LAUSR

Dear Editor, Neuromyelitis optica spectrum disease (NMOSD) is a disabling, inflammatory and demyelinating disorder of the central nervous system (CNS) and is characterized by severe attacks of optic neuritis and myelitis. Detection of antibodies against aquaporin-4 (AQP4) helped distinguish NMOSD from other demyelinating diseases of CNS in the last decade. Although AQP4-antibody seropositivity is included to the diagnostic criteria and the pathogenic role of AQP4-antibody is well-established in NMOSD, it is only detectable in 60–90% of NMOSD patients (Wingerchuk et al., 2007; Jarius and Wildemann, 2010). Recent studies have indicated that myelin oligodendrocyte glycoprotein (MOG) might also be a target antigen for NMOSD (Mader et al., 2011). Seronegative NMOSD patients show different demographic and clinical characteristics compared to seropositive patients. While female dominance and multiphasic clinical course are common in seropositive patients, equal male/female ratio, a higher proportion of Caucasian ethnicity, younger age at the time of presentation and simultaneous optic neuritis and transverse myelitis are characteristic for seronegative patients (Marignier et al., 2013). Besides the diagnostic challenges, clinical and imaging features of seronegative patients have raised the question whether seronegative NMOSD might represent a distinct pathophysiological entity (Marignier et al., 2013). A 21-year-old woman was admitted with a 10-day history of difficulty walking and painless vision loss in the left eye. Neurological examination revealed hypoesthesia on the left side of the face, paraparesis [4/5 with medical research council (MRC) scale], increased deep tendon reflexes, bilateral extensor plantar response and reduced vibration sense in both feet. The patient denied confusion, disorientation, memory loss or any other cognitive problems. MRI revealed longitudinally extensive transverse myelitis (LETM) extending from C3 to C6 and hyperintense lesions at diencephalon, dorsal midbrain, right parietal lobe and right cerebellar peduncle in T2-FLAIR weighted images (Fig. 1A–C). Cerebrospinal fluid (CSF) examination and IgG index were normal and oligoclonal bands were absent. Serum AQP4and MOG-antibodies were found negative with a commercial kit (Euroimmun, Luebeck, Germany). The diagnosis was established as seronegative NMOSD based on two core clinical characteristics (optic neuritis and myelitis) and supportive imaging findings (Wingerchuk et al., 2015). Although the patient was started on 1000 mg/day methylprednisolone treatment, she developed right optic neuritis at the third day and muscle weakness progressed (3/5 with MRC). In the repeat MRI studies, spinal cord and brainstem lesions were found to increase in size and new lesions in left cerebellar peduncle and posterior corpus callosum were identified (Fig. 1D–F). All detected lesions in first and second MRIs were contrast-enhancing. Following plasma exchange treatment, her neurological and neuroimaging findings completely resolved and she had no additional clinical episodes in the succeeding three years. Seronegative NMOSD patients might present with certain distinguishing clinical features. Simultaneous optic neuritis and transverse myelitis and monophasic disease course were found to be more frequent in the seronegative group. Also, time to diagnosis was shorter in seronegative NMOSD (Marignier et al., 2013; Jarius et al., 2012). In keeping with these reports, our case was admitted with simultaneous transverse myelitis, bilateral optic neuritis and additional brainstem, diencephalon and callosal lesions. Although these are frequently affected anatomical locations in NMOSD (Wingerchuk et al., 2015), to our knowledge, concurrent involvement of all these structures in the same attack has not been previously reported. Presence of newly emerging active contrast-enhancing lesions in a monophasic disease course, might require differential diagnosis with acute disseminated encephalomyelitis (ADEM), particularly in a seronegative case. However, involvement of most characteristic NMOSD locations, paucity of corticosubcortical lesions and absence of fever, encephalopathy or a preceding infectious disease all indicated NMOSD as the preferential diagnosis. Although optic neuritis, LETM and brainstem inflammation have been seldom reported in ADEM (Jain et al., 2016), the combined inflammation of all these rarely afflicted anatomical locations has not been documented. Also, as per recently published diagnostic criteria, a variable extent of acute onset encephalopathy is mandatory for definitive diagnosis of ADEM (Graus et al., 2016). Nevertheless, an overlapping ADEM and NMOSD syndrome or a predominantly subcortical ADEM syndrome (without cognitive dysfunction) may not be entirely excluded. A subgroup of NMOSD patients remain seronegative throughout their disease course and yet they benefit from immunosuppression. Moreover, sera of seronegative NMOSD patients induce more pronounced complement-dependent astrocyte death than that induced by sera of MS patients and healthy donors (Sabater et al., 2009), raising the possibility of unidentified pathogenic antibodies. Our seronegative case gave prompt response to antibody depleting plasma exchange treatment further supporting the novel antibody hypothesis. We had previously reported a seronegative case with optic neuritis, transverse myelitis, tumefactive lesions, conserved AQP4 expression in the