Neuromyelitis optica MOG-IgG causes reversible lesions in mouse brain.

INTRODUCTION: Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) are present in some neuromyelitis optica patients who lack antibodies against aquaporin-4 (AQP4-IgG). The effects of neuromyelitis optica MOG-IgG in the central nervous system have not been investigated in vivo. We microinjected MOG-IgG, obtained from patients with neuromyelitis optica, into mouse brains and compared the results with AQP4-IgG. RESULTS: MOG-IgG caused myelin changes and altered the expression of axonal proteins that are essential for action potential firing, but did not produce inflammation, axonal loss, neuronal or astrocyte death. These changes were independent of complement and recovered within two weeks. By contrast, AQP4-IgG produced complement-mediated myelin loss, neuronal and astrocyte death with limited recovery at two weeks. CONCLUSIONS: These differences mirror the better outcomes for MOG-IgG compared with AQP4-IgG patients and raise the possibility that MOG-IgG contributes to pathology in some neuromyelitis optica patients

Neuromyelitis optica MOG-IgG causes reversible lesions in mouse brain.

INTRODUCTION: Antibodies against myelin oligodendrocyte glycoprotein (MOG-IgG) are present in some neuromyelitis optica patients who lack antibodies against aquaporin-4 (AQP4-IgG). The effects of neuromyelitis optica MOG-IgG in the central nervous system have not been investigated in vivo. We microinjected MOG-IgG, obtained from patients with neuromyelitis optica, into mouse brains and compared the results with AQP4-IgG. RESULTS: MOG-IgG caused myelin changes and altered the expression of axonal proteins that are essential for action potential firing, but did not produce inflammation, axonal loss, neuronal or astrocyte death. These changes were independent of complement and recovered within two weeks. By contrast, AQP4-IgG produced complement-mediated myelin loss, neuronal and astrocyte death with limited recovery at two weeks. CONCLUSIONS: These differences mirror the better outcomes for MOG-IgG compared with AQP4-IgG patients and raise the possibility that MOG-IgG contributes to pathology in some neuromyelitis optica patients

Treatment of neuromyelitis optica: state-of-the-art and emerging therapies.

Neuromyelitis optica (NMO) is an autoimmune disease of the CNS that is characterized by inflammatory demyelinating lesions in the spinal cord and optic nerve, potentially leading to paralysis and blindness. NMO can usually be distinguished from multiple sclerosis (MS) on the basis of seropositivity for IgG antibodies against the astrocytic water channel aquaporin-4 (AQP4). Differentiation from MS is crucial, because some MS treatments can exacerbate NMO. NMO pathogenesis involves AQP4-IgG antibody binding to astrocytic AQP4, which causes complement-dependent cytotoxicity and secondary inflammation with granulocyte and macrophage infiltration, blood-brain barrier disruption and oligodendrocyte injury. Current NMO treatments include general immunosuppressive agents, B-cell depletion, and plasma exchange. Therapeutic strategies targeting complement proteins, the IL-6 receptor, neutrophils, eosinophils and CD19--all initially developed for other indications--are under clinical evaluation for repurposing for NMO. Therapies in the preclinical phase include AQP4-blocking antibodies and AQP4-IgG enzymatic inactivation. Additional, albeit currently theoretical, treatment options include reduction of AQP4 expression, disruption of AQP4 orthogonal arrays, enhancement of complement inhibitor expression, restoration of the blood-brain barrier, and induction of immune tolerance. Despite the many therapeutic options in NMO, no controlled clinical trials in patients with this condition have been conducted to date

The differential diagnosis of longitudinally extensive transverse myelitis.

Longitudinally extensive transverse myelitis refers to florid and widespread inflammation of the spinal cord causing T2 hyperintensity on spinal magnetic resonance imaging that is seen to extend over three or more vertebral segments. Whilst rare, longitudinally extensive transverse myelitis is clinically important as it can lead to catastrophic morbidity, and a group of these patients are at risk of further attacks. Early identification and establishment of the underlying aetiology is vital in order to initiate appropriate therapy and optimize outcomes. Whilst longitudinally extensive transverse myelitis is classically associated with neuromyelitis optica, there are many other causes. These include other inflammatory aetiologies, infection, malignancy and metabolic disturbance. Some of these are readily treatable. Laboratory and radiological investigations can help to differentiate these causes. Treatment of longitudinally extensive transverse myelitis hinges on distinguishing inflammatory and non-inflammatory aetiologies and identifying patients who are at high risk of a recurrent course

Opportunistic infections of the retina in patients with aquaporin-4 antibody disease.

IMPORTANCE: Patients with neuromyelitis optica who have aquaporin-4 antibodies are being identified and receiving immunosuppressant treatment earlier and more aggressively as a result of increasing awareness of the importance of preventing relapses responsible for the high morbidity and mortality associated with the disease. To our knowledge, opportunistic retinal infection in patients with aquaporin-4 antibodies who are receiving immunosuppressants has not been reported to date. OBSERVATIONS: We describe 2 patients with aquaporin-4 antibodies who were receiving conventional doses of first-line immunosuppressive therapy. Both patients presented with vision loss that was initially thought to be optic neuritis attacks. The subsequent diagnoses were ocular toxoplasmosis and cytomegalovirus retinitis. CONCLUSIONS AND RELEVANCE: Retinal opportunistic infections can occur in patients with aquaporin-4 antibodies who are receiving relatively low levels of immunosuppression, may mimic optic neuritis, and are a potentially reversible cause of vision loss when treated promptly

Opportunistic infections of the retina in patients with aquaporin-4 antibody disease.

IMPORTANCE: Patients with neuromyelitis optica who have aquaporin-4 antibodies are being identified and receiving immunosuppressant treatment earlier and more aggressively as a result of increasing awareness of the importance of preventing relapses responsible for the high morbidity and mortality associated with the disease. To our knowledge, opportunistic retinal infection in patients with aquaporin-4 antibodies who are receiving immunosuppressants has not been reported to date. OBSERVATIONS: We describe 2 patients with aquaporin-4 antibodies who were receiving conventional doses of first-line immunosuppressive therapy. Both patients presented with vision loss that was initially thought to be optic neuritis attacks. The subsequent diagnoses were ocular toxoplasmosis and cytomegalovirus retinitis. CONCLUSIONS AND RELEVANCE: Retinal opportunistic infections can occur in patients with aquaporin-4 antibodies who are receiving relatively low levels of immunosuppression, may mimic optic neuritis, and are a potentially reversible cause of vision loss when treated promptly