A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis

Summary

Background

Neuromyelitis optica is an inflammatory demyelinating disease with generally poor prognosis that selectively targets optic nerves and spinal cord. It is commonly misdiagnosed as multiple sclerosis. Neither disease has a distinguishing biomarker, but optimum treatments differ. The relation of neuromyelitis optica to optic-spinal-multiple sclerosis in Asia is uncertain. We assessed the capacity of a putative marker for neuromyelitis optica (NMO-IgG) to distinguish neuromyelitis optica and related disorders from multiple sclerosis.

Methods

Indirect immunofluorescence with a composite substrate of mouse tissues identified a distinctive NMO-IgG staining pattern, which we characterised further by dual immunostaining. We tested masked serum samples from 102 North American patients with neuromyelitis optica or with syndromes that suggest high risk of the disorder, and 12 Japanese patients with optic-spinal multiple sclerosis. Control patients had multiple sclerosis, other myelopathies, optic neuropathies, and miscellaneous disorders. We also established clinical diagnoses for 14 patients incidentally shown to have NMO-IgG among 85 000 tested for suspected paraneoplastic autoimmunity.

Findings

NMO-IgG outlines CNS microvessels, pia, subpia, and Virchow-Robin space. It partly colocalises with laminin. Sensitivity and specificity were 73% (95% CI 60–86) and 91% (79–100) for neuromyelitis optica and 58% (30–86) and 100% (66–100) for optic-spinal multiple sclerosis. NMO-IgG was detected in half of patients with high-risk syndromes. Of 14 seropositive cases identified incidentally, 12 had neuromyelitis optica or a high-risk syndrome for the disease.

Interpretation

NMO-IgG is a specific marker autoantibody of neuromyelitis optica and binds at or near the blood-brain barrier. It distinguishes neuromyelitis optica from multiple sclerosis. Asian optic-spinal multiple sclerosis seems to be the same as neuromyelitis optica.

Introduction

Neuromyelitis optica (Devic's syndrome) is a severe idiopathic inflammatory demyelinating disease that selectively affects optic nerves and spinal cord, typically spares the brain, and generally follows a relapsing course.1, 2, 3, 4 Within 5 years, 50% of patients lose functional vision in at least one eye or are unable to walk independently. In North America, the proportion of non-white individuals is higher among patients with neuromyelitis optica than among those with classic multiple sclerosis.3, 4 In Asia, an optic-spinal form of multiple sclerosis is a common inflammatory demyelinating disease. It accounts for 15–40% of multiple sclerosis cases in Japan.5, 6 Is the Asian optic-spinal form of multiple sclerosis the same entity as neuromyelitis optica seen in western populations?

When fully developed, neuromyelitis optica can be distinguished from multiple sclerosis by a combination of clinical, neuroimaging, and spinal-fluid findings.³ Characteristics typical of neuromyelitis optica include episodic myelitis—commonly severe and frequently accompanied by paroxysmal tonic spasms—with longitudinally extensive spinal-cord lesions spanning three or more vertebral segments, absence of clinical evidence of brain involvement, and usually lack of multiple-sclerosis-type lesions on MRI of the brain.⁷ During acute attacks, the spinal fluid contains inflammatory cells but there is no evidence of intrathecal IgG synthesis (panel). However, many patients showing initial symptoms of neuromyelitis optica are diagnosed with multiple sclerosis. Neither disorder has a specific diagnostic marker, but the prognosis and optimum treatments for the two diseases differ. Immunosuppressive drugs (eg, azathioprine and corticosteroids) are regarded as the best treatment for neuromyelitis optica,⁸ whereas immunomodulatory treatments (eg, interferon beta and glatiramer acetate) are presently recommended for early treatment of multiple sclerosis.⁹ When severe exacerbations of myelitis do not respond to corticosteroid therapy, plasmapheresis is more beneficial for patients with neuromyelitis optica than for those with multiple sclerosis¹⁰.

Early diagnosis and treatment are very important to reduce the morbidity of neuromyelitis optica. Early use of appropriate immunosuppressive therapy would be justified if this disorder could be reliably distinguished from multiple sclerosis at the initial onset of optic neuritis or transverse myelitis, before progression and fulfilment of all clinical diagnostic criteria. We describe a newly identified IgG autoantibody (NMO-IgG) that localises to the blood-brain barrier and seems to be a specific serological marker for neuromyelitis optica. We have assessed the diagnostic accuracy of this autoantibody for neuromyelitis optica and other high-risk syndromes that could lead to a diagnosis of the disorder (eg, longitudinally extensive transverse myelitis or recurrent optic neuritis).