Neuromyelitis optica (NMO) is an inflammatory central nervous system (CNS) disease associated with autoantibodies that target aquaporin-4, an astrocyte water channel. These researchers report on three patients who developed initial NMO symptoms following transient, self-limited episodes of fatigue and creatine kinase (CK) elevation (range, 12,520–59,660 IU/L) of unknown cause. The cases were identified through retrospective review of 733 serum samples from a diagnostic laboratory that provides testing for aquaporin-4 antibodies. In one pediatric case, CK elevation recurred without an associated NMO relapse (NMO relapses occurred independently). The authors could find no cause for the CK elevations; muscle biopsies were not performed.

Because aquaporin-4 is also the main water channel expressed in fast-twitch skeletal muscle fibers, the authors developed three hypotheses regarding NMO pathogenesis. In the first, exposure of muscle aquaporin-4 resulting from muscle destruction of any cause induces development of autoantibodies and T cells reactive against aquaporin-4. In the second, preexisting autoantibodies target aquaporin-4 in both muscle and the CNS. In the third, muscle injury activates preexisting autoantibodies and T cells reactive to aquaporin-4, resulting in blood–brain barrier disruption and facilitating an immune attack on CNS tissue.

Comment: Accumulating evidence, including from novel animal models of NMO, supports the pathogenic potential of aquaporin-4 autoantibodies in NMO. Spinal cord and optic nerve, and, to a lesser degree, the brain, are targets of inflammatory attacks. However, aquaporin-4 is also present on certain cells of the muscle, gut, kidney, and retinal systems, raising questions about why no dysfunction of these organs is clinically evident in NMO. The current report provides a systematic, albeit retrospective and nonspecific, assessment of muscle injury in NMO and suggests that such involvement may be underrecognized. Just as in the CNS, where some lesions are destructive and others are rapidly reversible, various physical and immunological factors may make systemic aquaporin-4 a less clinically important antigenic target. However, more-systematic pathological study of all tissues that express aquaporin-4 will enhance our understanding of NMO pathobiology.

— Dean M. Wingerchuk, MD, MSc, FRCP(C)

Dr. Wingerchuk is Professor of Neurology, Mayo Clinic College of Medicine, Mayo Clinic Arizona, Scottsdale.

Published in Journal Watch Neurology August 10, 2010