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Antibody Test Differentiates Pediatric Neuromyelitis Optica from MS in Children

ARTICLE IN BRIEF

  • ✓ An international team of investigators reported a similar frequency in the biomarker for neuromyelitis optica — NMO-IgG — in children and adults.

An antibody blood test that can minimize misdiagnosis of multiple sclerosis (MS) and neuromyelitis optica (NMO), a severe variant of MS predominantly affecting the spinal cord and optic nerves, seems to be equally useful in children and adults, according to an international study involving researchers in Canada, Argentina, and the Mayo Clinic in Rochester, MN.

In a blinded trial of blood samples from children with inflammatory demyelinating disorders (MS-related disorders), only children with NMO or limited forms of NMO tested positive for the aquaporin-4-specific water channel autoantibody associated with NMO — autoantibody NMO-IgG. Results were negative for children with other inflammatory demyelinating disorders, including classical MS. Reported in the Jan. 29 issue of Neurology, it is the first study to evaluate the diagnostic utility of the NMO-IgG biomarker in pediatric patients.

Four years ago the Mayo researchers reported in a 2004 study in The Lancet that the test could differentiate NMO from MS in adults, but it was not known if the same was true in children.

“What is really exciting is that this first blood test for any CNS inflammatory demyelinating disease has broadened the way we think about MS-related diseases,” said senior study author Sean J. Pittock, MD, a Mayo Clinic specialist in autoimmune neurology. Neurologists Brenda Banwell, MD, associate professor of pediatrics (neurology) at the University of Toronto, led the study in Canada, and Sylvia Tenembaum, MD, of the Hospital de Pediatria in Buenos Aires, led the research team in Argentina.

Previously a huge amount of resources (both financial and academic) focused on myelin, he said, but that changed with the identification of aquaporin-4 as the most likely candidate target of NMO-IgG as a causative agent of NMO and early and partial forms of NMO, Dr. Pittock noted. “These observations have opened a completely new direction for research and therapeutic approaches,” he added.

STUDY PROTOCOLS, RESULTS

In the current study, Dr. Pittock and colleagues analyzed demographic, clinical, and radiologic data, and serum NMO-IgG status in 87 children with various CNS inflammatory demyelinating disorders.

Forty-one children had relapsing-remitting multiple sclerosis (RRMS); 17 had NMO; 13, monophasic/recurrent optic neuritis (ON); 13, transverse myelitis, including 10 with longitudinally extensive lesions on MRI spine (LETM), and another three with LETM as part of acute disseminated encephalomyelitis (ADEM).

The investigators were blinded to the clinical diagnosis during the study. In all, seven of nine children with relapsing NMO (78 percent) and one of eight children with monophasic NMO (12.5 percent) were seropositive for the antibody. Only two children from other diagnostic groups were seropositive: one of five with recurrent ON (20 percent) and one child with recurrent LETM. None of the 44 children with RRMS or ADEM were seropositive.

Dr. Pittock said it is also important that none of nine children with monophasic LETM were NMO-IgG-seropositive, however, serial studies of larger adult and pediatric LETM cohorts are needed to ascertain the prevalence of NMO-IgG in pediatric LETM and whether the absence of the antibody is a negative predictor of relapse.

“In adult patients we find that 20- to 30-percent with a single episode of LETM are NMO-IgG seropositive and that seropositivity predicts relapse of LETM or future development of optic neuritis,” Dr. Pittock noted.

In the first year of follow-up in adult seropositive patients with LETM, 56 percent relapsed or developed ON while there were no second episodes in seronegative patients.

“For adults with an initial episode of presumed idiopathic longitudinal transverse myelitis, our observations justify testing for NMO-IgG and, for seropositive patients, consideration of prophylactic immunosuppressive treatment,” he said. Early diagnosis is important, he said, because optimal initial treatment for NMO requires immune suppressive medication [for example, azathioprine], in contrast with MS, for which immune modulatory treatments [such as interferon beta] are often prescribed.

DIAGNOSTIC IMPLICATIONS

In a telephone interview, Dr. Pittock told Neurology Today that although the number of children tested was small, the results are important because they so closely parallel those from the adult studies.

He also noted that MS specialists recognize that NMO-IgG seropositivity implies a broader spectrum of inflammatory demyelinating CNS disorders than the 19th century picture of NMO first described by the French neurologist Eugene Devic, which gave the syndrome its eponym.

“Before the advent of NMO-IgG many patients with the NMO spectrum of disorders were misdiagnosed as MS because of the commonly relapsing course and frequency of MRI brain lesions, usually silent,” he said. Devic disease was assumed to involve one episode restricted to the optic nerves and cervical spinal cord.

QUESTIONS REMAIN

While the antibody was present in nearly 80 percent of the children with relapsing-remitting NMO, the fact that only 12.5 percent of those with a monophasic illness tested positive shows how much remains to be done to better define and understand the antibody's usefulness, noted Steven L. Galetta, MD, the Ruth Wagner Van Meter and J. Ray Van Meter Professor of Neurology at the University of Pennsylvania School of Medicine in Philadelphia. Dr. Galetta was not involved with the current study.

“This large experience in children verifies that the antibody test may be useful for diagnosis and this is important information, but we certainly need more studies in larger populations, and in different geographic areas, because we find large differences. In Japan, for instance, there are differences [in NMO-IgG] specificity in the northern and southern populations that have been studied,” he said. “At the University of Pennsylvania we don't find higher sensitivity with this biomarker.”

He noted that some of these discrepancies reflect continued differences in how demyelinating disorders and NMO syndromes are defined clinically and by imaging.

Figure

(A) Sagittal T2-weighted cervical spine image in a 15-year-old girl with NMO demonstrates a contiguous hyperintense lesion extending from the lower medulla oblongata to C7 (arrows).(B) Coronal fluid attenuated inverse recovery weighted image in a 14-year-old boy with optic neuritis demonstrates high signal in the hypothalamic region extending to the optic chiasm (arrow).(C) Sagittal T2-weighted brain-cervical spine image in the 14-year-old boy (in B) demonstrates a hyperintense lesion involving the anterior and dorsomedial medulla (arrow).(D) Axial T1-weighted image with orbital views in a 9-year-old girl with monophasic NMO demonstrates gadolinium enhancement of the right optic nerve and chiasm (arrow).

“The bottom line is that the definition continues to evolve, and is being revised and debated. Devic described monophasic NMO, and only over time have other forms emerged, such as relapsing-remitting NMO, which have been incorporated under the rubric of NMO.”

Dr. Galetta said the findings in the new study further emphasize the need for greater understanding of NMO syndromes and similar disorders.

“The results are interesting, but we can't rely solely on this antibody to guide treatment. There's too much we don't know,” he said. “For example, it is odd that the number of seropositive patients with monophasic disease was so much lower than those with relapsing-remitting NMO. We really need to work this out, because it may be part of a larger spectrum of demyelinating disease… and there's a lot of overlap with multiple sclerosis.”

There is also a subpopulation of patients with benign symptoms, who nonetheless test positive for the NMO-IgG antibody, he continued.

“I've had a number of patients with benign NMO for twenty years or more, and they aren't taking any medication,” he told Neurology Today. “To me there's a spectrum [of disorders] here and we need to know much more. Right now it's still in the eyes of the beholder.”

REFERENCES

• Banwell B, Tenembaum S, Pittock S, et al. Neuromyelitis optica-IgG in childhood inflammatory demyelinating CNS disorders. Neurology 2008;70:344–352.
    • Galetta S, Bennet J. Neuromyelitis optica is a variant of multiple sclerosis. Arch Neurol 2007;64:901–903.
      • Wingerchuk DM, Lennon VA, Weinshenker BG, et al. Revised diagnostic criteria for neuromyelitis optica. Neurology 2006;66:1485–1489.
        • Pittock S, Lennon VA, Weinshenker BG, et al. Brain abnormalities in neuromyelitis optica. Arch Neurol 2006;63:390–396.
          • Lennon VA, Wingerchuk DM, Fujihara K, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004;364:2106–2112.