key: cord-0727978-h168kqjn authors: Ghosh, Ritwik; De, Kaustav; Roy, Devlina; Mandal, Arpan; Biswas, Subrata; Biswas, Subhrajyoti; Sengupta, Swagatam; Naga, Dinabandhu; Ghosh, Mrinalkanti; Benito-León, Julián title: A case of area postrema variant of neuromyelitis optica spectrum disorder following SARS-CoV-2 infection date: 2020-11-11 journal: J Neuroimmunol DOI: 10.1016/j.jneuroim.2020.577439 sha: 2b44acad296858d699dc756d1a55c6670ca498d4 doc_id: 727978 cord_uid: h168kqjn Neuromyelitis optica spectrum disorder (NMOSD) is a disabling autoimmune astrocytopathic channelopathy, characterized by the presence of pathogenic antibodies to aquaporin-4 (AQP-4) water channels. Several viral infections including HIV, influenza virus, varicella zoster virus, and Epstein Barr virus, among others, have been alleged to trigger NMOSD in both immunocompetent and immunocompromised individuals. Neurological manifestations of coronavirus infectious disease of 2019 (COVID-19) have been ever evolving and the spectrum of neuraxial involvement is broadening. Albeit it may affect any area of the neural axis, the involvement of the spinal cord is rare compared to that of the brain and of the peripheral nervous system. Cases with acute longitudinally extensive transverse myelitis (LETM) have been recently reported in SARS-CoV-2 infection but did not fulfill the international consensus diagnostic criteria for NMOSD. AQP-4-antibody-seropositive NMOSD following SARS-CoV-2 infection had not yet been reported. We herein report a novel case of a previously healthy man who presented with a clinical picture of bouts of vomiting and hiccoughs (area postrema syndrome), which rapidly evolved to acute LETM, all following SARS-CoV-2 infection. He was finally diagnosed to be a case of seropositive NMOSD which presented as area postrema syndrome. The response to immunomodulatory drugs was excellent. Neurological manifestations of coronavirus infectious disease of 2019 have been ever evolving and the spectrum of neuraxial involvement is broadening. (Roy et al. , 2020) Albeit it may affect any area of the neural axis, the involvement of the spinal cord is rare compared to thatof the brain and of the peripheral nervous system. (Ghosh et al. , 2020a , Ghosh et al. , 2020d , Rábano-Suárez et al. , 2020 , Roy, Ghosh, 2020 SARS-CoV-2 has immense propensity to dysregulate the host immune system resulting in generation of various autoantibodies, which are turning out to be extremely pathogenic. , Zhang et al. , 2020 Neuromyelitis optica spectrum disorder (NMOSD) is a disabling autoimmune astrocytopathic channelopathy, characterized by the presence of pathogenic antibodies to aquaporin-4 (AQP-4) water channels, expressed on astrocytic foot processes at blood brain barrier, subpial and subependymal regions. Long segments of spinal cord inflammation (myelitis), severe optic neuritis, and/or bouts of intractable vomiting and hiccoughs (area postrema syndrome) are the classic forms of presentation. ) From a pathological point of view, NMOSD mainly encompasses AQP-4-antibody-positive astrocytopathy and myelin oligodendrocyte glycoprotein (MOG)-antibody-positive inflammatory demyelinating disease. J o u r n a l P r e -p r o o f It has recently reported a case of a young man presenting with bilateral severe optic neuritis and myelitis, determined to be simultaneously SARS-CoV-2 and MOG IgG antibody positive, i.e. a variant of NMOSD. However, AQP-4-antibody-seropositive NMOSD following SARS-CoV-2 infection had not yet been reported. We herein report a novel case of a previously healthy man who presented with a clinical picture of bouts of vomiting and hiccoughs (area postrema syndrome), which rapidly evolved to acute LETM, all following SARS-CoV-2 infection. He was finally diagnosed to be a case of seropositive NMOSD which presented as area postrema syndrome. The response to immunomodulatory drugs was excellent. A previously healthy Asian-Indian 20-year-old man was admitted to the emergency department with rapidly progressive weakness and decreased sensation of all four limbs, urinary retention, and constipation. His past medical history was unremarkable. Ten days prior to his admission, he had developed a mild fever and non-productive cough for 3 days, which resolved spontaneously. Five days after this mild clinical picture, he developed rapidly progressive weakness of his lower limbs, followed by weakness of both upper limbs within 12 hours. Further, he complained of persistent hiccough, nausea and vomiting that started a few days before the progressive weakness of his limbs appeared. On the day of admission, on getting up from sleep, he found himself unable to get up from lying down position on his own. He also noticed reduced sensation in all 4 limbs and over his torso to all modalities for the same duration. He also complained of dull aching, deep seated, non-radiating pain over his nape of neck, that appeared the day before he developed weakness. Weakness was also associated with difficulty in voiding, pain and fullness in his lower abdomen, and constipation. There was no history suggestive of any similar previous episode, cranial nerve involvement, headache, eye pain, visual symptoms, diplopia, swallowing difficulty, seizures, loss of consciousness, vaccination, trauma, skin rash, joint pain, photosensitivity, orogenital ulcers, dry eyes, dry mouth, band/girdle-like sensation, root pain, thinning or twitching of muscles, flexor spasms, and respiratory distress. Family history was non-contributory. On physical examination, he was fully awake, conscious, afebrile, and normotensive (recorded supine blood pressure was 120/70 mm of Hg). His respiratory rate was 16/min and oxygen saturation of 96% in room air. Neurological examination revealed intact cognitive and cranial nerve functions. Motor system examination revealed asymmetric flaccid hypo-to-areflexic quadriparesis (muscle power estimation by MRC scale showed 1/5 in all 4 limbs). Sensory system examination revealed patchy areas of decreased sensation to all modalities over torso and extremities with reduced vibration sense and proprioception. Cerebellar functions could not be tested. The patient's nasopharyngeal and oropharyngeal swabs tests for SARS-CoV-2 by qualitative real-time reverse-transcriptase-polymerase-chain-reaction (RT-PCR) assay (Xpert® Xpress SARS-CoV-2 test) were positive. Blood analysis was remarkable for lymphocytopenia (800 cells/µl). Pro-inflammatory markers (ferritin, Creactive protein, and erythrocyte sedimentation rate) were mildly raised; however, D- were negative. Anti-MOG -antibodies were also negative. However, transfected HEK293 cell-based assay from paired sera for anti-AQP-4-antibodies was found to be positive. He was then diagnosed to be a case of seropositive NMOSD presenting with area postrema syndrome. MRI of the orbits and visual evoked potentials were otherwise normal. Albeit the diagnosis of long segment myelitis was obvious, the patient was also tested for nerve conduction studies, which unequivocally ruled out the possibility of co-existing SARS-CoV-2 related immune-mediated Guillain-Barré syndrome. As COVID-19-related illness was almost asymptomatic, he did not receive any specific therapy. However, even before the result of anti-AQP-4 antibodies was received, he was put on intravenous high dose methylprednisolone (1 g/day for 5 consecutive days) for treating the inflammatory myelitis. There was some improvement of the motor power in all limbs and resolution of the sensory symptoms on day 12 of admission. The patient's nasopharyngeal and oropharyngeal swabs J o u r n a l P r e -p r o o f Journal Pre-proof tests for SARS-CoV-2 by RT-PCR on day 14 were negative. Then, we put him on rituximab (1 g intravenous infusion, repeated after two weeks as a single course, and in every 6 months intervals till 2 years). After two doses of rituximab, he regained full motor power and catheter could be removed successfully on day 30 of admission. After 4 months follow-up, the patient was maintaining well on rituximab without any further attack. MRI revealed marked resolution of previous lesions and absence of new lesions. Over the last 20 years, pathogenesis, clinical-radiological spectrum, diagnostic criteria, and therapeutics of NMOSD have been changing and evolving. Recent evidences suggest that NMOSD is an autoimmune astrocytopathic channelopathy, mediated by anti-AQP-4-autoantibodies, , having predilection to selected areas of nervous system (i.e. neocortex, hippocampus, cerebellum, optic nerve, glial lamellae of the supraoptic nucleus, subfornical organ, ependymal and meningeal cells, and Muller cells of the retina). J o u r n a l P r e -p r o o f Pathogenetic mechanisms for the development of NMOSD following SARS-CoV-2 Infection may be either mediated by direct neurotropism or by aberrant immune mediated injury, the latter being the most likely. An aberrant immune response arguably manifest either in the form of molecular/immunological mimicry, bystander activation of immune responses following COVID-19 or aggravation and/or triggering/precipitation of pre-existing disease after systemic infection. Human molecular chaperones share with SARS-CoV-2 antigenic epitopes potentially capable of eliciting autoimmunity against nervous system. Neuroinvasion by SARS-CoV-2 may cause leakage of central nervous system antigens (i.e. AQP-4 peptides) to systemic circulation leading to bystander activation of immune responses. Again, systemic infection by SARS-CoV-2 could elicit an inflammatory response damaging the several AQP-4 expressing epithelial cells and thus triggering a bystander immune cascade. Azizi, 2020, Yachou, El Idrissi, 2020) In our patient there was no evidence for prior negativity to anti-AQP-4antibodies; indeed, the patient could have been positive for the antibodies before SARS-CoV-2 infection. Certain immunologic events (possibly infections, such as COVID-19, and other immune activations) might be needed to allow anti-AQP-4 antibodies to cross the blood-brain barrier to bind to AQP4 on astrocytes. (Nishiyama et al. , 2009) In this sense, emerging evidences suggest that, in genetically susceptible individuals, SARS-CoV-2 infection could trigger autoimmune responses. Besides, SARS-CoV-2 infection induces a cytokine storm, which results in an abundance of pro-inflammatory cytokines and, in turn, may damage the astrocytes directly or via immune mechanisms. J o u r n a l P r e -p r o o f Several case reports have already described acute transverse myelitis associated with SARS-CoV-2 infection, most of them being LETM.(AlKetbi et al. , , Maideniuc and Memon, 2020 , Zachariadis et al. , 2020 However, only one case was found to be seropositive NMOSD, precisely MOG IgG antibody positivity, in a young Hispanic man with bilateral optic neuritis and LETM. Our case is novel in this aspect. From the erstwhile discussion, a plausible nexus between NMOSD and SARS-CoV-2 could be considered. This taken together with obvious temporality in the course of the disease, anti-AQP-4 seropositivity and response to immunomodulators drugs, provide ample evidence emphasizing a causal link between COVID-19 and anti-AQP-4-antibody mediated astrocytopathy. To our knowledge, this is the first case of NMOSD preceded by area postrema syndrome where there was a clear temporal sequence between SARS-CoV-2 infection and disease onset. The current case stands out as a genuinely rare manifestation of COVID-19. It adds to the tally of cases reporting acute transverse myelitis in COVID-19 and, more importantly, brings to attention the potential involvement of area postrema in the cases of NMOSD associated with this novel infection. 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