Relevance of Aquaporin 4 Antibodies in Longitudinally Extensive Transverse Myelitis
Abstract & Commentary
By Jai S. Perumal, MD
Assistant Professor of Neurology, Weill Cornell Medical College
Dr. Perumal is a consultant for Biogen Idec and Genzyme, and is on the speakers bureau for Teva and Biogen Idec.
Synopsis:Based on a review of data from 76 adult patients with longitudinally extensive transverse myelitis, the authors highlight the importance of considering a differential diagnosis in those patients with longitudinally extensive transverse myelitis who are aquaporin 4 negative, yet who meet the diagnostic criteria for neuromyelitis optica.
Source: Kitley et al. Longitudinally extensive transverse myelitis with and without aquaporin 4 antibodies. JAMA Neurol Online doi:10.1001/jamaneurol.2013.3890.
Neuromyelitis optica (nmo) is an inflammatory disease of the central nervous system with selective involvement of the optic nerves and spinal cord. Classic NMO, or Devic's disease, is characterized by concurrent episodes of optic neuritis (ON) and transverse myelitis (TM). The current criteria for a diagnosis of NMO requires the presence of ON and TM and two out of the three supportive criteria: 1) MRI evidence of a contiguous spinal cord lesion extending three or more vertebral segments, 2) initial brain MRI not diagnostic for multiple sclerosis (MS), and 3) NMO IgG seropositivity. The identification of aquaporin 4 antibody (NMO IgG ab) led to an expansion of the disease phenotype, and, currently, patients with isolated ON or TM and who are NMO-antibody positive are classified as having an NMO-spectrum disorder.
In the present study, Kitley et al report their findings from analysis of data of 76 patients with longitudinally extensive transverse myelitis (LETM) in the context of the presence or absence of aquaporin 4 antibody. They report the similarities and differences between the two groups. They also describe the differential diagnosis of aquaporin 4 negative LETM patients who meet the criteria for a diagnosis of NMO as described above.
Seventy-six adult patients with LETM were selected from a database of patients at an outpatient neuroinflammatory specialty center and from inpatient records. Longitudinally extensive spinal cord lesions were those extending three vertebral segments or more. All of these patients had been tested for aquaporin 4 antibody at least twice. Forty-four out of 76 patients (58%) tested positive and 32/76 (42%) tested negative. When demographic data were analyzed, the aquaporin 4 positive group was older at disease onset (45.30 years vs 37.74 years), had a higher proportion of women (86% vs 44%), and had a greater frequency of patients with coexisting other autoimmune diseases (27% vs 3%) when compared to the aquaporin negative group. The severity of the initial presentation and recovery from the episode were similar between the two groups. On analysis of the MRI images, there was no difference in the mean length of the lesion between the two groups, but the conus was involved significantly more in the aquaporin negative group. On follow up, aquaporin positive patients were more likely to have a subsequent episode of central nervous system inflammation when compared to aquaporin negative patients (74% vs 31%,
P = 0.001).
Among the 32 LETM patients who were aquaporin negative, alternate causes were explored. Six patients tested positive for MOG-Ab, and one each had the following diagnoses — CNS vasculitis; leptomeningeal syndrome associated with connective tissue disease; infections including tuberculosis, mycoplasma, Epstein-Barr virus, west Nile virus; paraneoplastic syndrome due to mesothelioma; and spinal cord infarction. Five patients had acute disseminated encephalomyelitis (ADEM), and three patients went on to have typical MS. In the remaining 10 aquaporin negative patients, despite extensive workup, no specific cause was found. Five of these patients had a history of at least one episode of optic neuritis, met the diagnostic criteria for classic NMO, and were considered seronegative NMO, and five patients were classified as idiopathic transverse myelitis.
The authors further performed an analysis of those LETM patients who met the diagnostic criteria for NMO. Thirty-five of 76 (46%) met the criteria for NMO. Out of these 35 patients, 20 were aquaporin positive and 15 were negative. The authors point out that among the aquaporin negative patients who met the NMO diagnostic criteria, four patients were MOG-ab positive, three patients had ADEM, and three patients had MS.
The discovery of the highly specific serum aquaporin 4 antibody has expanded our knowledge of the immunopathogenesis of this group of disorders and has led to the identification of the NMO-spectrum of disorders. One of the important findings is that the aquaporin positive group was at a higher risk for subsequent relapses, which has implications for treatment. In determining prognosis in a patient with LETM, the presence of aquaporin 4 antibody predicts a higher risk of recurrence compared to a patient who does not have the antibody and, therefore, initiation of immunosuppressive treatment may be warranted at the time of the initial event in these patients.
The authors report that patients who fit the description of classic NMO, or Devic’s disease, with the simultaneous occurrence of bilateral ON and TM, were likely to be aquaporin 4 negative. These patients tended to have a monophasic disease course. Enrolling these patients in clinical trials aimed at gauging the benefit of disease-modifying treatments in NMO-spectrum disorders could lead to inaccurate results.
Finally, the authors demonstrate that a significant proportion of aquaporin 4 negative LETM patients who met the criteria for classic NMO had an alternate diagnosis. This emphasizes the importance of excluding other etiologies before a diagnosis NMO is confirmed.