Aug. 30, 2016
Neuromyelitis optica (NMO) is a relapsing inflammatory demyelinating disease distinct from multiple sclerosis (MS) that most commonly affects optic nerves and the spinal cord. Historically misdiagnosed as MS, NMO is characterized by more-severe attacks and less complete recovery. A single NMO attack can leave a patient blind or paraplegic.
Accurate and timely diagnosis is critical, as treatments that are effective for MS or other demyelinating disorders might be ineffective or even harmful for patients with NMO. Once considered an orphan disease, NMO might affect as many as half a million people worldwide, according to a recent Mayo Clinic study that also found the disease is 2.5 times more common in people of African descent than in Caucasians.
Mayo Clinic is a recognized center of excellence for the diagnosis and treatment of NMO. In 2004, Mayo Clinic researchers led by Vanda A. Lennon, M.D., Ph.D., reported the discovery of the first biomarker for the condition — serum aquaporin-4 immunoglobulin G (AQP4-IgG) antibodies. In 2015, an international consensus panel chaired by Mayo Clinic neurologists introduced new diagnostic criteria and defined the unifying term "neuromyelitis optica spectrum disorders" (NMOSD) to acknowledge that some patients with AQP4-IgG antibodies have recurrent transverse myelitis without optic neuritis and vice versa.
"The unified term is meant to capture a series of clinical and MRI patterns associated with AQP4-IgG," says Dean M. Wingerchuk, M.D., a consultant in Neurology at Mayo Clinic in Phoenix/Scottsdale, Arizona, and co-chair of the consensus panel. "The new consensus criteria are meant to guide clinicians toward recognition of these key clinical and MRI patterns, so they can establish a confident diagnosis and initiate treatment."
"Mayo Clinic has led the way in advancing therapeutic approaches for the treatment of both the acute attack — myelitis or optic neuritis — with plasmapheresis and prevention of attacks with immunosuppressant medications," adds Sean J. Pittock, M.D., director of the Center for Multiple Sclerosis and Autoimmune Neurology at Mayo Clinic in Rochester, Minnesota.
New diagnostic criteria
Prior diagnostic criteria for NMO required optic nerve and spinal cord involvement, although more-restrictive or more-extensive central nervous system involvement was known to occur.
Under the new criteria, as outlined in the July 14, 2015, issue of Neurology, a diagnosis of optic neuritis and myelitis is no longer required to identify NMOSD if serum tests are positive for AQP4-IgG antibodies. More-stringent clinical criteria, with additional neuroimaging findings, are required for NMOSD without AQP4-IgG or when serologic testing is unavailable. Early-stage diagnostic specificity is critical because some established MS therapies — such as interferon-beta, natalizumab, fingolimod and alemtuzumab — appear to aggravate NMOSD.
"We expect the new criteria to increase the number of both seropositive and seronegative cases, and shorten the time from symptom onset to diagnosis and appropriate treatment," Dr. Wingerchuk says.
About 15 to 20 percent of patients with NMOSD test negative for AQP4-IgG. "These cases present a diagnostic conundrum," says Eoin P. Flanagan, M.B., B.Ch., a consultant in Neurology at Mayo Clinic's campus in Minnesota. To capture more of these cases, Mayo Clinic researchers are investigating additional biomarkers of inflammatory demyelinating diseases — some of which have similar phenotypes to NMOSD, including anti-myelin oligodendrocyte glycoprotein (MOG) antibodies.
"Mayo Clinic's neuroimmunology laboratory has developed a live cell flow cytometry assay to detect MOG antibodies, and this will be available as an orderable test soon," Dr. Pittock says. "We have found that up to one-third of AQP-4 IgG-negative NMO cases and a similar proportion of pediatric acute disseminated encephalomyelitis cases test positive. Interestingly, patients with AQP4-IgG — where the target cell is the astrocyte — may have a very similar phenotype to patients with MOG IgG, where the target cell is the oligodendrocyte."
The results of several recent Mayo Clinic studies are helping to further refine diagnosis of NMOSD:
Enhancement characteristic of spinal cord sarcoidosis
MRI of a spinal cord shows a long, linear enhancement that is characteristic of spinal cord sarcoidosis.
- In a study published in the January 2015 issue of JAMA Neurology, Dr. Flanagan and colleagues found that short transverse myelitis — historically considered uncharacteristic of NMOSD — is not uncommon in the disorders and can delay diagnosis and treatment. "About 14 percent of NMOSD cases can have short lesions. Their presence doesn't exclude a diagnosis of NMOSD," Dr. Flanagan says. Other attributes associated with these short-lesion NMOSD cases included nonwhite race, tonic spasms, coexisting autoimmunity and lack of oligoclonal bands in cerebral spinal fluid.
- In a population-based comparative study published in the May 2016 issue of Annals of Neurology, Mayo Clinic researchers found that the incidence of NMOSD is about 2.5 times greater among people of African descent than among Caucasians. The researchers analyzed blood from individuals with inflammatory demyelinating diseases in Martinique (90 percent Afro-Caribbean) and Olmsted County, Minnesota (82 percent Caucasian). Results showed that NMOSD affects 10 out of 100,000 people in Martinique and 3.9 out of 100,000 people in Olmsted County. The age at onset (median 35 to 37 years) was similar in both populations. The researchers estimate that NMOSD affects 16,000 to 17,000 people in the United States.
- In a study published in the March 2016 issue of Annals of Neurology, Mayo Clinic researchers compared long myelitis of spinal cord sarcoidosis with that of NMOSD and found the MRI results to be particularly helpful in distinguishing these disorders. A long, linear enhancement pattern in the posterior of the spinal cord was characteristic of spinal cord sarcoidosis. "We found a ringlike enhancement in the spinal cord favored NMOSD," Dr. Flanagan says. NMOSD patients in the study also were more commonly women and were likelier to have systemic autoimmunity, concurrent or prior optic neuritis, and intractable vomiting episodes.
Lesions in the AQP4-enriched postrema
MRI shows lesions in the AQP4-enriched postrema, which can cause nausea and vomiting in patients with NMOSD.
Nausea and vomiting associated with NMOSD are due to the occurrence of lesions in the AQP4-enriched area postrema. "The first symptom for about 12 percent of people with NMOSD is intractable nausea or vomiting," Dr. Pittock notes. "These patients have multiple gastrointestinal investigations that don't find anything."
The Mayo Clinic Center for Multiple Sclerosis and Autoimmune Neurology is home to a large group of collaborative multidisciplinary physicians and basic scientists who are recognized leaders in understanding the immunopathogenic mechanisms of the disease and identification of novel therapeutic targets. Phase 3 clinical trials of a new immunosuppressant, the complement inhibitor eculizumab, are underway at Mayo Clinic's campuses in Minnesota and Arizona.
"Activation of complement is probably one of the very early immunological events that cause NMOSD attacks," Dr. Wingerchuk says. "In a phase 2 study of patients with highly active NMOSD with AQP4-IgG, we found that almost all subjects remained attack-free during one year of eculizumab therapy and that several of them relapsed once the drug was stopped. If the data from the phase 3 trial show that eculizumab is safe and effective, it will be an important targeted immunotherapy option for NMOSD patients."
For more information
Wingerchuk DM, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology. 2015;85:177.
Flanagan EP, et al. Short myelitis lesions in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders. JAMA Neurology. 2015;72:81.
Flanagan EP, et al. Epidemiology of aquaporin-4 autoimmunity and neuromyelitis optica spectrum. Annals of Neurology. 2016;79:775.
Flanagan EP, et al. Discriminating long myelitis of neuromyelitis optica from sarcoidosis. Annals of Neurology. 2016;79:437.