A case of NMO seropositive for aquaporin-4 antibody more than 10 years before onset

Abstract

Neuromyelitis optica (NMO) is characterized by severe optic neuritis and longitudinally extended transverse myelitis (LETM). The clinical and laboratory features of NMO are different from multiple sclerosis (MS). 1 An autoantibody to aquaporin-4 (AQP4) has been detected exclusively in the NMO sera. 1 Moreover, we demonstrated an extensive loss of AQP4 and glial fibrillary acidic protein immunoreactivities in the perivascular regions with complement and immunoglobulin deposition in NMO that suggests astrocytic impairment. However, when AQP4 antibody is produced in patients with NMO is unknown, and thus it remains unresolved whether there are long-term asymptomatic AQP4 antibody-positive carriers, whether AQP4 antibody alone can be pathogenic, and whether AQP4 antibody is produced secondarily as a result of tissue destruction in attacks of NMO. We herein report a case of NMO in which AQP4 antibody was detected years before the NMO onset.Case report. A 34-year-old healthy woman without previous history of inflammatory or neurologic diseases noticed temporary skin eruptions on her chest and shoulders in June 2007. A dermatologist made the diagnosis of eczema. Three weeks later, when the skin eruptions subsided, she noted progressive paresthesia in the chest and toes. Within a few days, she could not walk well due to right leg weakness, and then she was hospitalized. Neurologic examination on admission revealed flaccid paraparesis with hyperreflexia in both legs, sensory impairment below the T4 level, painful tonic spasm, and dysuria. Ophthalmologic examination was normal. MRI of the spinal cord depicted LETM typically seen in NMO with diffuse cord swelling and a T2-hyperintense lesion extending from C6 to T9, mainly involving the central gray matter on the axial view (figure). Brain MRI was normal. All blood tests including biochemistry and blood cell counts were normal. Antibodies against herpesviruses (herpes simplex virus, varicella zoster virus, Epstein-Barr virus, and cytomegalovirus), enteroviruses, and JC virus were not elevated or indicative of recent infection. PCR for herpes sim-plex and varicella zoster viruses in the CSF were negative. Antinuclear antibody, SS-A, and SS-B were negative. CSF examination showed pleocytosis (76 cells/L), elevated protein concentration (66 mg/ dL), normal glucose level, and no oligoclonal immunoglobulin G bands. AQP4 antibody assayed by the previously reported method (normal test: negative) was positive (128ϫ). 2 The patient was treated initially with three courses of high-dose IV methylprednisolone therapy (1 g for 3 days/course), followed by four plasma exchanges. Then, the AQP4 antibody titer declined (8ϫ), and a follow-up MRI disclosed shrinkage of the spinal cord lesions. Her paraparesis, sensory impairment, and dysuria were relieved, but painful tonic spasm remained.Later we found that the Figure MRI findings of longitudinally extended myelitis in the present case T2-weighted images taken 10 days after onset are shown. Diffuse cord swelling and longitudinally extensive ...

Pregnancy outcomes in aquaporin-4–positive neuromyelitis optica spectrum disorder

“…This finding may be explained by subclinical levels of circulating AQP4-IgG, which may be present years before clinical presentation. 24,25 The miscarriage rate of 42.9% is outside the 95% CI that would be expected if the true miscarriage rate post-NMOSD was equal to reported rates in multiple sclerosis (expected 95% CI 1.29%-40.9%) 26,27 and just within the expected range calculated from published rates in systemic lupus erythematosus (expected 95% CI 2.56%-45.5%). 28 This suggests that the miscarriage rate in patients with NMOSD is higher than in patients with multiple sclerosis, although larger prospective studies with adequate control groups are needed to test this hypothesis.…”

Relevance of Autoantibodies for the Classification and Pathogenesis of Neurological Diseases

“…A depletion of antibodies below a detectable threshold could explain a negative serostatus. Although, anti-AQP4 antibodies have been detected up to ten years before disease onset (Nishiyama et al, 2009), we have analyzed a small number of patients who were initially negative for NMO IgG and turned out to be low titer positive in longitudinal samples (unpublished results). For this reasons, one has to be careful when dealing with the term "seronegative NMO".…”

“…Latest findings by Pohl et al showed that AQP4 specific T cells are capable of inducing brain inflammation mainly in astrocytic glia limitans and therefore enable an entry of anti-AQP4 autoantibodies (Pohl et al, 2011). As anti-AQP4 antibodies are detectable more than ten years before disease onset (Nishiyama et al, 2009), the time point when these antibodies lead to NMO symptoms remains unresolved. It is tempting to speculate that anti-AQP4 antibodies are not harmful if they circulate peripherally and as long as they are excluded from the blood brain barrier.…”

Pathogenesis, diagnosis and treatment of neuromyelitis optica: Changing concept of an old disease

“…It can especially help early the introduction of therapy in NMO spectrum diseases (Figs 1 and 2), and might have a prognostic value in NMO; seropositivity has been suggested to be associated with more frequent relapses, greater attack-related disability, higher probability of brain lesions and more extensive lesions on spinal cord MRI. 6,31,58,60,100,[106][107][108][109] However, the lack of such associations has also been reported. 4,26,61,110 Anti-AQP4 antibody-positive Japanese patients with optico-spinal MS (OSMS) might be immunologically different from antibody-negative OSMS patients.…”

“…[28][29][30] However, myelin-specific T cell-mediated inflammation was necessary for pathogenecity. Lesions predominated in brain areas targeted by such autoreactive T cells and expressed high levels of AQP4; [28][29][30] (vii) anti-AQP4 antibodies can be present in the sera years before the first clinical event; 31 and (viii) removing circulating antibodies by plasma exchange in patients with NMO is beneficial. 32 Considering all these data, the generation of anti-AQP4 antibodies and their presence in the systemic circulation might initiate the disease (i) on disruption of the blood-brain barrier and (ii) under inflammatory conditions of the CNS.…”