognized to have distinct clinical, radiographic, and pathologic characteristics. Historically, the diagnosis of NMO required bilateral optic neuritis and transverse myelitis; however, the identification of a specific biomarker, NMO-IgG, an autoantibody against the aquaporin-4 (AQP4) water channel, has broadened NMO spectrum disease to include patients with diverse clinical and radiographic presentations. This chapter addresses the diagnosis, pathophysiology, and management of the disease.

Download Full-text

Neuromyelitis Optica Spectrum Disorder and Anti-MOG Syndromes

Biomedicines ◽

10.3390/biomedicines7020042 ◽

2019 ◽

Vol 7 (2) ◽

pp. 42 ◽

Cited By ~ 18

Author(s):

Marco A. Lana-Peixoto ◽

Natália Talim

Keyword(s):

Optic Neuritis ◽

Neuromyelitis Optica ◽

Area Postrema ◽

Water Channel ◽

Clinical Manifestations ◽

Transverse Myelitis ◽

Myelin Oligodendrocyte Glycoprotein ◽

Immunosuppressive Drugs ◽

Spectrum Disorder ◽

Neuromyelitis Optica Spectrum Disorder

Neuromyelitis optica spectrum disorder (NMOSD) and anti-myelin oligodendrocyte glycoprotein (anti-MOG) syndromes are immune-mediated inflammatory conditions of the central nervous system that frequently involve the optic nerves and the spinal cord. Because of their similar clinical manifestations and habitual relapsing course they are frequently confounded with multiple sclerosis (MS). Early and accurate diagnosis of these distinct conditions is relevant as they have different treatments. Some agents used for MS treatment may be deleterious to NMOSD. NMOSD is frequently associated with antibodies which target aquaporin-4 (AQP4), the most abundant water channel in the CNS, located in the astrocytic processes at the blood-brain barrier (BBB). On the other hand, anti-MOG syndromes result from damage to myelin oligodendrocyte glycoprotein (MOG), expressed on surfaces of oligodendrocytes and myelin sheaths. Acute transverse myelitis with longitudinally extensive lesion on spinal MRI is the most frequent inaugural manifestation of NMOSD, usually followed by optic neuritis. Other core clinical characteristics include area postrema syndrome, brainstem, diencephalic and cerebral symptoms that may be associated with typical MRI abnormalities. Acute disseminated encephalomyelitis and bilateral or recurrent optic neuritis are the most frequent anti-MOG syndromes in children and adults, respectively. Attacks are usually treated with steroids, and relapses prevention with immunosuppressive drugs. Promising emerging therapies for NMOSD include monoclonal antibodies and tolerization.

Download Full-text

Memantine ameliorates motor impairments and pathologies in a mouse model of neuromyelitis optica spectrum disorders.

10.21203/rs.3.rs-27104/v1 ◽

2020 ◽

Author(s):

Leung-Wah Yick ◽

Chi-Ho Tang ◽

Oscar Ka-Fai Ma ◽

Jason Shing-Cheong Kwan ◽

Koon Ho CHAN

Keyword(s):

Spinal Cord ◽

Neuromyelitis Optica ◽

Neurotrophic Factor ◽

Water Channel ◽

Transverse Myelitis ◽

Aquaporin 4 ◽

Glutamate Excitotoxicity ◽

Neuromyelitis Optica Spectrum Disorders ◽

Motor Impairments ◽

Spectrum Disorders

Abstract Background: Neuromyelitis optica spectrum disorders (NMOSD) are central nervous system (CNS) autoimmune inflammatory demyelinating diseases characterized by recurrent episodes of acute optic neuritis and transverse myelitis. Aquaporin-4 immunoglobulin G (AQP4-IgG) autoantibodies, which target the water channel aquaporin-4 (AQP4) on astrocytic membrane, are pathogenic in NMOSD. Glutamate excitotoxicity, which is triggered by internalization of AQP4-glutamate transporter complex after AQP4-IgG binding to astrocytes, is involved in early NMOSD pathophysiologies. We studied the effects of memantine, a N-methyl-D-aspartate (NMDA) receptor antagonist, on motor impairments and spinal cord pathologies in mice which received human AQP4-IgG. Methods: Purified IgG from AQP4-IgG-seropositive NMOSD patients were passively transferred to adult C57BL/6 mice with disrupted blood-brain barrier. Memantine was administered by oral gavage. Motor impairments of the mice were assessed by beam walking test. Spinal cords of the mice were assessed by immunofluorescence and ELISA. Results: Oral administration of memantine ameliorated the motor impairments induced by AQP4-IgG, no matter the treatment was initiated before (preventive) or after (therapeutic) disease flare. Memantine profoundly reduced AQP4 and astrocyte loss, and attenuated demyelination and axonal loss in the spinal cord of mice which had received AQP4-IgG. The protective effects of memantine were associated with inhibition of apoptosis and suppression of neuroinflammation, with decrease in microglia activation and neutrophil infiltration and reduction of increase in levels of proinflammatory cytokines including interleukin-1β (IL-1β), interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α). In addition, memantine elevated growth factors including brain-derived neurotrophic factor (BDNF), glial cell line-derived neurotrophic factor (GDNF) and vascular endothelial growth factor (VEGF) in the spinal cord. Conclusions: Our findings support that glutamate excitotoxicity and neuroinflammation plays important roles in complement-independent pathophysiology during early development of NMOSD lesions, and highlight the potential of oral memantine as a therapeutic agent in NMOSD acute attacks.

Download Full-text

Devic’s neuromyelitis optica: a critical review

Arquivos de Neuro-Psiquiatria ◽

10.1590/s0004-282x2008000100034 ◽

2008 ◽

Vol 66 (1) ◽

pp. 120-138 ◽

Cited By ~ 36

Author(s):

Marco Aurélio Lana-Peixoto

Keyword(s):

Multiple Sclerosis ◽

Spinal Cord ◽

Neuromyelitis Optica ◽

Brain Mri ◽

Water Channel ◽

Demyelinating Diseases ◽

Aquaporin 4 ◽

Igg Antibody ◽

Vascular Walls ◽

Devic’S Neuromyelitis Optica

Devic's neuromyelitis optica (NMO) is an idiopathic inflammatory demyelinating and necrotizing disease characterized by predominant involvement of the optic nerves and spinal cord. In Asian countries relapsing NMO has been known as opticospinal multiple sclerosis. It has long been debated if NMO is a variant of multiple sclerosis (MS) or a distinct disease. Recent studies have shown that NMO has more frequently a relapsing course, and results from attack to aquaporin-4 which is the dominant water channel in the central nervous system, located in foot processes of the astrocytes. Distinctive pathological features of NMO include perivascular deposition of IgG and complement in the perivascular space, granulocyte and eosinophil infiltrates and hyalinization of the vascular walls. These features distinguish NMO from other demyelinating diseases such as MS and acute demyelinating encephalomyelopathy. An IgG-antibody that binds to aquaporin-4, named NMO-IgG has high sensitivity and specificity. Magnetic resonance imaging (MRI) studies have revealed that more frequently there is a long spinal cord lesion that extends through three or more vertebral segments in length. Brain MRI lesions atypical for MS are found in the majority of cases. Treatment in the acute phase includes intravenous steroids and plasma exchange therapy. Immunosupressive agents are recommended for prophylaxis of relapses.

Download Full-text

Brain magnetic resonance imaging findings in acute relapses of neuromyelitis optica spectrum disorders

Multiple Sclerosis Journal ◽

10.1177/1352458507082617 ◽

2007 ◽

Vol 14 (2) ◽

pp. 248-251 ◽

Cited By ~ 21

Author(s):

JA Cabrera-Gómez ◽

A. Saiz-Hinarejos ◽

F. Graus ◽

A. González-Quevedo ◽

R. Rodríguez-Rojas ◽

...

Keyword(s):

Magnetic Resonance Imaging ◽

Magnetic Resonance ◽

Neuromyelitis Optica ◽

Brain Mri ◽

Brain Magnetic Resonance Imaging ◽

Transverse Myelitis ◽

Resonance Imaging ◽

Igg Antibody ◽

Magnetic Resonance Imaging Mri ◽

Extensive Transverse Myelitis

We studied cranial magnetic resonance imaging (MRI) lesions in three women with acute attacks of recurrent longitudinally extensive transverse myelitis (r-LETM), recurrent-optic neuritis (r-ON) and r-LETM-CNS. Neuromyelitis Optica -immunoglobulin (IgG) antibody was positive in all cases. Brain MRI (1.5 Tesla) was performed according to protocol from consortium MS centre. We described the cranial lesions in brain MRI of acute relapses. These lesions were different from MS, most had an asymptomatic course which disappeared with time, protocol from consortium of MS centre criteria for brain MRI and seropositivity of NMO-IgG are useful tools for differentiate acute lesions of NMO/MS. Multiple Sclerosis 2008; 14: 248—251. http://msj.sagepub.com

Download Full-text

Neuromyelitis optica immunoglobulins as a marker of disease activity and response to therapy in patients with neuromyelitis optica

Multiple Sclerosis Journal ◽

10.1177/1352458508092811 ◽

2008 ◽

Vol 14 (8) ◽

pp. 1061-1067 ◽

Cited By ~ 28

Author(s):

B Weinstock-Guttman ◽

C Miller ◽

EA Yeh ◽

M Stosic ◽

M Umhauer ◽

...

Keyword(s):

Multiple Sclerosis ◽

Neuromyelitis Optica ◽

Stable Disease ◽

Clinical Status ◽

Transverse Myelitis ◽

Biological Marker ◽

Response To Therapy ◽

Igg Antibodies ◽

Igg Antibody ◽

Cross Sectional

Objective To determine whether neuromyelitis optica (NMO) immunoglobulin (IgG) antibody status in NMO/Devic’s disease patients followed prospectively is persistent or can change relative to the clinical status and/or response to therapy. Design A cross-sectional group of patients with NMO, relapsing extensive longitudinal transverse myelitis (RLETM) or optico-spinal multiple sclerosis (OSMS) were evaluated for the presence of NMO IgG antibodies. Repeated evaluation was made in all NMO/RLETM patients and in a subgroup of OSMS patients. Setting Baird Multiple Sclerosis Center, Buffalo, New York, an academic multiple sclerosis center. Results Out of a consecutive cohort of 38 patients evaluated for the presence of NMO IgG, 12 had NMO and 26 had OSMS. Five of the 12 NMO/RLETM patients were NMO IgG positive at the time of their initial evaluation. Four of these patients were repeatedly tested for NMO IgG: two of these became negative and two remained positive. One patient who was initially negative became positive during an acute event and again became negative during the stable disease phase following treatment. A positive test result was associated with active disease, whereas a negative NMO IgG result was consistently found in stable, long-term treated patients. None of the OSMS patients were positive for NMO IgG even during acute attacks. Conclusions NMO IgG antibodies are associated with active NMO/RLETM. A well-controlled stable disease usually under effective immunosuppressive therapy can transform the NMO IgG to a negative status. Repeated NMO IgG testing should be considered as a useful biological marker for monitoring NMO/RLETM disease and or response to therapy.

Download Full-text

A Rare Presentation of Neuromyelitis Optica Spectrum Disorders

Clinical Medicine Insights Case Reports ◽

10.1177/1179547617752685 ◽

2018 ◽

Vol 11 ◽

pp. 117954761775268

Author(s):

Navneet K Singh ◽

Alexander J Sweidan ◽

Sarah Strube ◽

Ignacio Carrillo-Nunez

Keyword(s):

Neuromyelitis Optica ◽

Disease Process ◽

Transverse Myelitis ◽

Aquaporin 4 ◽

Treatment Modalities ◽

High Dose ◽

Neuromyelitis Optica Spectrum Disorders ◽

Rare Presentation ◽

Lower Extremity Weakness ◽

Spectrum Disorders

Neuromyelitis optica spectrum disorders (NMOSDs) are a set of demyelinating disorders that primarily target the optic nerves and the spinal cord. Previously thought to be a subset of multiple sclerosis (MS), now is recognized as a distinct entity. We present a 59-year-old female patient who was admitted for acute upper and lower extremity weakness. The patient had woken up from sleep with sudden onset of weakness. Patient was initially diagnosed with a right hemispheric stroke; however, magnetic resonance imaging of the cervical spine later performed showed abnormal enhancement from C2-C4, representing transverse myelitis. Cerebrospinal fluid was negative for organisms and inflammatory biomarkers. An anti-aquaporin-4 receptor antibody titer was found to be elevated with titers >80 units/mL. The patient was treated with high-dose steroids and plasmapheresis. The NMOSD is a rare entity and, here, we present a rare presentation of the disease. Since its description in 1870, it was confused with MS for years. The advent of anti-aquaporin-4 antibody has been instrumental in differentiating the disease process from MS. This distinction is important, in terms of agents used for treatment and prognostication. The NMOSD is a set of debilitating disease, which requires prompt recognition and appropriate treatment, to avoid the disabling sequelae. Future prospects of the disease include development of novel biological treatment modalities which focus on restoring the loss of immune tolerance which is key to the pathogenesis of the disease.

Download Full-text

Cytoprotective IgG antibodies in sera from a subset of patients with AQP4-IgG seropositive neuromyelitis optica spectrum disorder

Scientific Reports ◽

10.1038/s41598-021-01294-3 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lukmanee Tradtrantip ◽

Michael R. Yeaman ◽

A. S. Verkman

Keyword(s):

Neuromyelitis Optica ◽

Protective Factor ◽

Water Channel ◽

Spectrum Disorder ◽

Aquaporin 4 ◽

Neuromyelitis Optica Spectrum Disorder ◽

Igg Antibody ◽

Igg Binding ◽

Complement Dependent Cytotoxicity ◽

Wide Range

AbstractNeuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease of the central nervous system. Most NMOSD patients are seropositive for immunoglobulin G (IgG) autoantibodies against astrocyte water channel aquaporin-4 (AQP4), called AQP4-IgG. AQP4-IgG binding to aquaporin-4 causes complement-dependent cytotoxicity (CDC), leading to inflammation and demyelination. Here, CDC was measured in AQP4-expressing cells exposed to human complement and heat-inactivated sera from 108 AQP4-IgG seropositive NMOSD subjects and 25 non-NMOSD controls. AQP4-IgG positive sera produced a wide range of CDC, with 50% maximum cytotoxicity produced by as low as 0.2% serum concentration. Unexpectedly, 58 samples produced no cytotoxicity, and of those, four sera were cytoprotective against cytotoxic AQP4-IgG. Cytoprotection was found against different cytotoxic monoclonal AQP4-IgGs and NMOSD patient sera, and in primary astrocyte cultures. Mechanistic studies revealed that the protective factor is an IgG antibody that did not inhibit complement directly, but interfered with binding of cytotoxic AQP4-IgG to AQP4 and consequent C1q binding and complement activation. Further studies suggested that non-pathogenic AQP4-IgG, perhaps with altered glycosylation, may contribute to reduced or ineffectual binding of cytotoxic AQP4-IgG, as well as reduced cell-surface AQP4. The presence of natural cytoprotective antibodies in AQP4-IgG seropositive sera reveals an added level of complexity in NMOSD disease pathogenesis, and suggests the potential therapeutic utility of ‘convalescent’ serum or engineered protective antibody to interfere with pathogenic antibody in AQP4-IgG seropositive NMOSD.

Download Full-text

Treatment of Neuromyelitis Optica Spectrum Disorders

International Journal of Molecular Sciences ◽

10.3390/ijms22168638 ◽

2021 ◽

Vol 22 (16) ◽

pp. 8638

Author(s):

Koon-Ho Chan ◽

Chi-Yan Lee

Keyword(s):

Side Effects ◽

Neuromyelitis Optica ◽

Water Channel ◽

Transverse Myelitis ◽

Aquaporin 4 ◽

Reproductive Age ◽

Glutamate Excitotoxicity ◽

In Vivo Studies ◽

Inflammatory Disorder

Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune central nervous system (CNS) inflammatory disorder that can lead to serious disability and mortality. Females are predominantly affected, including those within the reproductive age. Most patients develop relapsing attacks of optic neuritis; longitudinally extensive transverse myelitis; and encephalitis, especially brainstem encephalitis. The majority of NMOSD patients are seropositive for IgG autoantibodies against the water channel protein aquaporin-4 (AQP4-IgG), reflecting underlying aquaporin-4 autoimmunity. Histological findings of the affected CNS tissues of patients from in-vitro and in-vivo studies support that AQP4-IgG is directly pathogenic in NMOSD. It is believed that the binding of AQP4-IgG to CNS aquaporin-4 (abundantly expressed at the endfoot processes of astrocytes) triggers astrocytopathy and neuroinflammation, resulting in acute attacks. These attacks of neuroinflammation can lead to pathologies, including aquaporin-4 loss, astrocytic activation, injury and loss, glutamate excitotoxicity, microglial activation, neuroinflammation, demyelination, and neuronal injury, via both complement-dependent and complement-independent pathophysiological mechanisms. With the increased understanding of these mechanisms underlying this serious autoimmune astrocytopathy, effective treatments for both active attacks and long-term immunosuppression to prevent relapses in NMOSD are increasingly available based on the evidence from retrospective observational data and prospective clinical trials. Knowledge on the indications and potential side effects of these medications are essential for a clear evaluation of the potential benefits and risks to NMOSD patients in a personalized manner. Special issues such as pregnancy and the coexistence of other autoimmune diseases require additional concern and meticulous care. Future directions include the identification of clinically useful biomarkers for the prediction of relapse and monitoring of the therapeutic response, as well as the development of effective medications with minimal side effects, especially opportunistic infections complicated by long-term immunosuppression.

Download Full-text