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Multiple sclerosis relapse after COVID-19 vaccination: A case report-based systematic review

Published:August 18, 2022DOI:https://doi.org/10.1016/j.jocn.2022.08.012

      Highlights

      • Recently there were reports of MS relapses after the COVID-19 vaccination which emerged safety concerns.
      • Among patients, 22 cases experienced relapse after their first dosage of the COVID-19 vaccine.
      • Overall, the COVID-19 vaccination may trigger relapses in some MS patients but the infection itself can stimulate relapse.

      Abstract

      Background

      Concerns about vaccination increased among patients with multiple sclerosis (MS) regarding side effects, efficacy, and disease exacerbation. Recently there were reports of MS relapses after the COVID-19 vaccination, which emerged the safety concerns. Therefore, we aimed to perform a systematic review of case reports and case series studies to investigate the MS relapses after COVID-19 vaccination with most details.

      Methods

      We systematically searched three databases, including PubMed, Scopus, and Web of Science, in February 2022. Case reports and case series which reported relapse after COVID-19 vaccination in MS patients were eligible to include in our study.

      Results

      Seven studies were included in our systematic review after the abstract and full-text screening with a total of 29 cases. The mean duration between COVID-19 vaccination and relapse appearance was 9.48 ± 7.29 days. Among patients, 22 cases experienced relapse after their first dosage of the COVID-19 vaccine, one after the second dose, and five after the booster dose. The type of vaccine was unknown for one patient. The most common symptoms of relapses were sensory deficits (paresthesia, numbness, dysesthesia, and hypoesthesia) and weakness.

      Conclusion

      Overall, the COVID-19 vaccination may trigger relapses in some MS patients, but as the infection itself can stimulate relapse, the benefit of vaccination outweighs its risk in this population, and mass vaccination against COVID-19, especially in MS patients, should be continued and encouraged.

      Keywords

      1. Introduction

      The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which is responsible for coronavirus infection, was declared a worldwide pandemic by the World Health Organization (WHO) in March 2020 [
      • Hassaniazad M.
      • Farshidi H.
      • Gharibzadeh A.
      • Bazram A.
      • Khalili E.
      • Noormandi A.
      • et al.
      Efficacy and safety of favipiravir plus interferon-beta versus lopinavir/ritonavir plus interferon-beta in moderately ill patients with COVID-19: A randomized clinical trial.
      ]. Vaccination against COVID-19 is the primary long-term strategy to stop this pandemic globally [
      • Huang Y.
      • Rodgers W.J.
      • Middleton R.M.
      • Baheerathan A.
      • Tuite-Dalton K.A.
      • Ford D.V.
      • et al.
      Willingness to receive a COVID-19 vaccine in people with multiple sclerosis – UK MS Register survey.
      ]; thus, worldwide initiatives were done to develop vaccines against this pandemic which has claimed over 6 million lives and affected over 500 million people as of April 2022 [
      • Hu B.
      • Guo H.
      • Zhou P.
      • Shi Z.L.
      Characteristics of SARS-CoV-2 and COVID-19.
      ]. Patients with comorbidities, especially autoimmune diseases, have been considered at higher risk to develop a more severe form of the disease [
      • Fang L.
      • Karakiulakis G.
      • Roth M.
      Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection?.
      ]. A systematic review and meta-analysis in 2021 showed the pooled prevalence of suspected covid-19 in patients with multiple sclerosis (MS) was 4%, hospitalization was 10%, and death in hospitalized patients was 4% [
      • Moghadasi A.N.
      • Mirmosayyeb O.
      • Barzegar M.
      • Sahraian M.A.
      • Ghajarzadeh M.
      The prevalence of COVID-19 infection in patients with multiple sclerosis (MS): a systematic review and meta-analysis.
      ].
      MS is the most prevalent disabling permanently neurological disease among young adults and is associated with high socioeconomic cost and diminished quality of life [
      • Persson R.
      • Lee S.
      • Ulcickas Yood M.
      • Wagner C.M.
      • Minton N.
      • Niemcryk S.
      • et al.
      Infections in patients diagnosed with multiple sclerosis: a multi-database study.
      ]. Infectious diseases are the leading cause of death and a common cause of comorbidity among patients with MS and may cause the exacerbation of MS symptoms; thus, vaccination in patients with MS should be purposed as a general policy to decrease the risk of infections [
      • Persson R.
      • Lee S.
      • Ulcickas Yood M.
      • Wagner C.M.
      • Minton N.
      • Niemcryk S.
      • et al.
      Infections in patients diagnosed with multiple sclerosis: a multi-database study.
      ].
      Concerns about vaccination increased among health care providers and patients with MS regarding side effects, efficacy, and disease exacerbation [
      • Yazdani A.
      • Mirmosayyeb O.
      • Ghaffary E.M.
      • Hashemi M.S.
      • Ghajarzadeh M.
      COVID-19 vaccines and patients with multiple sclerosis: willingness, unwillingness and hesitancy: a systematic review and meta-analysis.
      ]. Neurological manifestations are rare complications of COVID-19 infection and vaccination [
      • Patone M.
      • Handunnetthi L.
      • Saatci D.
      • Pan J.
      • Katikireddi S.V.
      • Razvi S.
      • et al.
      Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection.
      ]. Among neurological manifestations, autoimmune disorders which affect the nervous system are rare (<0.1%) after COVID-19 vaccination [
      • Thomas S.J.
      • Moreira E.D.
      • Kitchin N.
      • Absalon J.
      • Gurtman A.
      • Lockhart S.
      • et al.
      Safety and efficacy of the BNT162b2 mRNA covid-19 vaccine through 6 months.
      ]. In another study, after the first dose of Pfizer BioNTech and AstraZeneca vaccines, the most common complications were Guillain–Barré syndrome and Bell’s palsy [
      • Baden L.R.
      • El Sahly H.M.
      • Essink B.
      • Kotloff K.
      • Frey S.
      • Novak R.
      • et al.
      Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine.
      ]. Recently there were reports of MS relapses after the COVID-19 vaccination, which emerged safety concerns [
      • Etemadifar M.
      • Sigari A.A.
      • Sedaghat N.
      • Salari M.
      • Nouri H.
      Acute relapse and poor immunization following COVID-19 vaccination in a rituximab-treated multiple sclerosis patient.
      ,
      • Kataria H.
      • Hart C.G.
      • Alizadeh A.
      • Cossoy M.
      • Kaushik D.K.
      • Bernstein C.N.
      • et al.
      Neuregulin-1 beta 1 is implicated in pathogenesis of multiple sclerosis.
      ,
      • Nistri R.
      • Barbuti E.
      • Rinaldi V.
      • Tufano L.
      • Pozzilli V.
      • Ianniello A.
      • et al.
      Case report: multiple sclerosis relapses after vaccination against SARS-CoV2: a series of clinical cases.
      ]. A study by Fragoso et al. revealed that patients with no evidence of MS activity and no change in their medications developed a new relapse with new lesions on magnetic resonance imaging (MRI) along with increased disability following their first dose of AstraZeneca vaccine for COVID-19 [
      • Fragoso Y.D.
      • Gomes S.
      • Gonçalves M.V.M.
      • Mendes Junior E.
      • Oliveira B.E.S.
      • Rocha C.F.
      • et al.
      New relapse of multiple sclerosis and neuromyelitis optica as a potential adverse event of AstraZeneca AZD1222 vaccination for COVID-19.
      ]. Therefore, we aimed to perform a systematic review of case reports and case series studies to investigate the MS relapses after COVID-19 vaccination with most details.

      2. Methods

      This study was conducted following preferred reporting items for systematic reviews and meta-analyses (PRISMA) guideline [

      Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009;339:b2535.

      ].

      2.1 Search strategy

      We systematically searched three databases, including PubMed, Scopus, and Web of Science, in February 2022. Our search strategy included the following terms: (Multiple sclerosis) AND (COVID-19 OR SARS-COV-2 OR corona virus OR Coronavirus Disease OR 2019-nCoV Disease) AND (Vaccination OR Vaccine OR immunization).

      2.2 Eligibility criteria

      All case reports and case series which reported relapse after COVID-19 vaccination in MS patients were eligible to include in our study. The non-English article, studies with other vaccination for another virus, review papers, and other types of original studies (cohorts, case-control, and clinical trials) were excluded.

      2.3 Study selection

      Two independent reviewers (F.N, K.K) screened the title and abstracts and excluded irrelevant studies. Then the same reviewers checked the full text of the remaining articles to evaluate their eligibility to include in our study.

      2.4 Data extraction

      The same investigators (F.N, K.K) extracted the following information based on a predesigned datasheet: Study the demographic, type of MS, age, sex, MS duration, clinical presentation before relapse, MRI findings, type of COVID-19 vaccination, vaccine dosage, the interval between relapse and vaccination, the clinical presentation of relapse, treatments, and outcomes.

      2.5 Quality assessments

      The quality of included studies was assessed using the Joanna Briggs Institute Critical Appraisal tools for Case Reports independently by two reviewers (F.N, K.K) [

      M P. Moola S MZ, Tufanaru C, Aromataris E, Sears K, Sfetcu R, Currie M, Lisy K, Qureshi R, Mattis P. JBI Manual for Evidence Synthesis. JBI Manual for Evidence Synthesis. 2020.

      ]. The answer to the questions was based on “Yes” or “No” and the score ranged from 0 to 8.

      3. Results

      Our initial search yielded 1386 studies (Fig. 1). After duplicate removing, 779 papers were screened. At this step, 686 articles were excluded via title and abstract evaluation, and the remaining studies underwent full-text review. Finally, seven studies entered our systematic review [
      • Etemadifar M.
      • Sigari A.A.
      • Sedaghat N.
      • Salari M.
      • Nouri H.
      Acute relapse and poor immunization following COVID-19 vaccination in a rituximab-treated multiple sclerosis patient.
      ,
      • Kataria H.
      • Hart C.G.
      • Alizadeh A.
      • Cossoy M.
      • Kaushik D.K.
      • Bernstein C.N.
      • et al.
      Neuregulin-1 beta 1 is implicated in pathogenesis of multiple sclerosis.
      ,
      • Nistri R.
      • Barbuti E.
      • Rinaldi V.
      • Tufano L.
      • Pozzilli V.
      • Ianniello A.
      • et al.
      Case report: multiple sclerosis relapses after vaccination against SARS-CoV2: a series of clinical cases.
      ,
      • Fragoso Y.D.
      • Gomes S.
      • Gonçalves M.V.M.
      • Mendes Junior E.
      • Oliveira B.E.S.
      • Rocha C.F.
      • et al.
      New relapse of multiple sclerosis and neuromyelitis optica as a potential adverse event of AstraZeneca AZD1222 vaccination for COVID-19.
      ,
      • Łagosz P.
      • Biegus J.
      • Gruszka E.
      • Zymliński R.
      The surprising course of multiple sclerosis relapse in a patient after SARS-CoV-2 vaccination.
      ,
      • Maniscalco G.T.
      • Manzo V.
      • Di Battista M.E.
      • Salvatore S.
      • Moreggia O.
      • Scavone C.
      • et al.
      Severe multiple sclerosis relapse after COVID-19 vaccination: a case report.
      ,
      • Seyed Ahadi M.
      • Ghadiri F.
      • Ahraian M.A.
      • Naser Moghadasi A.
      Acute attack in a patient with multiple sclerosis 2 days after COVID vaccination: a case report.
      ]. The demographical and clinical characteristics of included studies are detailed in Table 1. A total of 29 cases with a mean age of 43.2 ± 11.5 and a range [22–66] were included in our study. 68% of the patients were female, and eight cases were reported as RRMS. The mean duration between COVID-19 vaccination and relapse appearance was 9.48 ± 7.29 days (Fig. 2). Twelve patients received Oxford/AstraZeneca, twelve received PfizerBioNTech, two Moderna, and each one received Sputnik and Sinopharm (Fig. 2). Among patients, 22 cases experienced relapse after their first dosage of the COVID-19 vaccine, one after the second dose, and five after the booster dose. The type of vaccine was unknown for one patient. The most common symptoms of relapses were sensory deficits (n = 14) (paresthesia, numbness, dysesthesia, and hypoesthesia) and weakness (n = 6). After relapse, most of the patients received glucocorticoids, and 13 patients recovered, five partially recovered, and five patients not yet recovered until the end of the study follow-up (see Fig. 3).
      Figure thumbnail gr1
      Fig. 1PRISMA flow diagram depicting the flow of information through the different phases of a systematic review.
      Table 1Demographical and clinical findings of the included studies.
      StudyCountryType of MSAgeSexMS disease durationClinical presentation of MS before relapseDMTsMRI FindingsType COVID-19 vaccineVaccine dosageTime interval between vaccination and relapseRelapse clinical presentationsTreatmentsOutcome
      Lagosz et al. 2022PolandNR64MNRNRNRA hypodense lesion in the left frontal-parietal areaNRNR1 dayFeeling numbness, worsened mobility in the arms and fatigueGlucocorticoidsRecovered
      Kataria et al. 2022USANR57F6 yearsNRInterferon-betaMultiple confluent and distinct hyperintense white matter enhancing lesions in both hemispheres on T2-weighted and diffusion-weighted images. Spine MRI was normal.BNT162b2/PfizerBioNTech2nd18 daysFatigue, involuntary eye movements, numbness, tingling, stiffness in her left upper and lower limbsIntravenous methylprednisolone and physiotherapy , baclofenRecovered
      Etemadifar et al. 2021IranRRMS34F13 yearsoptic neuritis and bilateral lower limb paresthesia / paraparesisInterferon-beta 1a.Several new periventricular, juxtacortical and brainstem lesions on T2Sputnik1st3 daysSevere right hemiplegia and ataxiaOral methylprednisolone for 3 weeksRecovered
      Ahadi et al. 2021IranRRMS42F20 yearsoptic neuritis/ hemiparesthesia and monoparesis/ paraparesisInterferon-beta 1b.Showed numeral periventricular, anterior medullary white matter hyper-intensitiesSinopharm1st2 daysProgressive paraparesis without paresthesiaIntravenous methylprednisoloneRecovered
      Maniscalco et al. 2021ItalyNR31F5 yearsTinnitus and dizzinessFingolimodThree new voluminous enhancing lesionsBNT162b2/PfizerBioNTech1st48 hoursParaesthesia and weakness in her left arm and limbsIntravenous methylprednisoloneRecovered
      Fragoso et al. 2021BrazilRRMS22F5 yearsNRFingolimodNon-Gd tumefactive lesionOxford/AstraZeneca1st7 daysFacial paralysis, hemiparesis, ataxiaPulsotherapy methylprednisoloneNot yet recovered
      RRMS32F2 yearsNRDimethyl fumarateNew Gd + lesions in the left eyeOxford/AstraZeneca1st10 daysLoss of vision and papillitis in the left eyePulsotherapy methylprednisolone ImmunoglobulinPartial recoved
      SPMS35M3 yearsNRNatalizumabHigh lesion load , new lesionsOxford/AstraZeneca1st7 daysWorsening of disability, could not walk, severe weakness of both legsOral prednisoneNot yet recovered
      RRMS30F1 yearNRNatalizumabNew Gd + lesionsOxford/AstraZeneca1st25 daysRight hemiparesisPulsotherapy methylprednisoloneRecovered
      RRMS42F3 yearsNRFingolimodNew Gd+ lesions in spinal cord, T2 levelOxford/AstraZeneca1st15 daysRapidly progressive weakness in both arms , grade III at its worstPulsotherapy methylprednisoloneRecovered
      RRMS35M4 yearsNRTeriflunomideNew Gd+ lesions in brainstemOxford/AstraZeneca1st20 daysIncoordination of right arm and handPulsotherapy methylprednisoloneNot yet recovered
      PPMS51M2 yearsNRNRNew Gd+ lesions in cervical cordOxford/AstraZeneca1st25 daysHypoesthesia in both armsNo treatmentNot yet recovered
      RRMS32F6 yearsNRGlatiramer acetateNew Gd+ lesions+ new lesionsOxford/AstraZeneca1st7 daysMotor and sensitive deficits in right leg and footPulsotherapy methylprednisoloneNot yet recovered
      Nistri et al. 2021ItalyNR48FNew diagnosisvisual acuity deficit from right eyeNREnhancing lesion in the corpus callosum, multiple white matter unenhanced lesions and lesions in the occipital lobe were detectedOxford/AstraZeneca1 st8 daysVisual acuity deficit from right eyeHigh dose of intravenous methylprednisoloneRecovered
      NR45M9 yearsNROcrelizumabTwo new lesions in the temporal gyri and a new spinal cord lesion at T3 levelOxford/AstraZeneca1st3 weeksDysesthesia in both legsSteroidsNR
      NR54F28 yearsNRNROne enhancing lesion in the spinal cordOxford/AstraZeneca1 st3 daysDeveloped hypoesthesia below the T6 levelIntravenous methylprednisoloneRecovered
      NR66FNew diagnosisvisual disturbance and postural instability on the right limbsNRMultiple white matter lesions, four of them enhancing in the left paratrigonal and periventricular white matterOxford/AstraZeneca1 st1 weekVisual disturbance and postural instability on the right limbsIntravenous methylprednisolonePartial recovered
      NR42F2 yearsprogressive weakness on the right side of bodyOcrelizumabEnhancing brain lesion in the right corona radiataModerna1 st2 weeksSlight weakness of the left upper limbNRNR
      NR57M20 yeasNRNREnhancing pontine lesionModernabooster2 weeksSevere motor deficit in both legsIntravenous methylprednisolonePartial recovered
      NR49F8 yearsNRDimethyl fumarateA periventricular lesion and a spinal lesion at C3 level, both enhancingBNT162b2/PfizerBioNTech1 st5 daysNumbness on the left hand and left side of her headIntravenous methylprednisoloneRecovered
      NR39M7 yearshypoesthesia on left sideDimethyl fumarateThree new lesions, two of which were enhancing in the left parietal lobe and in the periventricular white matterBNT162b2/PfizerBioNTech1st10 daysParesthesia on left legOral steroidsPartial recoverd
      NR39FNew diagnosisNRNRA new enhancing lesion in the mesencephalonBNT162b2/PfizerBioNTech1st3 daysDysesthesia on her right hand and footIntravenous methylprednisoloneRecovered
      NR60F23 yearsNRDimethyl fumarateOne enhancing brain lesion in the left periventricular white matterBNT162b2/PfizerBioNTech1st2 daysFatigue and numbness in both legsNRNR
      NR30F3 yearsoptic neuritisCladribineTwo enhancing brain lesions, one in the right corona radiata and one with conspicuous oedema in the left centrum semiovaleBNT162b2/PfizerBioNTechbooster20 daysLanguage disturbanceNRNR
      NR58F21 yearsNRNRA new area with ring enhancement in the white matter of the left frontal lobeBNT162b2/PfizerBioNTech1st3 daysHeadache, balance disturbance, urinary incontinence, difficulties in walking and dysphagiaIntravenous methylprednisoloneRecovered
      NR34F3 monthsnumbness and hyposthenia on her right handNRThree brain enhancing lesion (one right posterior paraventricular and two in the left periventricular white matter) and a new unenhanced lesion on spinal cordBNT162b2/PfizerBioNTechbooster4 daysNeck pain and hypoesthesia on right armNRNR
      NR35F16 yearsNRDimethyl fumarateThree enhancing lesions in the left temporal lobe and left centrum semiovaleBNT162b2/PfizerBioNTechbooster1 dayParesthesia on the left side of bodyNRNR
      NR54M18 yearsNRTeriflunomideTwo ring-enhancing lesions located in the left periventricular white matterbNT162b2/PfizerBioNTech1st1 weekRight hemiparesisIntravenous methylprednisoloneRecovered
      NR37M2 yearsNRDimethyl fumarateA new tumefactive contrast-enhancing lesion in the left fronto-parietal white matterBNT162b2/PfizerBioNTechbooster11 daysWeakness on right limbsIntravenous methylprednisolonePartial recovered
      Abbreviations: NR, Not Reported, RRMS, relapsing remitting multiple sclerosis; SPMS, secondary progressive multiple sclerosis; PPMS, primary progressive multiple sclerosis, DMTs, disease modyfing therapies.
      Figure thumbnail gr2
      Fig. 2The mean duration between vaccination and relapse based on type of vaccine (A), and type of COVID-19 vaccine used among cases (B).
      Figure thumbnail gr3
      Fig. 3Mechanism of relapse in patients with MS following COVID-19 vaccination, by BioRender.
      The result of the quality assessment using JBI criteria revealed that six studies scored more than 7, and only one study scored 5 (Table 2). The mean JBI score for all included studies was 7.28.
      Table 2The Joanna Briggs Institute Critical Appraisal tools for Case Reports.
      Lagosz et al. 2022Kataria et al. 2022Etemadifar et al. 2021Ahadi et al. 2021Maniscalco et al. 2021Fragoso et al. 2021Nistri et al. 2021
      Were patient’s demographic characteristics clearly described?NoYesYesYesYesYesYes
      Was the patient’s history clearly described and presented as a timeline?NoNoYesYesYesYesNo
      Was the current clinical condition of the patient on presentation clearly described?YesYesYesYesYesYesYes
      Were diagnostic tests or assessment methods and the results clearly described?YesYesYesYesYesYesYes
      Was the intervention(s) or treatment procedure(s) clearly described?NoYesYesYesYesYesYes
      Was the post-intervention clinical condition clearly described?YesYesYesYesYesYesYes
      Were adverse events (harms) or unanticipated events identified and described?YesYesYesYesYesYesYes
      Does the case report provide takeaway lessons?YesYesYesYesYesYesYes
      Total rank5788887

      4. Discussion

      Although mass vaccination against COVID-19 is the preferred way of controlling the disease, concerns around the long-term safety of these vaccines have remained unclear, in particular in patients with underlying comorbidities [
      • Knoll M.D.
      • Wonodi C.
      Oxford-AstraZeneca COVID-19 vaccine efficacy.
      ]. Autoimmune disorders comprise a group of these comorbidities for which vaccination may trigger undesired responses. Post-vaccination relapses in neurological autoimmune disorders such as MS and Guillen Barre have been previously reported with HBV, Influenza, polio, and tetanus vaccines [
      • Confavreux C.
      • Suissa S.
      • Saddier P.
      • Bourdès V.
      • Vukusic S.
      Vaccinations and the risk of relapse in multiple sclerosis.
      ,
      • Geier M.R.
      • Geier D.A.
      • Zahalsky A.C.
      Influenza vaccination and Guillain Barre syndrome.
      ]. Available COVID-19 vaccines are no exception, and reports of Bell's palsy, transverse myelitis, Guillen Barre syndrome and MS relapses have emerged [

      Li X, Raventós B, Roel E, Pistillo A, Martinez-Hernandez E, Delmestri A, et al. Association between covid-19 vaccination, SARS-CoV-2 infection, and risk of immune mediated neurological events: population based cohort and self-controlled case series analysis. BMJ. 2022;376:e068373.

      ].
      To the current time point, there is no contraindication for COVID-19 vaccination in MS patients except for living attenuated vaccines in patients under immunosuppressive or immunomodulatory regimens [
      • Dema M.
      • Eixarch H.
      • Villar L.M.
      • Montalban X.
      • Espejo C.
      Immunosenescence in multiple sclerosis: the identification of new therapeutic targets.
      ]. In addition, no vaccine is favored for MS patients [
      • Fragoso Y.D.
      • Gomes S.
      • Gonçalves M.V.M.
      • Mendes Junior E.
      • Oliveira B.E.S.
      • Rocha C.F.
      • et al.
      New relapse of multiple sclerosis and neuromyelitis optica as a potential adverse event of AstraZeneca AZD1222 vaccination for COVID-19.
      ]. However, reports of relapses after either first or booster doses of COVID-19 vaccines indicate an association between disease pathophysiology and vaccination. In an interval ranging from one to 25 days after vaccination, a portion of MS patients manifested neurological symptoms, with the most common ones being paralysis, visual loss, weakness, and motor deficits. The extent of immune response in MS patients depends on both individual genetic susceptibility, and the type of vaccine used [
      • Nistri R.
      • Barbuti E.
      • Rinaldi V.
      • Tufano L.
      • Pozzilli V.
      • Ianniello A.
      • et al.
      Case report: multiple sclerosis relapses after vaccination against SARS-CoV2: a series of clinical cases.
      ,
      • Langer-Gould A.
      • Qian L.
      • Tartof S.Y.
      • Brara S.M.
      • Jacobsen S.J.
      • Beaber B.E.
      • et al.
      Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases.
      ].
      Cross-reactivity and bystander activation are well-established theories justifying autoimmunity after vaccination. Depending on the vaccine type, one of these mechanisms may be more relevant. In the case of Pfizer, which is an RNA virus coding for spike proteins in lipid membrane without any adjuvant, cross-reactivity may explain the situation as the COVID-19 spike protein antibody is structurally similar to myelin basic protein [
      • Langer-Gould A.
      • Qian L.
      • Tartof S.Y.
      • Brara S.M.
      • Jacobsen S.J.
      • Beaber B.E.
      • et al.
      Vaccines and the risk of multiple sclerosis and other central nervous system demyelinating diseases.
      ]. Besides, the interaction between spike proteins and Angiotensin-Converting Enzyme 2 (ACE2) receptors located in the Blood-Brain Barrier (BBB) and spinal neurons have been reported in several in vivo studies [
      • Farez M.F.
      • Correale J.
      • Armstrong M.J.
      • Rae-Grant A.
      • Gloss D.
      • Donley D.
      • et al.
      Practice guideline update summary: vaccine-preventable infections and immunization in multiple sclerosis: report of the guideline development, dissemination, and implementation subcommittee of the american academy of neurology.
      ]. This is true for Coronavirus itself, as it can cross BBB either with transcytosis using ACE2 receptors or reach brain parenchyma via the olfactory bulb [
      • Fragoso Y.D.
      • Gomes S.
      • Gonçalves M.V.M.
      • Mendes Junior E.
      • Oliveira B.E.S.
      • Rocha C.F.
      • et al.
      New relapse of multiple sclerosis and neuromyelitis optica as a potential adverse event of AstraZeneca AZD1222 vaccination for COVID-19.
      ]. However, autoimmunity after the AstraZeneca vaccine is less likely to happen because of this cross-reactivity. AstraZeneca has an adjuvant (MF59) that has clearly been shown to induce inflammation by secretion of cytokines, including IL-6, IL-8, chemokine CCL-2, CCL-3, and CCL-4 [
      • Ko E.J.
      • Kang S.M.
      Immunology and efficacy of MF59-adjuvanted vaccines.
      ]. The adjuvant can activate the Toll-Like Receptor (TLR) that per se prompts nuclear factor kappa B (NF-κB) phosphorylation. NF-κB is a transcription factor of up to 1500 inflammatory genes, including cytokines and chemokines. These molecules supply T and B cells with adequate stimuli to recognize their specific antigen and initiate clonal activation. In MS patients, these inflammatory molecules can interfere with control over self-reacting clones and activate unrelated lymphocytes, something that is called bystander activation [
      • Amaral M.P.
      • Branco L.M.
      • Strasser A.
      • Dixit V.M.
      • Bortoluci K.R.
      Paradise revealed III: why so many ways to die? Apoptosis, necroptosis, pyroptosis, and beyond.
      ,
      • Taniguchi K.
      • Karin M.
      NF-κB, inflammation, immunity and cancer: coming of age.
      ]. In this way, clonal expansion occurs, and the disease relapses.
      Despite the fact that these relapses were temporally associated with vaccine administration, with current studies, it is impossible to disentangle post-vaccination relapses from the relapses that would have manifested regardless of COVID-19 vaccination [
      • Nistri R.
      • Barbuti E.
      • Rinaldi V.
      • Tufano L.
      • Pozzilli V.
      • Ianniello A.
      • et al.
      Case report: multiple sclerosis relapses after vaccination against SARS-CoV2: a series of clinical cases.
      ]. In a study on 555 MS patients, 2.1% of patients receiving the first dose and 1.6% with the second dose experienced relapses; however, no difference in the relapse rate was highlighted when the results were compared to previous years [
      • Achiron A.
      • Dolev M.
      • Menascu S.
      • Zohar D.-N.
      • Dreyer-Alster S.
      • Miron S.
      • et al.
      COVID-19 vaccination in patients with multiple sclerosis: What we have learnt by February 2021.
      ]. This study was limited to a short follow-up period and therefore its results should be interpreted with caution. More studies are warranted to show a causal association.
      Overall, the COVID-19 vaccination may trigger relapses in some MS patients but as the infection itself can stimulate relapse, the benefit of vaccination outweighs its risk in this population, and mass vaccination against COVID-19 especially in MS patients should be continued and encouraged [
      • Diem L.
      • Friedli C.
      • Chan A.
      • Salmen A.
      • Hoepner R.
      Vaccine hesitancy in patients with multiple sclerosis: preparing for the SARS-CoV-2 vaccination challenge.
      ]. In the meanwhile, most of the relapsed cases were fully recovered after receiving methylprednisolone showing the relapse can be controlled without consequences [
      • Etemadifar M.
      • Sigari A.A.
      • Sedaghat N.
      • Salari M.
      • Nouri H.
      Acute relapse and poor immunization following COVID-19 vaccination in a rituximab-treated multiple sclerosis patient.
      ,
      • Nistri R.
      • Barbuti E.
      • Rinaldi V.
      • Tufano L.
      • Pozzilli V.
      • Ianniello A.
      • et al.
      Case report: multiple sclerosis relapses after vaccination against SARS-CoV2: a series of clinical cases.
      ,
      • Fragoso Y.D.
      • Gomes S.
      • Gonçalves M.V.M.
      • Mendes Junior E.
      • Oliveira B.E.S.
      • Rocha C.F.
      • et al.
      New relapse of multiple sclerosis and neuromyelitis optica as a potential adverse event of AstraZeneca AZD1222 vaccination for COVID-19.
      ,
      • Łagosz P.
      • Biegus J.
      • Gruszka E.
      • Zymliński R.
      The surprising course of multiple sclerosis relapse in a patient after SARS-CoV-2 vaccination.
      ,
      • Maniscalco G.T.
      • Manzo V.
      • Di Battista M.E.
      • Salvatore S.
      • Moreggia O.
      • Scavone C.
      • et al.
      Severe multiple sclerosis relapse after COVID-19 vaccination: a case report.
      ].

      Funding

      We do not have any financial support for this study.

      Ethical approval

      Since the data in this paper were obtained from the PPMI database (ppmi.loni.usc.edu), it does not include any research involving human or animal subjects.

      Availability of data and material

      The datasets analyzed during the current study are available upon request with no restriction.

      Consent for publication

      This manuscript has been approved for publication by all authors.

      Author contributions

      All the authors listed in the manuscript have participated actively in preparing the final version of this case report.

      Declaration of Competing Interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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