The new severe acute respiratory syndrome- coronavirus 2 is reported to affect the nervous system. Among the reports of the various neurological manifestations, there are a few documented specific processes to explain the neurological signs. We report a para-infectious encephalitis patient with clinical, laboratory, and imaging findings during evolution and convalescence phase of coronavirus infection. This comprehensive overview can illuminate the natural history of similar cases. As the two previously reported cases of encephalitis associated with this virus were not widely discussed regarding the treatment, we share our successful approach and add some recommendations about this new and scarce entity. Â© 2020 Elsevier B.V

Afshar, H.

Aloosh, O.

Emamikhah, M.

Kalantari, S.

Lotfi, T.

Moghaddasi, M.

Sadeghipour, A.

Yassin, Z.

eprints Iran University of Medical Sciences

Contents lists available at ScienceDirectMultiple Sclerosis and Related Disordersjournal homepage: www.elsevier.com/locate/msardCase reportEvolution and resolution of brain involvement associated with SARS- CoV2infection: A close Clinical – Paraclinical follow up study of a caseHale Afshar (MD)a, Zeynab Yassin (MD)b, Saeed Kalantari (MD)b, Oldooz Aloosh (MD)a,Tayebeh Lotfi (MD)c, Mehdi Moghaddasi (MD)c, Alireza Sadeghipour (MD)d,Maziar Emamikhah (MD)c,⁎a Department of Internal Medicine, School of Medicine, Hazrat- e Rasool Akram General Hospital, Iran University of Medical Sciences (IUMS), Tehran, IranbAntimicrobial Resistance Research Center, Iran University of Medical Sciences (IUMS), Tehran, Iranc Department of neurology, School of Medicine, Hazrat Rasool-e Akram General Hospital, Iran University of Medical Sciences (IUMS), Tehran, IrandDepartment of pathology, Oncopathology research center, Iran University of Medical Sciences (IUMS), Tehran, IranA R T I C L E I N F OKeywords:COVID-19SARS-Cov-2encephalitispost-infectiousnatural historyimmunotherapyA B S T R A C TThe new severe acute respiratory syndrome- coronavirus 2 is reported to affect the nervous system. Among thereports of the various neurological manifestations, there are a few documented specific processes to explain theneurological signs. We report a para-infectious encephalitis patient with clinical, laboratory, and imagingfindings during evolution and convalescence phase of coronavirus infection. This comprehensive overview canilluminate the natural history of similar cases. As the two previously reported cases of encephalitis associatedwith this virus were not widely discussed regarding the treatment, we share our successful approach and addsome recommendations about this new and scarce entity.1. IntroductionAs the new emerging coronavirus, severe acute respiratory syn-drome- coronavirus 2 (SARS- CoV 2), spreads all over the world, newfeatures of this coronavirus disease 2019 (COVID- 19) is being reported.It is reported that there might be some mechanisms by which the dis-ease can affect the central nervous system (CNS) (Li et al. 2020). De-spite various neurological signs and symptoms, which have been re-ported (Mao et al. 2020), there are only a few reported cases withdocumented specific neurological processes to explain the CNS signs(Liu et al. 2020). To our knowledge, no cases of post infectious en-cephalitis (PIE) and its close follow up have been reported. Herein wereport a case with clinical (including respiratory and neurological),laboratory, chest Computed Tomography and Brain Magnetic Re-sonance Imaging (B-MRI) findings during evolution and convalescencephase which can illuminate the natural history of similar cases.2. Case reportA 39-year-old female presented to emergency department (ED) withfever, myalgias, anorexia, drowsiness and dry cough. Fever andmyalgias had been present for nine days; she did not experience anyimprovement with rest and anti-inflammatory drug (NSAIDS). She hadprolonged exposure to a covid-19 patient for prior 2 weeks. Past med-ical history was otherwise insignificant.After presentation to ED (day 10), she demonstrated a decline inconsciousness along with respiratory distress, ultimately needed en-dotracheal intubation. Chest CT showed multiple peripheral patchyground-glass opacities with typical covid-19 distribution (day 10); theseopacities later formed bilateral peripheral consolidation (day 22)(figure 1). She was transferred to intensive care unit (ICU) and treatedwith broad-spectrum IV antibiotics (meropenem 1g tid, levofloxacin750 mg daily, linezolide 600 bid), hydroxychloroqine 400 mg bid forthe first day, then 200 mg bid, atazanavir 400 mg daily and intravenousimmunoglobulin (IVIg) 25 g/day for 3 days. RT-polymerase chain re-action (PCR) of a nasopharyngeal swab was negative for SARS-CoV 2yet she was admitted with a diagnosis of Covid-19, based on clinicalhistory and chest CT scan findings.The patient experienced an episode of self-limited generalized tonic-clonic seizure (GTCS) on the following day (day 11) treated with in-travenous (IV) levetiracetam 500 mg bid. She experienced anotherepisode of GTCS on the same day, managed with increment inhttps://doi.org/10.1016/j.msard.2020.102216Received 10 May 2020; Received in revised form 15 May 2020; Accepted 18 May 2020⁎ Corresponding author: Maziar Emamikhah, MD, Assistant professor of Neurology, Division of Neurology – Hazrat- e Rasool Akram General Hospital, IranUniversity of Medical Sciences (IUMS), Niyayesh St, Sattarkhan Ave, Tehran, Iran, Postal code: 1445613131, Phone: +98 21 66 52 5331, Fax: +98 21 66 52 5331.E-mail address: maziar.emamikhah@yahoo.com (M. Emamikhah).Multiple Sclerosis and Related Disorders 43 (2020) 1022162211-0348/ © 2020 Elsevier B.V. All rights reserved.Tlevetiracetam dosage (500 mg tid). After improvement of respiratoryfunction, she was extubated (day 15). Despite improvement in in-flammatory and metabolic tests, she had a fluctuating level of con-sciousness. During investigation for decreased level of consciousness, B-MRI revealed T2- fluid attenuated inversion recovery (FLAIR) highsignal intensities in bilateral thalami, medial temporal and pons(figure 2). Corresponding areas in T1 images were hypo-signal andwithout gadolinium enhancement or restriction on T1 post-contrast anddiffusion weighted imaging (DWI) sequences, respectively. Cere-brospinal fluid (CSF) analysis showed normal protein (19 mg/dl) andglucose (61 mg/dl) levels with no white or red blood cells. PCR tests fordetecting viruses including SARS-CoV 2 and herpes simplex virus in CSFwere negative. No oligoclonal bands (OCB) was detected. Autoimmuneserologic markers including SS-A/SS-B and Anti-phospholipid anti-bodies were unremarkable. There was a borderline positive anti-nuclearantibody (ANA=2.7, positive>1.2) result. Other laboratory tests andtheir changes during disease course are listed in table 1. These resultsled to the diagnosis of para- infectious encephalitis associated withCOVID-19 and treatment with IVIg continued to a total dosage of 3g/kgof body weight (250g total) which resulted in considerable improve-ment in consciousness, but discontinued because of headaches (day 28).She complained of diplopia and was drowsy, even though the orienta-tion seemed fully recovered (day 28). At this point, we continued thetreatment with high dose methylprednisolone (500mg/day) IV for 6days, after which the diplopia resolved and she regained completeconsciousness. Subsequent B-MRIs (figure 2) showed marked resolutionFigure 1. Axial chest CT scans of the patient at days 10 (upper row), 22 (middle row) and 28 (bottom row) after onset of symptoms.Figure 2. Three sets of axial (A-M except E) and coronal (E) brain MRIs obtained at days 11 (planes A1-M1), 22 (planes A2-M2) and 33 (planes A3-M3) aftersymptoms onset, show the evolution of brain lesions over time. There are T2-FLAIR high signal lesions in bilateral pons (A1, B1, E1, F1 & G1), medial temporal lobes(C1 & H1) and thalami (D1 & I1) and with low signal in T1 sequences (J1-M1). Corresponding images in second and third series show considerable resolution ofsignal intense lesions. There was neither gadolinium enhancement nor diffusion restriction in post-contrast T1 and diffusion weighted imagings (not shown here).H. Afshar, et al. Multiple Sclerosis and Related Disorders 43 (2020) 1022162Table1Thesequenceofclinical,laboratoryandimagingfindingsduringthenaturalhistoryofourpatient'sdisease.DaysfromsymptomsonsetDay1Day10Day11Day22Day28Day33Daysafteradmission-FirstadmissiondaySecondadmissionday13thadmissionday19thadmissionday24thadmissiondayClinicalsymptomsandtreatmentsFever,MyalgiaFever,Drycough,Myalgia,Anorexia,DrowsinessStartingantibiotics,hydroxychloroqine,atazanavirandIVIg(75ginthenextthreedays)Fever,Myalgia(?),Anorexia(?),Respiratorydistress,Coma,GTCSIntubation(forfourdays)Myalgia(?),Anorexia(?),Norespiratorydistress,LethargyReinstitutionofIVIg(175ginthenextsevendays;total=250g)Drowsiness,diplopia,headache(improvedwithIVIgdiscontinuation)IVmethylprednisolonestarted(totaldoseof3ginthenextsixdays)Normalconsciousness,NodiplopiaorotherabnormalfindingsLaboratoryfindings(inbloodunlessspecified)-CBC(WBC=20000,Neut=15000,Lym=800,Plt=168000),CPK=540,Cr=1.6,CRP=48,ESR=31,LDH=1744,O2Sat=76%,Pro-BNP=1458,PCT≥200,Tn=296,VBG(pH=7.3,pCO2=79,HCO3=18.9)CBC(WBC=14600,Neut=12200,Lym=1460,Plt=180000),CPK=N/A,Cr=1.6,CRP=N/A,ESR=N/A,LDH=938,O2Sat=81%,Pro-BNP=N/A,PCT=14.96,VBG(pH=7.34,pCO2=32,HCO3=18)CBC(WBC=4600,Neut=2990,Lym=1380,Plt=199000),CPK=N/A,Cr=0.8,CRP<6,ESR=89,LDH=394,O2Sat=92%,Pro-BNP=N/A,PCT=N/A,VBG(pH=7.39,pCO2=64,HCO3=28)CBC(WBC=4100,Neut=2660,Lym=1230,Plt=241000),CPK=N/A,Cr=0.8,CRP<6CRP<6,ESR=33,LDH=466,O2Sat=88%,Pro-BNP=N/A,PCT=0.11,Tn=N/A,VBG(pH=N/A,pCO2=N/A,HCO3=N/A)CBC(WBC=15800,Neut=10400,Lym=4700,Plt=349000),CPK=N/A,Cr=0.7,CRP<6,ESR=N/A,LDH=584,O2Sat=96%,Pro-BNP=N/A,PCT=N/A,Tn=N/A,(pH=N/A,pCO2=N/A,HCO3=N/A)ChestCTfindings-Multipleperipheralpatchyground-glassopacities-ObviousperipheralconsolidationsinbothlungesMarkedresolutionofconsolidations,hazyopacities-BrainMRIfindings-T2highsignalabnormalitiesinbilateralthalami,PonsandmedialtemporallobesT2highsignalabnormalitiesinbilateralPons-ResidualT2signalabnormalitiesinlowerponsCBC:completebloodcount;CPK:creatinphosphokinase;Cr:creatinine;CRP:C-reativeprotein(mg/L,negative<6);CT:computedtomography;ESR:erythrocytesedimentationrate(mm/hr);GTCS:generalizedtonicclonicseizure;HCO3:bicarbonate(meq/L);IVIg:intravenousimmunoglobulins;LDH:lactatedehydrogenase;Lym:lymphocytes(permm3);MRI:magneticresonanceimaging;N/A:notavailable;Neut:neutrophils(permm3);O2Sat:oxygensaturation;pCO2:partialpressureofcarbondioxide(mmHg);pH:powerofhydrogen;Plt:platelets(permm3);PRO-BNP:prob-typenatriureticpeptide(pg/ml,abnormal>125);PCT:Procalcitonin(ng/ml,normal<0.5);Tn=troponin-n(ng/ml,normal<19);VBG:venousbloodgas;WBC:whitebloodcells(permm3);?:unknownbecauseofdecreasedconsciousnessH. Afshar, et al. Multiple Sclerosis and Related Disorders 43 (2020) 1022163of medial temporal and thalami involvements as well as partial im-provement in pontine lesions after reinstitution of IVIg (day 22) andadministration of methylprednisolone (day 33). Results of SARS-CoV 2serology tests taken during admission became available after dischargeand were positive for both IgG and IgM.3. DiscussionBrain involvement during COVID-19 pandemic has been reported invarious forms, but the prevalence and proportion of each type of in-volvement is unknown (Mao et al. 2020, Liu et al. 2020). Stroke andencephalitis are specific CNS disorders reported in COVID-19 but thereare many reports of neurological findings without obvious pathophy-siologic explanations. The most common reported neurological mani-festations have been headache, dizziness, encephalopathy and delirium.Some of these patients have been undergone a neurological workup, yetdespite reports of CNS symptoms in up to 40% of these patients, thereare only few cases where distinct etiology has been discovered(Liu et al. 2020). Among these there is only one established cases ofencephalitis with evidence of virus in CNS (Moriguchi et al. 2020) andanother case with acute necrotizing encephalitis (ANE) but withoutevidence for direct viral invasion (Poyiadji et al. 2020). The distributionof cerebral lesions in MRI for our patient was similar to both afore-mentioned cases but with more extensive and symmetrical involvementof thalami and medial temporal lobes. The involvement of pons has notbeen present in previous reported cases. Contrary to the ANE case, inour patient there was no evidence for hemorrhage or necrosis in serialB-MRIs. A recent paper has described a number of B-MRI changes inCOVID-19 patients, but none of them have been the same as those inour patient (Kandemirl et al. 2020). Although in ANE the authorsmentioned treatment with IVIg, but exact dosage, protocol and re-sponse to treatment has not been described. Our patient before diag-nosis of neurologic involvement had received IVIg (25 g/day for threedays) as a part of treatment for COVID-19 severe pulmonary involve-ment; and after the CNS lesions were established, it was reinstituted anddue to very good clinical and radiological response, we decided tocontinue IVIg therapy until complete recovery, unless there is a com-plication. After administration of a total 250 g (3 g/kg) IVIg, it wasstopped due to occurrence of headaches that seemed related to druginfusion. After discontinuation of IVIg, the headaches resolved com-pletely and due to presence of diplopia and drowsiness treatment wasthen continued with methylprednisolone (500 mg/day for six days),which led to complete resolution of neurological symptoms. Upondischarge from the hospital, the patient was completely asymptomatic.We consider this type of brain involvement, a para- infectious auto-immune encephalitis, as we believe was the case for ANE patient, andrecommend prompt immunotherapy upon diagnosis of similar cases.The use of IVIg in severe COVID-19 patients may prevent or ameliorateCNS involvement, as seemed to happen for our patient compared toANE case.4. ConclusionNeurological involvement in COVID-19 is increasingly reported andthe investigations regarding etiology, natural history and appropriatetreatment are essential. As for our patient, neurological symptoms notcorrelated with respiratory and metabolic conditions should be analarm for the possibility of CNS involvement. Similar to many otherviral agents, SARS-CoV 2 seems capable of causing encephalitis. Thenature of etiology regarding encephalitis remains the matter of debateas both direct invasion and para-infectious mechanisms seem possible.We recommend prompt assessment of CSF for overt signs of viral in-fection (marked cellular reaction, increased protein and positive PCRtest) and considering immunotherapy with IVIg in cases compatiblewith para-infectious origin. The usefulness of prophylactic IVIg in se-vere COVID-19 and the role of serology in CSF for diagnosing neu-roinvasion, remain interesting discussions that we are unable to com-ment about at this moment.DisclosuresFunding sourcesThis research did not receive any specific grant from fundingagencies in the public, commercial, or not-for-profit sectors.Compliance with ethical standardsThis study was approved by the ethics committee of Iran Universityof Medical Sciences, Tehran, Iran and also have been conducted inaccordance with the ethical standards of Declaration of Helsinki.Informed consent was obtained from the patient for publication ofthis report.CRediT authorship contribution statementHale Afshar: Conceptualization, Investigation, Methodology,Supervision, Writing - review & editing. Zeynab Yassin: Investigation,Methodology, Writing - review & editing. Saeed Kalantari:Investigation, Resources, Writing - review & editing. Oldooz Aloosh:Resources, Writing - review & editing. Tayebeh Lotfi: Investigation,Writing - original draft. Mehdi Moghaddasi: Conceptualization,Investigation, Supervision, Writing - review & editing. AlirezaSadeghipour: Investigation, Resources. Maziar Emamikhah:Conceptualization, Data curation, Investigation, Methodology, Projectadministration, Resources, Software, Supervision, Writing - originaldraft, Writing - review & editing.Declaration of Competing InterestNone.AcknowledgementNone.ReferencesLi, YC, Bai, WZ, Hashikawa, T., 2020. The neuroinvasive potential of SARS‐CoV2 mayplay a role in the respiratory failure of COVID‐19 patients. Journal of medical vir-ology.Mao, L, Jin, H, Wang, M, Hu, Y, Chen, S, He, Q, et al., 2020. Neurologic manifestations ofhospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA neu-rology.Liu, K, Pan, M, Xiao, Z, Xu, X, 2020. Neurological manifestations of the coronavirus(SARS-CoV-2) pandemic 2019–2020. Journal of Neurology, Neurosurgery &Psychiatry 91 (6), 669–670.Moriguchi, T, Harii, N, Goto, J, Harada, D, Sugawara, H, Takamino, J, et al., 2020. A firstCase of Meningitis/Encephalitis associated with SARS-Coronavirus-2. InternationalJournal of Infectious Diseases 94, 55–58.Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B. COVID-19–associated acutehemorrhagic necrotizing encephalopathy: CT and MRI features. Radiology.2020:201187.Kandemirli, SG, Dogan, L, Sarikaya, ZT, Kara, S, Akinci, C, Kaya, D, et al., 2020. BrainMRI Findings in Patients in the Intensive Care Unit with COVID-19 Infection.Radiology, 201697.H. Afshar, et al. Multiple Sclerosis and Related Disorders 43 (2020) 1022164

Evolution and resolution of brain involvement associated with SARS- CoV2 infection: A close Clinical â�� Paraclinical follow up study of a case

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Evolution and resolution of brain involvement associated with SARS- CoV2 infection: A close Clinical â�� Paraclinical follow up study of a case

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