Recurrent spinal cord and/or optic nerve inflammation reminiscent of relapsing-remitting MS occurs in 80% of NMO patients. A monophasic course appears in 20%; visual and motor involvement is severe initially. However, recovery, although delayed, is usually substantial. In contrast, in patients with relapsing NMO, although less severely affected initially, progressive disability develops with recurrent attacks. Total blindness and quadriplegia sometimes result. A 30% incidence of upper cervical cord and medullary dysfunction leads to respiratory failure, usually fatal, in recurrent NMO.
Most NMO patients have elevated levels of an IgG antibody to a water channel called aquaporin-4 (NMO-IgG). This antibody is considered pathogenic because it binds complement-causing tissue destruction. However, not all NMO patients have anti–aquporin-4 antibody. Other pathologic mechanisms must exist. T cells initially cause blood-brain barrier (BBB) perturbation, with subsequent anti–aquaporin-4 antibodies entering brain parenchyma with CNS destruction.
NMO lesions are distinct when compared with lesions of classic MS or acute disseminated encephalomyelitis (ADEM). Spinal cord lesions exhibit prominent vascular fibrosis and hyalinization involving gray and white matter with prominent necrosis, cavitation, and axonal loss. Extensive demyelination occurs, with extensive oligodendrocyte loss, prominent infiltration of neutrophils, eosinophils, and ringlike perivascular IgM and IgG deposits. Complement products are deposited in NMO lesions. Myelopathic lesions are primarily central in NMO rather than peripheral as in MS, with gray matter preferentially involved in NMO and white matter in MS. Spinal cord MRI demonstrates lesions of a greater longitudinal extent in NMO than those typically seen in MS.
Specific radiologic and laboratory criteria proposed to differentiate NMO from MS include (1) spinal cord MRI lesions extending contiguously over three or more vertebral segments (longitudinally extensive transverse myelitis [LETM]), (2) brain MRI not meeting MS diagnostic criteria, and (3) positive NMO-IgG aquaporin-4 antibody titer. Two of these three criteria are required for NMO diagnosis. In clinical practice, some patients present initially with LETM or severe optic neuritis having neither NMO-IgG antibodies nor brain lesions resembling MS. Some patients continue with recurrent attacks of LETM or ON with or without associated positive NMO-IgG. Such patients are considered to have restricted forms of NMO or are classified as NMO spectrum of disease.
In general, patients presenting with acute optic neuritis or LETM receive urgent care. Attacks are often treated with high-dose systemic glucocorticoids. Methylprednisolone 1 g daily intravenously for 7 to 10 days, sometimes longer, is popular currently. Controlled trials are lacking, and whether lasting benefit accrues remains uncertain. Plasmapheresis and intravenous immunoglobulin as adjunctive therapies have their advocates but, again, whether meaningful benefit ensues remains cloudy. Prophylactic therapy aimed at lessening relapse frequency in those at high risk (positive NMO-IgG or a history of recurrences) has been attempted with an array of immunosuppressants including azathioprine, methotrexate, mitoxantrone, cyclophosphamide, mycophenolate mofetil, and even stem cell replacement regimens, among others. Their number alone argues for limited efficacy, at best, for any of them. Not one is without hazard.
Because it is easily administrated, rituximab is a popular NMO therapy used to chronically suppress B cells. This monoclonal antibody, directed against the CD20 protein expressed on B-cell surfaces potently depletes B cells for several months. It is often given twice a year and is generally well tolerated. Rituximab may be more effective than other immunosuppressive agents in preventing NMO relapses. However, rituximab may not be effective in all patients; breakthrough relapses sometimes occur. NMO is an aggressive disease; sometimes the most intense regimens do not produce favorable results. Long-term safety of rituximab in NMO or MS is not yet established; rituximab use sometimes is associated with progressive multifocal leukoencephalopathy (PML), a generally fatal disorder. Hence rituximab therapy for chronic NMO needs to be used cautiously.
ACUTE DISSEMINATED ENCEPHALOMYELITIS (ADEM)
Acute disseminated encephalomyelitis (ADEM) is an acute demyelinating monophasic central nervous system (CNS) disease that follows an infectious illness or immunization, usually within 6 to 8 weeks. Although described more often in children after measles infection, it can occur after any nondescript viral illness. Most ADEM cases develop in children. ADEM is seen in the adult population, but with lesser frequency. Because pediatric multiple sclerosis (MS) is rare, the higher occurrence of ADEM in children, as opposed to adults, suggests that ADEM constitutes a distinctive entity.
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