Neuromyelitis optica

Mayo Clinic blood test supports clinical diagnosis

One patient has uncontrolled vomiting. Another patient has eye pain and blurry vision that quickly progresses to blindness. Another has weakness and spasms of the legs. All three patients test positive for the neuromyelitis optica (NMO) antibody.

NMO is a demyelinating disease that affects the optic nerves and the spinal cord. It can lead to blindness, paraplegia, bladder and bowel dysfunction, respiratory failure, and death. For nearly 100 years, NMO, also known as Devic's disease, was considered a variant of multiple sclerosis (MS). There was no effective diagnostic test or treatment.

The story of how NMO came to be differentiated from MS is a tale of turning accepted dogma on its head:

  • The diagnostic criteria for NMO were redefined.
  • The first biomarker for an inflammatory demyelinating central nervous system (CNS) disease was identified.
  • A blood test was developed.
  • An intervention strategy was established.

It is a story that is still being written, with implications for treating autoimmune-mediated CNS conditions using targeted therapies. It is a story made possible only in the context of the free flow of information between clinical practice and basic science.

Devic's disease: correct and incorrect assumptions

The correct association between the spinal cord and optic nerve symptoms in what would be named Devic's disease was first made by Sir Thomas Albutt in 1870.

In 1894, Eugène Devic and Fernand Gault described 16 cases, from which the diagnostic criteria were taken.

For the next 105 years, recognition of Devic's disease was frozen by a rigid and arbitrary set of diagnostic criteria. Most cases that were relapsing with "lesions disseminated in time and space" also satisfied the criteria for MS and were accordingly labeled MS. This dogma persisted throughout the 20th century, despite debate over observations that:

  • Acute episodes were more immediately devastating than in MS.
  • The lesions were fewer and rarely found on MRI of the brain.
  • Therapy for MS was unsuccessful in Devic's disease.

Identifying the biomarker that redefined NMO

From his extensive clinical experience, Brian G. Weinshenker, M.D., a neurologist at Mayo Clinic, had long suspected that Devic's disease was a separate entity. In 1999, he and a neurology colleagues, Dean M. Wingerchuk, M.D., presented retrospective data on 60 cases at Mayo Clinic whose profile appeared to distinguish NMO from MS.

In the audience, Vanda A. Lennon, M.D., Ph.D., a Mayo Clinic research immunologist, was struck by the fact that NMO patients often had accompanying autoimmune disorders that are not part of the MS profile. She asked Dr. Weinshenker to send some serum samples from his patients to her laboratory.

What Dr. Lennon discovered was a previously undescribed antibody that attached to a component of the mouse blood-brain barrier in a similar pattern as samples that she had archived from patients who had been tested to rule out a paraneoplastic disease.

Checking back with referring physicians, Dr. Lennon and Dr. Weinshenker discovered that all 12 of the cases whose histories they could acquire had optic neuritis and myelitis. They realized that they had found the antibody for Devic's disease. They labeled it NMO-immunoglobulin G (NMO-IgG).

At the same time, Claudia F. Lucchinetti, M.D., a Mayo Clinic neurologist and MS investigator specializing in mechanisms of tissue damage in demyelinating diseases of the CNS, recognized a unique pattern of demyelination in NMO and proposed that NMO was an autoimmune disease that targeted the perivascular space. She published her findings in 2002.

In 2004, the combined Mayo Clinic team published results of a prospective study confirming that NMO-IgG was specific for NMO.

By 2006, Dr. Lennon had identified the antibody target, a water channel protein called aquaporin-4, which is abundant in astrocytes in the CNS. It is most strongly expressed in the medulla, spinal cord, and optic nerves — areas most affected by NMO. Dr. Lennon's laboratory then developed a blood test for NMO-IgG that is 99% specific and 70% sensitive for NMO. The antibody is absent in patients with MS, including those with optic neuritis and myelitis.

Aquaporin-4 is the main channel through which water enters and leaves the CNS. It is neither a component of myelin nor expressed by oligodendroglial cells that produce myelin. Its discovery has opened up new ways of thinking about immunopathophysiological mechanisms of other demyelinating diseases, including MS.

Diagnosis

Misdiagnosis is a common problem in NMO. The presenting symptom in 10% of cases is vomiting or prolonged hiccups (reflecting medullary involvement), for which neurologic disease is rarely suspected. The optic neuritis and myelitis of NMO are often confused with those of MS. The defining features of NMO are transverse myelitis and optic neuritis with at least two of the following characteristics:

  • MRI results nondiagnostic for MS
  • A spinal cord lesion extending over three or more vertebral segments (short segment lesions are typical of MS)
  • A serologic test result positive for NMO-IgG

Early diagnosis of NMO is critical. In MS, individual inflammatory episodes are usually mild. Their cumulative effect over time causes progressive disability. In NMO, the opposite is true; acute episodes are usually severe and, if untreated, can have devastating, irreversible effects on function. Episodes may occur from days to years apart. Seventy percent of NMO patients have relapses after their initial symptoms.

NMO can affect children as young as 3 years and adults as old as 90 years. MS predominates in whites, but NMO affects all ethnic groups and is as common among nonwhite persons as it is among whites. NMO is far more prevalent in women than men. Its onset is typically 10 years later than MS (average age of onset, 39 years).

Blood test

Because NMO-specific lesions may not be evident on MRI, a blood test result that is positive for NMO-IgG enhances diagnostic accuracy. Mayo Clinic, where the test was developed, is currently the only laboratory in the United States that offers it.

Mayo Clinic, however, has licensed the technology to facilitate the development of test kits for use in laboratories worldwide. Of the 1,000 tests conducted per month at Mayo, approximately 70 results are positive. For the 30% of patients who have NMO symptoms but yield a negative test result, periodic retesting is recommended. Complementary second-generation tests are reducing the percentage of NMO patients with results negative for NMO-IgG.

Treatment

At Mayo Clinic, patients who test positive for NMO-IgG after an acute episode are treated immediately with drugs to prevent future relapses. To facilitate recovery from an acute attack, the first line of treatment is usually a short course of intravenous corticosteroids. Plasmapheresis can be used to remove the antibody from the blood when corticosteroid therapy is not successful.

The effects can be dramatic. Immunosuppressants, which are not generally used as first-line drugs in MS, appear to reduce the frequency of future episodes of NMO.

Future directions

Since Mayo Clinic's pioneering work on NMO in 2004, researchers at other institutions have confirmed Mayo Clinic's findings. In addition to Drs. Lennon, Lucchinetti, Weinshenker, and Wingerchuk, the Mayo Clinic NMO team includes:

Together, the Mayo investigators are conducting a multipronged NMO research program that includes:

  • Epidemiology
  • Genetics
  • Investigations of mechanisms of tissue injury
  • Development of animal models to investigate the basis of NMO-IgG effects on myelin and gray matter injury and to explore new therapeutic approaches
  • Development and validation of new diagnostic and prognostic tests
  • Therapeutic trials in NMO

The synergy between clinical practice and its laboratory science at Mayo Clinic has redefined NMO and its spectrum of disorders and continues to inform the development of targeted treatment options.