key: cord-0969385-r3zor64d authors: Tutar, Nurhan Kaya; Omerhoca, Sami; Coban, Eda; Kale, Nilufer title: Sars-Cov-2 infection related inflammatory and demyelinating disease; a brief case series date: 2021-03-13 journal: Mult Scler Relat Disord DOI: 10.1016/j.msard.2021.102900 sha: c3553e12a44e6ba96324d8545e70a94831a352ec doc_id: 969385 cord_uid: r3zor64d Background: Since March 2020, during the Coronavirus disease 2019 (COVID-19) pandemic, it has been observed that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has neurological involvement with various clinical tables. Methods: We present 3 new cases admitted to our clinic with various neurological findings which were affected by SARS-CoV-2. Results: Imaging studies have shown that inflammatory/demyelinizing lesions appeared in different areas of the central nervous system which were accepted as an atypical demyelinating spectrum associated with Covid 19. Conclusions: With increasing experience, it has been suggested that SARS-CoV-2 may also have a neurotrophic effect. The spectrum of neurological involvement is also expanding as the pandemic continues. These 3 cases suggest that the virus plays a role in the clinical onset of the inflammatory/demyelinating disease. Coronavirus disease 2019 (COVID-19) is typically manifested by fever and respiratory symptoms caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Although SARS-CoV-2 is a respiratory infection agent, it has been shown to be able to involve other systems, including the nervous system. To date, various neurological syndromes have been reported, such as encephalitis, cerebrovascular diseases and peripheral neuropathy cases, which may be associated with SARS-CoV-2 [1]. In terms of demyelinating diseases, there have been limited number of case reports with acute disseminated encephalomyelitis (ADEM), myelitis and also atypical demyelinating event thought to be related to this virus [2, 5] . Most recently, a case diagnosed with multiple sclerosis (MS) after an optic neuritis (ON) attack associated with COVID-19 infection has been published. [6] . Here we describe 3 new cases that have developed inflammatory / demyelinating lesions which were suspected to be associated with SARS-CoV-2. A 28-year-old male patient was admitted to the emergency service with left hemiparesis and hemihypoesthesia, which he noticed when he woke up in the morning. There was no feature in his medical history and did not describe oral or genital ulcer. Neurological examination revealed 4/5 hemiparesis and globally limb hyperreflexia. His blood test had normal hemogram, biochemistry, sedimentation, C-reactive protein (CRP), procalcitonin, fibrinogen, D-dimer but ferritin level was mildly elevated (356 ng/mL, > 336). Chest CT scan shows multiple ground-glass opacity areas and nasopharyngeal swab a realtime polymerase chain reaction (RT-PCR) test resulted positively for SARS-CoV-2, compatible with COVID-19. Brain magnetic resonance imaging (MRI) showed hyperintense nodular lesions on T2-weighted fluid-attenuated inversion recovery (FLAIR) in both centrum semiovale adjacent to the lateral ventricles with diffusion restriction and contrast enhancement, which were considered as an inflammatory procces ( Figure 1A -F). There were no lesion in cortical/juxtracortical, posterior fossa and medulla spinalis. Visual evoked potential (VEP) and fundus evaluation, autoimmune panel, Cranial MR-angiography, transthoracic echo were all normal for the differential diagnosis of ischemic/vasculitic and demyelinating disease. Lumbar puncture was performed; cerebrospinal fluid (CSF) opening pressure was 24 cm water, and CSF analysis showed slightly increased protein levels (36,8 mg/dL, >35) and no cell. Oligoclonal bands (OCB) resulted in type 1, with normal IgG-index. Although the patient had no respiratory symptoms and all vital parameters (blood pressure, pulse, respiratory rate, fever) were normal, hydroxychloroquine 400 mg / day was started for 5 days. After management of the infection, intravenous methylprednisolone (IVMP) treatment was given to the patient for 5 days and neurological deficits were fully recovered. An 18-year-old woman presented to the neurology outpatient clinic with a 10 days history of headache and a antibodies was not available in our laboratory. Serological tests for tuberculosis, borreliosis, lyme, syphilis, and HIV remained negative. SARS-CoV-2 PCR analysis of nasopharyngeal exudate and immunological testing was IgG was negative whereas positive for IgM, suspicious for a possible active infection. Her chest CT was normal and she was referred to infectous diseases clinics. Treatment was not recommended as she was asymptomatic and had no systemic involvement. Because her vision was nearly counting fingers on her right eye, she was started on IVMP and despite completion to 10 days, recovery was only achieved by 70%. A 48-year-old man admitted to the emergency department with complaints of arthralgia, weakness and cough and he was hospitalized. Chest CT scan was compatible with viral pneumonia and nasopharyngeal swab RT-PCR testing for SARS-CoV-2 returned positive ( Figure 3A ). The patient was given hydroxychloroquine 400 mg/day+favipiravir 1200mg/day treatment with the diagnosis of Covid-19. On the 10th day of his hospitalization he was consulted to our neurology department with right hemiparesia that developed 1 day ago. Neurological examination revealed frust hemiparesis, globally limb hyperreflexia and Babinski's sign positive on the right side. Brain MRI showed T2-FLAIR hyperintense lesions in corpus callosum and right cerebellum adjacent to the fourth ventricle, both with contrast fixation and diffusion restricton ( Figure 3B-G) . The MRI of the whole spinal cord was normal. CSF analysis showed a mild pleocytosis (24-lymphocyte) without atypical cell, normal glucose, and increased protein levels (100 mg/dL, >35). OCB was type 1 but elevated IgG index (0,76, >0,66) was detected. Anti-IgG-NMO-AQP4 were not identified in serum samples. There is increasing evidence for neurological manifestations that might be associated with COVID-19 [1]. The spectrum of neurological involvement is also expanding as the pandemic continues. Up to date, some of the human coronaviruses (HCoV) strains have been shown to have neurotropic effect as they can spread from the respiratory tract to the central nervous system (CNS) [7] . When it comes to the novel coronavirus, there is little evidence to date to suggest that SARS-CoV2 might invade neural cells [8] . In this case series, we suggest that the virus might play a role in the clinical onset of the inflammatory demyelinating diseases. The responsible mechanism leading to this involvement may not be directly related to the the virus itself, but rather may play a triggering role in autoimmune processes in susceptible individuals as previouly suggested for other viral agents such as Ebstein Barr Virus (EBV) [9] . The World Health Organization (WHO) has established provisional case definitions for meningitis, encephalitis, myelitis or CNS vasculitis associated with SARS-CoV-2 [10]. Accordingly, it is accepted as a confirmed case only under one of the following conditions: 1) SARS-CoV-2 is detected in CSF or brain tissue 2) if there are intrathecal antibodies specific to SARS-CoV-2. If there is evidence of SARS-CoV-2 in respiratory or other non-CNS sample, or SARS-CoV-2 specific antibodies detected in serum indicating acute infection; it is considered as possible case. All 3 patients we share here are considered to be possible cases of COVID-19 related neurological disease. In patients 1 and 3, the SARS-CoV-2 PCR positivity was accompanied by radiological evidence of infection, but in patient 2, only Ig M seropositivity was detected although she was asymptomatic in terms of infection. Relating to only one positive seromarker compatible with coronavirus infection the question of a possible false positivity of the test rises. However, the patient might also be asymptomatic relating to COVID-19 disease. Suhandynata et al showed that viral specific IgM and IgG had a very low false positive rate in a longitudinal study of 54 PCR-confirmed COVID-19 patients [11] . In their study, the positive predictive values (PPV) was demonstrated for IgM, IgG, and IgG/IgM panel; 94.4%, 89.4%, and 85.6%, respectively. In such cases, as in our case 2, even if there is a possibility of false positivity, it will still be necessary to carefully evaluate the patient in terms of COVID-19 disease while the pandemic continues. In our patients, it was not possible to check SARS-CoV-2 PCR in the CSF. In cases of neurological involvement, positivity of SARS-CoV-2 PCR in the CSF has been rarely reported in the literature (1). Neurological involvement was severe in all cases of COVID-19 associated demyelinating disease that were shared in the literature, and treatments varying from IVMP to plasmapheresis were given according to the severity of the disease. On the other hand, these patients also received treatments for infection [2, 5] . In our cases, patient 2 had a severe ON which is rare for idiopathic retrobulbar optic neuritis however the other patients showed full recovery. Uptodate there is a dilemma relating to how to treat COVID-19 disease and each institution has a protocol for managing the infection. In our patiens our approach is primarily focused on keeping the infection under control. The first patient was asymptomatic but had radiological lung involvement, so he was treated with hydroxychloroquine monotherapy before IVMP. The second patient had no symptoms and no systemic involvement, so IVMP treatment was started immediately due to severe vision loss. In the third patient, the infection clinic was serious and antiviral and antibiotic therapy were given together. IVMP was not given because the neurological symptoms were mild. Our ON patient was filling the MS criteria, so immunomodulatory treatment was started, with glatiramer acetate. It is wondering whether the other 2 patients will stay as a single attack or will they be multiphasic. Further long-term studies relating to the pathophysiology of COVID-19 are warranted. SARS-CoV-2 can induce brain and spine demyelinating lesions COVID-19-associated acute disseminated encephalomyelitis: a case report Acute myelitis after SARS-CoV-2 infection: a case report Multiple Sclerosis following SARS-CoV-2 infection. Multiple Sclerosis and Related Disorders A case of possible atypical demyelinating event of the central nervous system following COVID-19. Multiple Sclerosis and Related Disorders Human Coronaviruses and Other Respiratory Viruses: Underestimated Opportunistic Pathogens of the Central Nervous System? Viruses Evidence of central nervous system infection and neuroinvasive routes, as well as neurological involvement in the lethality of SARS-CoV-2 infection Viral infections and multiple sclerosis COVID-19): situation report, 61. Geneva: World Health Organization The authors declare that they have no conflict of interest.