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NEW WAYS TO DIFFERENTIATE ADEM FROM MS

MIAMI BEACH—Making a differential diagnosis between acute disseminated encephalomyelitis (ADEM) and multiple sclerosis (MS) can be challenging – given that both appear as clinically similar demyelinating disorders. (See “The Clinical Picture: ADEM and MS” on page 58.)

But new research that sheds light on the underlying differences in the pathogenesis of ADEM and MS may make it easier to distinguish the two disorders, according to a new study led by Kevin C. O'Connor, PhD, Instructor of Neurology at Harvard Medical School.

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Dr. Kevin OConnor: “Hopefully this research will pave the way for an assay that can rapidly diagnose ADEM and rule out MS.”

ASSAYS FOR DIFFERENTIATION

“Using protein arrays and solid and solution phase antibody binding assays, we were able to identify a fundamental difference in the humoral response of these clinically similar diseases,” said Dr. O'Connor, who led the study along with Bill Robinson, MD, of Stanford University, and David Hafler, MD, of Harvard.

“Hopefully this research will pave the way for an assay that can rapidly diagnose ADEM and rule out MS,” he added.

The vast majority of assays measuring antibody binding in MS have been done with solid phase assays, such as ELISA, with which the antigens are immobilized on a solid surface, he explained. Collectively, the literature is not in agreement regarding their detection.

Solution phase assays – in which the antigen is soluble – are in most cases more stringent. The key development that allowed the specific and sensitive detection of autoantibodies in diabetes was the use of a solution-phase radioimmunoassay (RIA). The assay format has been carefully compared to solid phase ELISA.

Discrepancies between the results of solid and solution-phase assays have been reported when measuring autoantibodies in diabetes and several other autoimmune disease. Solution-phase RIA proved to be more reliable than ELISA for autoantibody detection.

Collectively, these data indicate that many autoantibodies demonstrating clinical significance share the characteristic of solution-phase antigen recognition, suggesting that immunologically relevant autoantibodies may be more consistently detectable by solution-phase RIA.

ROBUST BINDING TO AUTOANTIGENS

In the current study, serum and CSF samples from 20 patients with ADEM revealed robust binding to a wide range of autoantigens. Robust, in this case, refers to relative high titer and relative high affinity binding. “However, among patients with MS or encephalitis and normal controls, binding was less broad and much lower in terms of titer,” Dr. O'Connor noted.

To confirm this finding, two myelin antigens were selected for further evaluation using traditional solid and fluid phase assays.

Solid-phase binding to myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) – was observed at much lower levels in patients with MS and encephalitis; however, solution phase binding, a characteristic of higher affinity antibodies, was absent.

In contrast, autoantibodies found in serum and CSF of patients with ADEM demonstrated robust solution phase binding. Reports concerning autoantibody measurement ADEM are few and limited in terms of number of patients, control groups and antigens measured. In MS, findings are generally inconsistent.

“What is not clear is whether these antibodies to myelin antigens are merely an indicator of the severity of the disease or whether they are actually involved in the development of MS and ADEM in humans,” noted Mark Freedman, MD, Director of the Multiple Sclerosis Clinic and Professor of Medicine at the University of Ottawa in Ontario, Canada, who was not involved in the study.

Although ADEM is a rare disease in adults, it is more common in children.

“There is an increasing awareness of children with MS,” Dr. Freedman said. “When children first present, it is almost impossible to differentiate between ADEM and the first symptoms of MS.”

If there was a readily available test to distinguish between the two diseases in children, clinicians would be able to avoid treating children unnecessarily for MS, Dr. O'Connor added.

Although these findings are exciting, we need to perform a longitudinal study,” Dr. O'Connor cautioned. “This is because ADEM so often looks like a first episode of MS. Thus, we need to wait and see if another episode occurs before totally ruling MS.”

THE CLINICAL PICTURE: ADEM AND MS

According to Tanuja Chitnis MD, Head of the Pediatric MS Center at Massachusetts General Hospital, ADEM often presents in children, and occasionally in young adults as a monophasic inflammatory demyelinating illness resulting in neurological deficits.

In contrast, MS is characterized by repeated episodes of CNS demyelination. The problem lies in distinguishing an episode of ADEM from the first attack of multiple sclerosis.

ADEM is generally treated with intravenous steroids during the acute episode, while MS requires lifelong treatment. Although clinical characteristics and MRI features suggest differences between these two diseases, a biological test that can definitively differentiate the two entities would greatly facilitate early and more accurate diagnosis of MS. In addition, biological markers such as autoantibodies may provide a prognostic indicator after a first demyelinating event.

ARTICLE IN BRIEF

  • ✓ Investigators reported that by using protein arrays and solid and solution phase antibody binding assays, they identified a fundamental difference in the humoral response of multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM), two clinically similar demyelinating disorders.