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Corresponding author at: Associate Professor, Department of Neurology, Faculty Block First Floor, Behind Neurocenter, National Institute of Mental Health And Neurosciences, Bangalore 560029.
We retrospectively reviewed neurologic syndromes in temporal association with COVID-19 vaccination.
•
The spectrum comprised CNS demyelination, Guillain Barre syndrome, stroke, encephalitis and myositis.
•
Female sex had a greater pre-disposition.
•
Majority of neurologic events occurred after the first dose (79.3%).
•
Majority of the patients had favourable clinical outcome at discharge.
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The incidence of adverse events following COVID-19 vaccination is low and hence the benefits outweigh the risk.
Abstract
Background
Recent studies have shown various neurological adverse events associated with COVID-19 vaccine.
Objective
We aimed to retrospectively review and report the neurological diseases temporally associated with COVID-19 vaccine.
Methods
We performed a retrospective chart review of admitted patients from 1st February 2021 to 30th June 2022. A total of 4672 medical records were reviewed of which 51 cases were identified to have neurological illness temporally associated with COVID-19 vaccination.
Results
Out of 51 cases, 48 had probable association with COVID-19 vaccination while three had possible association. Neurological spectrum included CNS demyelination (n = 39, 76.5 %), Guillain-Barré-syndrome (n = 3, 5.9 %), stroke (n = 6, 11.8 %), encephalitis (n = 2, 3.9 %) and myositis (n = 1, 2.0 %). Female gender had a greater predisposition (F:M, 1.13:1). Neurological events were more commonly encountered after the first-dose (n = 37, 72.5%). The mean latency to onset of symptoms was 13.2 ± 10.7 days after the last dose of vaccination. COVIShield (ChAdOx1) was the most commonly administered vaccine (n = 43, 84.3 %). Majority of the cases with demyelination were seronegative (n = 23, 59.0 %) which was followed by anti-Myelin oligodendrocyte-glycoprotein associated demyelination (MOGAD) (n = 11, 28.2 %) and Neuromyelitis optica (NMOSD) (n = 5, 12.8 %). Out of 6 Stroke cases, 2 cases (33.3 %) had thrombocytopenia and coagulopathy. At discharge, 25/51 (49.0 %) of the cases had favourable outcome (mRS 0 to 1). Among six patients of stroke, only one of them had favourable outcome.
Conclusion
In this series, we describe the wide variety of neurological syndromes temporally associated with COVID-19 vaccination. Further studies with larger sample size and longer duration of follow-up are needed to prove or disprove causality association of these syndromes with COVID-19 vaccination.
In the recent years the world has witnessed an unprecedented challenge of the Coronavirus disease 2019 (COVID19) pandemic caused by a beta coronavirus, the novel severe acute respiratory syndrome coronavirus2 (SARS-CoV2). Vaccination against this virus has emerged as one of the most efficient armours in curbing the pandemic. Several candidate vaccines have been tried and tested in clinical trials. (Refer to Table 1). As of 25th March 2022, a total of 153 candidate vaccines are undergoing various phases of clinical trials, whereas 196 candidates are in pre-clinical development. [
] Based on variations in core ingredients and delivery systems, several types of vaccines such as mRNA-1273, viral vector replicating (VVr), viral vector non-replicating(VVnr), inactivated virus, live attenuated, protein subunit, DNA, virus-like particle, Bacterial antigen-spore expression vector, Despite their efficacy, the adverse events following vaccination have also been seen. [
McDonald I, Murray SM, Reynolds CJ, Altmann DM, Boyton RJ. Comparative systematic review and meta-analysis of reactogenicity, immunogenicity and efficacy of vaccines against SARS-CoV-2. npj Vaccines [Internet]. 2021;6(1). Available from: http://dx.doi.org/10.1038/s41541-021-00336-1.
] Many databases including Vaccine Adverse Event Reporting System (VARES), and VigiBase have been dedicated to report these adverse events. A large spectrum indeed has been detected so far. In line with rheumatological, hematological, and cardiac adverse events, neurological complications following COVID19 vaccination have also been witnessed. [
Garg RK, Paliwal VK. Spectrum of neurological complications following COVID-19 vaccination [Internet]. Vol. 43, Neurological Sciences. Springer International Publishing; 2022. 3–40 p. Available from: https://doi.org/10.1007/s10072-021-05662-9.
Approved in India, Total vaccine doses administered as on 26/03/22 is 1,50,80,58,152
BBV152
Covaxin
Inactivated vaccine
Bharat Biotech, ICMR; Ocugen; ViroVax
Approved in India, Total vaccine doses administered as on 26/03/22 is 30,52,68,845
rAd26 and rAd5
Sputnik V
Recombinant adenovirus vaccine
Gamaleya Research Institute, Acellena Contract Drug Research and Development
Approved in India, Total vaccine doses administered as on 26/03/22 is 12,21,106
Corbevax
Corbevax
Adjuvanted protein subunit vaccine
Biological E, Baylor College of Medicine, Dynavax, CEPI
Approved in India, Total vaccine doses administered as on 26/03/22 is 1,20,88,254
BNT162b2
COMIRNATY
mRNA-based vaccine
Pfizer, BioNTech, Fosun Pharma
Approved in India
ZyCoV-D
ZyCoV-D
DNA vaccine (plasmid)
Zydus Cadila
Approved in India
mRNA-1273
Spikevax
mRNA-based vaccine
Moderna, BARDA, NIAID
Approved in India
rAd26
Sputnik Light
Recombinant adenovirus vaccine
Gamaleya Research Institute, Acellena Contract Drug Research and Development
Approved in India
NVX-CoV2373
Covovax (India), TAK-019(Japan) Nuvaxovid,
Prefusion protein recombinant nanoparticle vaccine
Novavax; CEPI, Serum Institute of India
Approved in India
Sinopharm COVID-19 Vaccine (BBIBP-CorV)
BBIBP-CorV/NVSI-06–07
Inactivated vaccine
Beijing Institute of Biological Products; China National Pharmaceutical Group (Sinopharm)
EpiVacCorona/ (Aurora-CoV)
EpiVacCorona
Peptide vaccine
Federal Budgetary Research Institution State Research Center of Virology and Biotechnology
JNJ-78436735; Ad26.COV2.S
Janssen
Non-replicating viral vector
Janssen Vaccines (Johnson & Johnson)
CoviVac
CoviVac
Inactivated vaccine
Chumakov Federal Scientific Center for Research and Development of Immune and Biological Products
ZIFIVAX
ZF2001
Recombinant vaccine
Anhui Zhifei Longcom Biopharmaceutical, Institute of Microbiology of the Chinese Academy of Sciences
QazCovid-in
QazVac
Inactivated vaccine
Research Institute for Biological Safety Problems
CoronaVac (formerly PiCoVacc)
CoronaVac
formalin-inactivated and alum-adjuvanted vaccine
Sinovac
Convidicea (Ad5-nCoV)
Ad5-nCoV /PakVac
Recombinant vaccine (adenovirus type 5 vector)
CanSino Biologics
WIBP-CorV
WIBP-CorV
Inactivated vaccine
Wuhan Institute of Biological Products; China National Pharmaceutical Group (Sinopharm)
COVIran Barekat
COVIran Barekat
Inactivated vaccine
Shifa Pharmed Industrial Group
CIGB 66
Abdala
Protein subunit vaccine
Center for Genetic Engineering and Biotechnology
Soberana 02/Soberana Plus
Soberana 02/Soberana Plus
Conjugate vaccine
Finlay Institute of Vaccines; Pasteur Institute
MVC-COV1901
MVC-COV1901
Protein subunit vaccine
Medigen Vaccine Biologics Corp.; Dynavax
COVAX-19
Spikogen
Monovalent recombinant protein vaccine
Vaxine Pty ltd.; CinnaGen
FAKHRAVAC (MIVAC)
FAKHRAVAC (MIVAC)
Inactivated vaccine
The Stem Cell Technology Research Center; Organization of Defensive Innovation and Research
Turkovac (ERUCOV-VAC)
Turkovac (ERUCOV-VAC)
Inactivated vaccine
Health Institutes of Turkey
Covifenz (CoVLP)
Covifenz (CoVLP)
Plant-based adjuvant vaccine
Medicago; GSK; Dynavax
VLA2001
Valneva;UK National Institute for Health Research; Dynavax
Inactivated vaccine
France, United States
Noora
Noora
Recombinant protein vaccine
Baqiyatallah University of Medical Sciences
As per government of India database (Co-WIN), till 28th February 2022, a total of 1,48,26,49,754 doses of AstraZeneca, Covishield (ChAdOx-1) and 28, 80, 80,355 doses of COVAXIN (BBV152) was administered.
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Association of COVID-19 vaccines ChAdOx1 and BNT162b2 with major venous, arterial, or thrombocytopenic events: A population-based cohort study of 46 million adults in England.
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Chen S, Fan X-R, He S, Zhang J-W, Li S-J. Watch out for neuromyelitis optica spectrum disorder after inactivated virus vaccination for COVID-19. Neurol Sci [Internet]. 2021;42(9):3537–9. Available from: https://doi.org/10.1007/s10072-021-05427-4.
Arnao V, Maimone MB, Perini V, Giudice G Lo, Cottone S. Bilateral optic neuritis after COVID vaccination. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2022. p. 1–2.
Cellina M, D’Arrigo A, Floridi C, Oliva G, Carrafiello G. Left Bell’s palsy following the first dose of mRNA-1273 SARS-CoV-2 vaccine: A case report. Clin Imaging [Internet]. 2022;82(November 2021):1–4. Available from: https://doi.org/10.1016/j.clinimag.2021.10.010.
Mussatto CC, Sokol J, Alapati N. Bell’s palsy following COVID-19 vaccine administration in HIV+ patient. Am J Ophthalmol Case Reports [Internet]. 2022;25(November 2021):101259. Available from: https://doi.org/10.1016/j.ajoc.2022.101259.
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Parrino D, Frosolini A, Gallo C, De Siati RD, Spinato G, de Filippis C. Tinnitus following COVID-19 vaccination: report of three cases. Int J Audiol [Internet]. 2021;0(0):1–4. Available from: https://doi.org/10.1080/14992027.2021.1931969.
Jeong J, Choi HS. Sudden sensorineural hearing loss after COVID-19 vaccination. Vol. 113, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 2021. p. 341–3.
Moslemi M, Ardalan M, Haramshahi M, Mirzaei H, Sani SK, Dastgir R, et al. Herpes simplex encephalitis following ChAdOx1 nCoV-19 vaccination: a case report and review of the literature. BMC Infect Dis [Internet]. 2022;22(1):22–5. Available from: https://doi.org/10.1186/s12879-022-07186-9.
Al-Mashdali AF, Ata YM, Sadik N. Post-COVID-19 vaccine acute hyperactive encephalopathy with dramatic response to methylprednisolone: A case report. Ann Med Surg [Internet]. 2021;69(August):102803. Available from: https://doi.org/10.1016/j.amsu.2021.102803.
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Coincidental Onset of Ocular Myasthenia Gravis Following ChAdOx1 n-CoV-19 Vaccine against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).
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Moyamoya disease with Sjogren disease and autoimmune thyroiditis presenting with left intracranial hemorrhage after messenger RNA-1273 vaccination: A case report.
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]. While the temporal relation of these adverse events to vaccination were observed, most of the reports couldn’t establish causality.
The type of vaccine and dosing have differed significantly in different parts of the world. The World Health Organization (WHO) has approved nine vaccines so far, while the United States Food and Drug Administration (US-FDA) and European Medicines Agency (EMA) have approved two and five vaccines respectively. The safety and side effect profiles of the individual vaccines are expected to show variation since they are biologically different compounds. [
] Many observations have shown the neurological complications in different populations with different types of COVID19 vaccines. India’s vaccination drive against COVID19 is mostly based on two types of vaccines, i.e. AstraZeneca, Covishield (ChAdOx-1), and COVAXIN (BBV152). As per the government of India database (Co-WIN), till 28th February 2022, a total of 1,482,649,754 doses of AstraZeneca, Covishield (ChAdOx-1), and 28 8,0 80,355 doses of COVAXIN (BBV152) was administered. [
Based on this backdrop, we present here a series of 51 cases with various vaccine associated neurological disorders (VAN), temporally associated with vaccination against SARS-CoV2. For delineating the spectrum of the same, we also performed a systematic review of the available medical literature. The proposed hypotheses were reviewed, in accordance of which, the underlying pathophysiological mechanisms were highlighted.
2. Patients and methods
The study was conducted in a tertiary care hospital in India. Retrospective analysis of medical records of all patients who presented to the outpatient, inpatient or emergency services between 1st February 2021 and 30th June 2022 was done for identifying cases with VAN.
Recruitment of patients were conducted in two steps. As a first step, cases with any neurological illness, with a history of a recent vaccination against SARS-CoV2 (i.e. within 6 weeks of onset of the first symptom of neurological disorder), not otherwise explained by any alternate etiology [
Organization WH. Extract from report of GACVS meeting of 30 November-1 December 2016, published in the WHO Weekly Epidemiological Record on 13 January 2017 [Internet]. Available from: https://www.who.int/groups/global-advisory-committee-on-vaccine-safety/topics/yellow-fever-vaccines/campaigns.
] were segregated and then based on the following inclusion and exclusion criteria cases were selected.
Inclusion criteria comprised patients with a new onset neurological syndrome with a) history of first or second or booster dose of COVID-19 vaccination by any route or type, approved in India, b) the last dose of vaccination not beyond 6 weeks (42 days) (as per World Health Organization Global Advisory Committee on Vaccine safety- WHO GACVS) [
Organization WH. Extract from report of GACVS meeting of 30 November-1 December 2016, published in the WHO Weekly Epidemiological Record on 13 January 2017 [Internet]. Available from: https://www.who.int/groups/global-advisory-committee-on-vaccine-safety/topics/yellow-fever-vaccines/campaigns.
], and c) no history of any proven or radiologically suspected COVID-19 infection irrespective of severity, in the past 3 months. Patients with a) history of receipt of any other (non-SARSCoV2) vaccination in the past 6 weeks, b) presence of an alternate diagnosis, c) pre-existing active neurological disease, and d) relapse of a pre-existing neurological syndrome were excluded. Data were extracted with regards to the demographics, clinical examination findings as evaluated by a consultant neurologist, the type, dosing and route of COVID-19 vaccine, investigations, treatment strategies and clinical outcome. The details of investigations including lumbar puncture for cerebrospinal fluid (LP-CSF) analysis, serum with or without CSF anti-Aquaporin 4 antibody i.e. neuromyelitis optica (NMO) antibodies, myelin oligodendrocyte glycoprotein (MOG) antibodies (testing done with IgG1), creatinine phosphokinase (CPK), C- reactive protein (CRP), erythrocyte sedimentation rate (ESR), magnetic resonance imaging (MRI) of the brain and/or spine, muscle MRI, nerve conduction studies, electromyography, evoked potentials including brainstem auditory evoked response (BAER), visual evoked potentials (VEP), somatosensory evoked potential (SSEP), serum and CSF autoimmune antibody profile (NMDA, VGKC, LGI-1, CASPR, GABA-A/B), serum antinuclear antibodies (ANA) profile, antineutrophil cytoplasmic antibodies (ANCA), serum myositis panel, and serum paraneoplastic antibody profile were considered. Other relevant investigations for the exclusion of alternative etiologies were recorded. (Refer to supplementary appendix).
In the second step, the cases were selected for analysis based on the causality label. This was done by two independent authors (SMM, SV) who were blinded to the study design. All selected cases in step 1 were subjected to the proposed criteria for casualty labelling as per the criteria proposed by Butler et al. [
Considerations for causality assessment of neurological and neuropsychiatric complications of SARS-CoV-2 vaccines: from cerebral venous sinus thrombosis to functional neurological disorder.
] Accordingly, the cases were categorized to probable, possible and unlikely to be casually related to post-vaccination neurological complication. Only probable and possible cases were included for further analysis, whereas cases with “unlikely” causality association were excluded. Our retrospective recruitment strategy identified some cases of demyelination temporally associated with COVID-19 vaccination which were previously published from the institute (cases 1, 2, 6, 8, 10, 11, 13–15, 16, 17, 20–37). [
] In order to encompass the entire spectrum of COVID-19 vaccine related neurological complications, these cases were included. The cases were reported in accordance with consensus-based clinical case reporting (CARE) guidelines. [
]. Informed consent and ethical committee approval were obtained. A scoping review was done for all published articles pertaining to neurological manifestations following COVID vaccination using PUBMED, SCOPUS, EMBASE, Google Scholar, Ovid and MedRxiv till June 2022.
3. Statistical analysis
In the descriptive statistics, categorical variables were denoted as frequency with percentage while the continuous variables were expressed as median ± IQR and mean ± SD. The categorical variables in multiple groups were analysed with χ2tests to look for any significant difference overall between the groups. If found significant, Fisher exact test was used to compare the two individual subgroups. The quantitative variables, in the three independent demyelination subgroups were tested for significance using one way ANOVA. If found significant, post-hoc analysis was done between the individual groups. A p value of < 0.05 was considered to be statistically significant. Inter-rater reliability was assessed using Cohen’s kappa.IBM-SPSS Version 26 was used for the computation of these statistics.
4. Results
In the given timeframe a total of 4672 medical records were reviewed, out of which 109 cases were identified. Subsequently, 51 cases (probable, n = 48 and possible, n = 3) were included as per casuality assessment based on the criteria by Butler et al by two independent authors SMM and SV Cohen’s kappa was 0.73 and inter-rater agreement was 86.24 %. Amongst these 51 patients, CNS demyelination (n = 39, 76.5 %) was the most common. This was followed by three cases of GBS (5.9 %), six cases of stroke (11.8 %), two cases (3.9 %) of encephalitis and a single case of myositis (Table 2, Table 3). Female sex was slightly higher than the male counterpart (F:M, 1.13:1). The mean (±SD) age was 40.1 ± 14.5 years. Majority of the patients belonged to the age group between 25 and 45 years (26, 51.0 %). Majority of the patients received ChAdOx-1 nCoV (COVIShield) vaccine (n = 43, 84.3 %) while the rest of the patients received BBV152 (COVAXIN) (n = 8, 15.7 %). The frequency of neurological complications was higher after the first dose (n = 37, 72.5 %) as compared to the second dose (n = 14, 27.5 %). The latency to the onset of neurological symptoms was 14 (IQR 5.5 to 15) days from the first dose and 12 (IQR 3.3 to 14) days from the second dose. Overall, the latency was 13.2 ± 10.7 days from the last dose of vaccination. Majority of the patients presented in the second week after vaccination (n = 20, 39.2 %).
Table 2Enumerates the clinical details of the cases.
Demyelination
Serial No
Age(years)
Gender
Presenting Complaints
Total Duration (days) of Illness
Type of Vaccine/dose
Interval from last vaccination to the onset of first neurological symptoms
Examination finding
Investigations
Diagnosis
Treatment
Prognosis
Causality label$
1
35
F
Body ache, headache, vomiting followed by altered sensorium and, inability to walk, excessive sleepiness and bladder retention. Known case of well controlled T2DM
10
ChAdOx-1/1st dose
9 days
Hypotonia in both lower limbs and lower limb power 2/5 with biceps, supinator and triceps hyperreflexia and knee and ankle hyporeflexia and left extensor plantar.
CRP, RA factor, ANA profile and ANCA- negative. LP-CSF: Cells- 58/hpf cells (50 L),protein- 47 mg/dl. VEP b/l and BAER, SSEPs – Normal. MRI of Brain and spine T2/FLAIR hyperintensities in mid brain, pons, left MCP, bilateral posterior internalcapsule, thalamus, bilateral centrum semiovale and longitudinally extensive transverse myelitis involving cervical cord and conus. Serum MOG was positive
MOGAD
IV MP (1gm) * 7daysFollowed Mycophenolate mofetil maintenance
CRP, RA factor, ANA profile and ANCA- negative. LP-CSF: Cells- 4/hpf cells (2 L),protein- 26.6 mg/dl. VEP- right eye prolonged P100 and BAER, SSEPs – Normal. MRI of Brain suggestive of right optic neuritis. Serum and CSF aNTI-AQ-4 ANTIBODY and MOG – Negative
Seronegative Optic neuritis
IV MP (1gm) * 5 days followed by oral prednisolone gradual tapering
Improved (mRS = 0)
Probable
3
27
F
Hiccups and vomiting, tingling numbness in all four limbs and decreased sensation over trunk and lower limbs, weakness in left upper and lower limbs, weakness in right upper limb and lower limb, spasms and pain in right upper limb and lower limb and neck
80
BBV152/1st dose
17 days
Right hemiparesis, Tone:- Tone increased in right upper and lower limbsRight upper and lower limb flexor spam present every 30 min. Right Biceps, triceps,knee,ankle jerks brisk, plantar no response b/l. Sensory- Touch, vibration, JPS impaired b/l Ul and LL.
ESR, and CRP – Elevated. LP-CSF: cells-2(lymphocytes-100 %) protein-23.8 mg/dlSSEP showed absence of wave forms. MRI of Brain and spine – s/o cervical myelitis and medullary involvementSerum aNTI-AQ-4 ANTIBODY – Strongly positive.
NMOSD
LVPP*5 cylcles f/bRituximab
Improved (mRS = 1)
Probable
4
38
M
Urinary incontinence, and weakness in all 4 limbs. Known case of well controlled T2DM
4
ChAdOx-1/1st dose
14 days
Quadriparesis with brisk DTRs andsensory loss over V3 division of trigeminal nerve bilaterally, trunk (till C4 level) and all 4 limbs.
LP-CSF- 370 cells (80 percent neutrophils and 20 percent lymphocytes), protein 174 mg/dl. CSF OCB is positive, serum OCB is negative. ACE, RA factor, ANA profile and ANCA- negative. MRI of Brain and spine – longitudinally extensive transverse myelitis from cervico-medullary junction upto D1 and hyper intensity in left middle cerebellar peduncle and pons. Serum aNTI-AQ-4 ANTIBODY and MOG – Negative
Seronegative CNS demyelination
IV MP (1gm) * 5 days followed by PLEX * 7 cycles followed by Rituximab
Mild Improvement (mRS = 2)
Probable
5
54
M
Tingling paresthesia of right Lower limb and associated with transient tonic posturing of right upper limb lasting for seconds.
6
ChAdOx-1/1st dose
14 days
Tone and power normal, brisk DTRs and flexor plantar response. Sensory examination normal.
MRI of Brain and spine – symmetrical T2/FLAIR hyperintensities in b/l corticospinal tract and, cerebral peduncles and middle cerebellar peduncle. Serum aNTI-AQ-4 ANTIBODY and MOG – Negative
Seronegative CNS demyelination
Symptomatic management of paresthesia and antiepileptic
Improved (mRS = 0)
Probable
6
36
F
Tingling parasthesia in both lower limbs,weakness of both lower limb and urinary symptoms
20
ChAdOx-1/2nd dose
32 days
Hypotonia with sluggish DTRs in lower limb and lower limb power 0–1/5, sensory loss till D4.
CRP, RF, ANA, ANCA and Paraneoplastic profile -negative. LP-CSF: 720 cells (lymphocytes-580, polymorphs-20, degenerated cells-120), elevated protein (144 mg/dl), elevated lactate (32 mg/dl) and normal glucose. VEPwas absent in right eye and prolonged in left eye. SSEP- absent wave forms LL and prolonged in UL. MRI of Brain and spine – longitudinally extensive transverse myelitis predominantly involving central and posterior cord sparing anterior part extending from obex till conus with cord swelling with left optic neuritis. Serum MOG – Positive
MOGAD
IV MP (1gm) * 5 days followed by PLEX * 7 cycles
Improved (mRS = 1)
Probable
7
30
M
Pain in the right eye and diminution of vision,and pain in left eye and diminution of vision.
13
ChAdOx-1/1st dose
14 days
Right RAPD was present. Right eye perception on light was absent. Left eye 6/60.Fundus showed bilateral papilledema grade 3 (right more than left)
ANA profile and ANCA were negative. Serum NMO MOG panel was negative. Viral markers were negative. CSF analysis showed 1 cell with normal protein. Evoked potentials showed bilateral absence of P100 and BAER and SSEP were normal. MRI brain showed optic nerves hyperintensities bilaterally with volume loss more on left side. MRI spine screening was normal.
Bilateral Optic neuritis
LVPP*5 cylcles f/b1gm IVMP*2 days f/b oral steroid and Rituximab
No improvement (mRS = 5)
Probable
8
50
F
Tingling paresthesia and both upper and right lower limbs weakness. Known case of hypothyroidism on treatment.
10
ChAdOx-1/1st dose
28 days
Right lower limb power 3–4/5, spastic and DTRs in right side, Knee and ankle jerks are brisk with right extensor plantar
ANA profile – PCNA 1 +.LP-CSF: Cells- 2/hpf cells (2 L),protein- 28.3 mg/dl. MRI of spine C7 level short segment T2/FLAIR hyperintensities. Serum aNTI-AQ-4 ANTIBODY and MOG – Negative
Short segment transverse myelitis
Oral prednisolone and mycophenolate mofetil
Improved (mRS = 1)
Probable
9
44
M
Imbalance while walking and vomiting, acute urinary retention, band like sensation and double vision
12
ChAdOx-1/1st dose
13 days
Quadriparesis with brisk DTRs andsensory loss over V3 division of trigeminal nerve bilaterally, trunk (till C4 level) and all 4 limbs.
LP-CSF: Lymphocytic pleocytosis with elevated proteinMRI of Brain and spine – T2/FLAIR long segment non expansile hyperintensities in the cervical and dorsal cord and conus medullaris with involvement of 2/3rd cross sectional area of cord. Serum SARS-CoV2 S1,S2 (IgG&IgM)- PositiveSerum MOG – Positive
MOGAD
IV MP (1gm) * 5 days followed by Mycophenolate mofetil
Improved (mRS = 0)
Probable
10
38
M
Vertigo, double vision on looking left, Imbalance while walking and blurring of vision in Right eye with Headache
26
ChAdOx-1/1st dose
6 days
Pupils:3 mm equal and reactiveV/A- 6/9 in RE, 6/6 in LEFundus – NormalEOM: fullGaze evoked horizontal and torsional nystagmus.
CRP,RF, ANA profile and ANCA- Negative. LP-CSF- Traumatic tap. MRI of Brain and spine – patchy areas of demyelination in left MCP, right corona radiata with T2/FLAIR hyperintensity in right vestibular apparatus. VEP- Prolonged P100 latency and low amplitude BAER waveforms. Serum aNTI-AQ-4 ANTIBODY and MOG – Negative
CNS demyelination with Vestibulopathy
IVMP 1gm *5 days f/b oral steroid
Mild Improvement(mRS = 2)
Probable
11
53
F
Paresthesia of both lower limb, urinary hesitancy, paresthesia and tightness of both upper limbs over trunk,and band like sensation over chest. Known case of medically controlled hypertension since 1 year.
12
ChAdOx-1/2nd dose
1 day
Fine touch reduced bilaterally from toes to epigastrium and in bilateral medial part of forearm and middle and little fingersPain: decreased bilaterally from toes to epigastriumVibration: Absent on both sides till knee. Joint position sense: Absent in great toes, thumbs on both sides. Plantar: Bilateral extensor. Rhomberg s: Positive
ACE levels, ANA Profile, ANCA, CRP, RA Factor- Negative. LP-CSF showed 6 cells, 57 mg/dl protein. Serum anti-recoverin- Positive. MRI of Brain and spine – T2/FLAIR hyper-intensities in the bilateral periventricular white matter, bilateral insula and bilateral cerebellar hemispheres. Few short segment expansive T2 hyperintensities are noted in the cervical cordat C5,6,7 levels and dorsal cord at D6-7 level with involvement of central cord. SARS-CoV2 S1,S2 (IgG&IgM)- PositiveSerum and CSF aNTI-AQ-4 ANTIBODY and MOG – Negative
CNS demyelination
IVMP 1gm *5 days f/b oral steroid
Mild Improvement (mRS = 1)
Probable
12
35
F
Blurring of vision of both eyes, walking difficulty, mild pain thorax and breathing problem in supine position.
20
ChAdOx-1/2nd dose
14 days
Visual acuity-bilateral 6/9. E.O.M.-full. Pupils-bilateral 3 mm,pupils equally reactive to light. Lower limb power 3–4/5, Sensory-90 percent loss of pain,touch,temperature in bilateral lower limbs,bilateral upper limbs. 100 percent pain,touch,temperature sensation present in right side of face. Joint,position sensation, and vibration impaired in bilateral lower limbs.
ESR-raised, CRP,ANA-Negative. LP-CSF: cells-17(all lymphocytes), protein-64 mg/dlV.E.P.-left(P100-115.8), right(P100-125.7),prolonged S.S.E.P inlower limb(P37-43),normal S.S.E.P. in upper limb(N20-19.3)and normal value of ABR. MRI of Brain and spine – few short segment T2 hyperintensities in thecervical (C2-3 level) and dorsal cord (D1 to D3) with patchy heterogeneous enhancement. Posterior intra-orbital segment of bilateral optic nerves, optic chiasm and the bilateral proximal optic tracts also showed T2/ FLAIR hyperintensity with patchy contrast enhancement along with signal change in the hypothalamus, left trigeminal nerve (root entry zone and cisternal segment), right lateral medulla extending to the cervicomedullary junction. Serum aNTI-AQ-4 ANTIBODY and MOG – NegativeCSF OCB- Pattern 4.
Bilateral Optic Neuritis and Brainstem demyelination
LVPP*5 cylcles f/b1gm IVMP*5 days f/b oral steroid and Rituximab
Improved (mRS = 0)
Probable
13
30
F
Shock like sensation on flexing the neck and tingling paraesthesia of B/l hand
3 months
ChAdOx-1/2nd dose
15 days
Tone- Normal. Power-normal in U/L and L/L including intrinsic muscles of handReflexes −2Plantar bilateral- flexorSensory system −40 percent reduction in sensation to touch over both palms.
ESR-68 mm, ACE,RA, ANA profile-negativeMRI of Brain and spine – T2 hyperintensities short segment at C3 level. Evoked potentials are normal. Serum SARS-CoV2 S1,S2 (IgG&IgM)- Positive. CSF OCB- Positive. Serum aNTI-AQ-4 ANTIBODY and MOG – Negative
Seronegative CNS demyelination
LVPP*5 cylcles f/b1gm IVMP*5 days f/b oral steroid
Improved (mRS = 0)
Probable
14
26
F
Weakness of bilateral lower limbs,sensory loss below the chest, urinary retention, weakness and paresthesias of both upper limbs
4
BBV152/1st dose
5 days
Quadriparesis Sensory examination – absent sensation to touch and pin prick below T4 Level. JPS and vibrationimpaired in lower limbs. DTRs – upper limb 2, lower limbs absent
ANCA, RA factor, and CRP – negative. ANA profile – anti PCNA strongly positive. LP-CSF: cells-207(lymphocytes-40 %, PMN-60 %), protein-95.8 mg/dlSSEP showed absence of wave forms. MRI of Brain and spine – long egment transverse myelitis from cervical region to lower lumbar region. Serum aNTI-AQ-4 ANTIBODY and MOG – Negative
Seronegative CNS demyelination
LVPP*5 cylcles f/b1gm IVMP*5 days f/b oral steroid
Improved (mRS = 2)
Probable
15
27
F
Pain in left upper and lower limb and right lower limb, headache, weakness of left upper and lower limb and right lower limb
30
ChAdOx-1/ 1st dose
5 days
MotorGrade 1 spasticity in left upper limbPower- 5/5Tendon reflexes- 3Plantars- Bilaterally flexorSensory- Touch, pain, joint position sense- Normal
ANA profile, ANCA, ACE – negative. LP-CSF: cells-0, protein-27.7 mg/dlMRI Brain – multifocal mildly expansile discrete T2 heterogeneously hyperintense lesions without FLAIR suppression in periventricular white matter along lateral ventricles, subcortical -deep white matter of bilateral frontal -parietal – temporal lobes, right caudate nucleus body, right PLIC -adjacent thalamus. Larger lesion in bilateral corona radiata show peripheral diffusion restriction and peripheral thin rim of blooming on SWI. Post contrast enhancementin few lesions in bilateral periventricular -deep white matter. Serum aNTI-AQ-4 ANTIBODY and MOG – Negative
Acute disseminated encephalomyelitis(ADEM)
IVMP 1gm*5 days f/b oral steroid
Improved (mRS = 2)
Probable
16
45
F
Bilateral visual loss
4
ChAdOx-1/ 1st dose
5 days
VA- Bilateral lowMotor, sensory, cerebellar- normal
RA factor, and ANA profile – negativeLP-CSF: cells-2(lymphocytes-100 %), protein-52.3 mg/dlVEP- b/l prolonged P100. CSF OCB- Negative. MRI of Brain and spine – No significant signal changes. Serum MOG – Positive
MOGAD
LVPP*5 cylcles f/b1gm IVMP*5 days f/b mycophenolate mofetil
Improved (mRS = 1)
Probable
17
20
F
Double vision
5
ChAdOx-1/1st dose
3 days
Brisk DTRs and mild spatic lower limbs.
CRP, RA factor, ANA profile and ANCA- negative. MRI of Brain multple discrete T2/FLAIR hyperintensities in pericallosal, callosal and frontal regions. Serum aNTI-AQ-4 ANTIBODY and MOG – Negative
Seronegative CNS demyelination
IV MP (1gm) * 5 days followed by oral prednisolone gradual tapering
Improved (mRS = 0)
Probable
18
55
F
Right lower limb pain and weakness and then after 2 month paresthesia left lower limbKnown case of medically controlled T2DM
60
ChAdOx-1/ 1st dose
2 days
Pupil, EOM- fullRight hemiparesisRight UL and LL DTRs brisk
ESR (57 mm) and CRP(11 mg/L) – elevated. ANA profile – NegativeParaneoplastic profile: anti-Tr and anti-GAD65, LP-CSF: cells-2(lymphocytes-100 %), protein-28.3 mg/dlSSEP showed absence of wave forms. MRI of Brain and spine – multiple T2 hyper intensities in the cervico-dorsal spine. CT abdomen, pelvis, thorax- negative for malignancy. Serum and CSF aNTI-AQ-4 ANTIBODY and MOG – Negative
Seronegative CNS demyelination
1gm IVMP*5 days f/b oral steroid
Improved (mRS = 1)
Probable
19
16
F
Recurrent vomiting, burning sensation of both upper limbs, tremuloousness of b/l upper limbs, imbalance while walking, double vision and swallowing difficulty
90
BBV152/2nd dose
14
EOM: Bilaterally abduction, Upbeat nystagmus in all directions ofgaze. Bilateral LMN facial palsy. Trismus, jaw opening restricted. Power 4/5Cerebellar signs present b/l, DTRs brisk, plantar b/l extensorSevere gait ataxia
Serum ANA, ANCA negative. MRI brain-T2/Flair diffuse white matter hyper-intensities involving lower mid brain to C4 level of spinal cord. LP-CSF: nil cells-2, protein-28.0 mg/dl. Serum and CSF NMO was strongly positive.
NMOSD
LVPP*5 cylcles f/b1gm IVMP*5 days f/b oral steroid and Rituximab
Mild Improved (mRS = 3)
Probable
20
54
M
Imbalance, Dysarthria, weakness of both lower limbs, dysphagia
Lt VA: 6/9, Rt – 6/6. spasticquadriparesis, bilateral cerebellarsigns in UL
CSF: Lymphocytic pleocytosis with elevated protein. ANA, ANCA -negativeSerum and CSF MOGStronglypositive, MRI: T2 hyperintensities inthe cervico-dorsalcord and conus
MOGAD
Inj. MP 1 gm × 5 days 5 cycles ofLVPP T. Prednisolone 40 mg OD
Mild Improved (mRS = 2)
Probable
24
39
M
Rt eye painfollowed byblurring of vision
20
ChAdOx1nCoV- 19 /1st dose
14
RT eye-RAPD, Rt VA: Finger counting at 2 m Visual field- rightinferonasal quadrantinvolvement
H/o progressiveslurring of speechwith right upperlimb and lowerlimb weakness, followed byappearance ofswallowingdifficulty
51
ChAdOx1nCoV- 19 /1st dose
35
Spastic anarthria + Gaze restrictedleft > right Rightfacial weaknessMotor examinationhypotonicrightupper and lower limbwith 0/5 power, leftsided power-5/5,BLDTRs brisk andplantars extensor
CSF-2 CELLS,P-40.5 mg/dl,G-56 mg/dlESR-18,CRP-POSITIVEANA,ANCA-Negative, VDRL-Negative S. NMO and MOGNegativeMRI brain: tumefactivedemyelination in leftfrontal hemispherewith insularinvolvement alongwith left more thanright midbraininvolvement
H/o tingling intips of right handfollowed byprogressive imbalance whilewalking
24
ChAdOx1nCoV- 19 /2nd dose
39
V/A-6/6 BL Motorexamination: Toneincreased in rightupper limb and lower limb Power − 5/5 inall 4 limbs DTRs: normal Plantar rightextensor and leftflexor Sensorysystem- Pain andtouch decreased by10 percent in rightupper and lower limbJPS normal Vibrationnormal Rombergpositive Gait ataxic
CSF- 4 CELLS,P-23 mg/dl,G-111 mg/dl, CSF- OCB + ANA-,ANCA-,CRP-13 mg/dl,,EBV-IGG + S.NMO and MOG-NegativeMRI brain: hyperintensities in BLjuxtacortical, subcortical, periventricular whitematter, anteriortemporal lobes as wellas infratentorialregions includingpons, MCP andmedulla MRI Spine: short segment lesionsin cervical and dorsalspine
CNS Demyelination- MS
I/V MP-5 daysTab Wysolone40 mg InjRituximab
Mild Improved (mRS = 1)
Probable
38
23
F
Heaviness in the legs followed by weakness of both legs over 7 days
13
ChAdOx1nCoV- 19 /2nd dose
1
VA-Right- 6/24, Left- 6/9Power- UL 5/5, LL-0–1/5, DTRs- BriskPlantars- B/l extensorPain touch decreased below T4, JPS- impaired in LL
ANA screening positive (1:80 titres), and anti sm-RNP 2 positive. CSF −9 cells (all lymphocytes) with normal protein and glucose. Serum and CSF NMO- MOG strongly positive for NMO. MRI spine – long segment transverse myelitis in thoracic spinal cord.
NMOSD
LVPP*5 cylcles f/b1gm IVMP*2 days f/b oral steroid and Rituximab
Mild Improved (mRS = 1)
Probable
39
28
M
Right eye visual loss
12
ChAdOx1nCoV- 19 /1st dose
11
RAPD right eyeVA- right 6/36, left-6/6
LP-CSF- Normal cell and proteinMRI Brain-Intraneural T2WI-FLAIR hyperintensity noted involving right optic nerve intraconal & intracanalicular segments.
SeronegativeCNS demyelination
IVMP*5 days f/b oral steroid
Mild Improved (mRS = 1)
Probable
Guillain Barre Syndrome
40
34
F
Numbness in both upper and lower limbs, weakness in all limbs, speech disturbances and swallowing difficulty. Is a known patient of Rheumatoid arthritis since 2014. Currently asymptomatic since 2 years, not on any medication.
10
ChAdOx-1/ 2nd dose
14 days
Bifacial weakness present. tongue movements reduced. Tone: hypotonia in all 4 limbs. Quadriparesis, global areflexia
NCS- Motor axonopathyLP-CSF: Albuminocytological dissociation (cells-Nil, protein-147.0 mg/dl) LFT, RFT, Serum electrolytes, CBC, homocysteine,folate, Vit B12, thyroid function test were within normal limits. Antiganglioside antibody IgM,IgG negative. Serum Rheumatoid factor elevated (33 Iu/ml)
Guillain Barre Syndrome
LVPP * 7 cycles
Improved (mRS = 2)
Probable
41
34
F
Weakness of both lower limbs, weakness of both upper limbs and paresthesias of all 4 limbs
20
ChAdOx-1/ 2nd dose
3 days
Tone: hypotonia in all 4 limbs. Quadriparesis, global areflexia
NCS- Axonal and demyelinating neuropathyLP-CSF: Albuminocytological dissociation (cells-Nil, protein-123.6 mg/dl) ANA profile, ANCA, ACE levels and anti-ganglioside antibodies werenegative. Urine for Bence jones proteins was negative. Serum Rheumatoid factor elevated (33 Iu/ml)
Guillain Barre Syndrome
LVPP * 7 cycles f/b IVMP 1gm * 5 days
Improved (mRS = 2)
Probable
42
44
M
eakness of both upper and lower limbs, and paresthesias of all 4 limbs
10
ChAdOx-1/ 1st dose
16 days
Tone: hypotonia in all 4 limbs. Quadriparesis, global areflexia
NCS- Axonal and demyelinating neuropathyLP-CSF: Albuminocytological dissociation (cells-Nil, protein-75.7 mg/dl) ANA profile, ANCA, ACE levels and anti-ganglioside antibodies werenegative. Urine for Bence jones proteins was negative. Serum Rheumatoid factor elevated (33 Iu/ml)
Guillain Barre Syndrome
IvIg 0.4 g/kg/day * 5 days
Improved (mRS = 1)
Probable
Stroe
43
16
F
Headache followed by right upper and lower limb weakness with slurred speech
3
BBV152/1st dose
5 days
right upper and lower limbs spastic hemiparesis
MRI- acute infarcts in left MCA territory with left M1 MCA occlusionESR-51mmPlatelet-57Lakh/cmmPT,INR,aPTT-NormalANA Profile, ANCA- NegativeFasting lipid profile-Normal panelHbA1C,FBS,PPBS-NormalSickling test- NegativeCardiac evaluation-Normal
Acute ischemic stroke
Statin, antiplatelet and antioedema measures
Status quo (mRS = 3)
Probable
44
35
Headache and left upper limb and face paresthesia and weaknsess
2
ChAdOx-1/ 2nd dose
10 days
left upper and lower limbs spastic hemiparesis
MRI- venous sinus filling defect involving the anterior 2/3rd of the superior sagittal sinus and bilateral frontal and parietal infarctESR-12 mm, CRP- NegativePlatelet-376Lakh/cmmPT,INR,aPTT-NormalPCV-NormalHomocysteine, Vitamin B12-Folate- Normal. Fasting lipid profile-Normal panelHbA1C,FBS,PPBS-NormalCardiac evaluation-Normal
Cerebral Sinus Venous Thrombosis
Anticoagulation
Status quo (mRS = 3)
Probable
45
80
M
Sudden onset right upper and lower limbs weakness.
CRP-24 mg/L. Serum homocysteine- 132 umol/LVitamin B12- 50 pg/ml (low) LP-CSF: cells-14(PMN-10), protein-27.5 mg/dl. Normal sugar. HSV and other viral agents including chikunguniya, AFB staining, culture sensitivity. ANA profile, ANCA, serum and CSF autoimmune encephalitis panel, RF, creatine kinase, TFT, lipid profile, viral markers including HIV, HbSAg, HCV, VDRL were all normal or negative. Serum dengue and chikunguniya was negative. EEG showed bilateral intermittent slowing (Left more than right). MRI of Brain and spine – left temporal lobe FLAIR hyperintensity suggestive of cerebritis. Serum lactate was persistently elevated (70 mg/dl).
Possible Postvaccinal encephalitis with pre-existing possible mitochondrial cytopathy with primary hyper homocysteinemia
Acyclovir 500 mg iv TID × 7 daysCeftriaxone 1gm iv BD × 7 daysAnd Inj Methyl prednisolone 1gm iv OD × 5 daysFollowed by mitochondrial supplements and oral steroid.
Improved (mRS = 1)
Possible
50
52
F
Pain in the both lower limbs and Stiffness of both lower limbs
360
ChAdOx-1/ 22nd dose
7
Severe spasticity (grade 4) in both lower limbs(left > right) Plantar- b/l extensor
LP-CSF: nil cell, protein-26.7 mg/dl. ANA profile- anti- SS-A and AntiRo-52 positive. Serum and CSF NMO-MOG were negative. Paraneoplastic antibody- Anti GAD65 ab strongly positive. MRI Brain and Spine: Unremarkable. Whole bodyPET MRI: Normal tracer uptake
Stiff Person Syndrome
Oral steroidDiazepamBaclofen
Mild Improved (mRS = 2)
Probable
Myositis
51
58
M
Pains of both lower limbs, weakness of both lower limbs, weakness of both upper limbs.
60
BBV152/1st dose
15 days
Wasting of bilateral supraspinatus, ifraspinatus, deltoid, biceps, and triceps was noted. Tone- Hypotonia in all 4 limbs. Quadriparesis, proximal and flexor group predominant weakness in UL and LL. DTRs- Hyporeflexic
ESR was 22 mm/hr and CRP was positiveSerum Creatine kinase (CPK) was elevated (13,786 U/L at presentation). Urine routine showed 2 plus blood and myoglobin was positive. ANA profile showed anti-RO52 1plus positive. Myositis profile showed anti-SRP 3 plus positive. Muscle biopsy: polygonal to rounded, myofibers with moderate variation in fiber size and prominent features of active myopathy in the form of myonecrosis. ACR/EULAR2017: Definite myositis
Out of 39 cases with CNS demyelination majority had received ChAdOX-1 vaccine (n = 39, 76.5 %). Majority of the patients were of female sex (F:M, 1.3:1). The mean age of presentation was lower compared to that of overall age in this series (37.8 ± 12.6 years vs 40.1 ± 14.5 years). Majority of the patients belonged to the group of 25 to 45 years. (Table 2, Table 4)The median interval from the last dose to the onset of the neurological symptoms was 13 (10to14) days. Majority of the cases were vaccinated with COVIShield (ChAdOx1) vaccine (n = 35, 89.7 %). The clinical manifestations occurred after first dose in 29/39 (74.4 %) cases. Majority of the cases were seronegative (n = 23, 59.0 %) which was followed by MOGAD (n = 11, 28.2 %) and NMOSD (n = 5, 12.8 %). LETM was the most common mode of presentation (n = 19, 48.7 %). ON was the presentation in 9/39 cases (23.1 %) cases. Interestingly, none of the cases of NMOSD presented with ON. Neuroimaging showed supratentorial lesions in 16/39 (41.0 %) cases while infratentorial lesions were present in 15/39 (38.5 %) cases. (Fig. 1, Fig. 2) As per casuality labelling, all cases were found to be probable temporal association. CSF analysis revealed pleocytosis in 19/37 (77.8 %) and elevated CSF protein in 14/37 (37.8 %), respectively. Favorable mRS scores (0to1) were attained by 21/39 (81.9 %) patients at discharge. There was no significant difference with regards to the latency to presentation, investigational profile or clinical outcomes among the various demyelination subgroups. (Refer to Table 4)
Table 4Characteristics of cases with CNS demyelination.
MOGAD
NMOSD
Seronegative Demyelination
p value
Number of cases (%)
11 (28.2)
5 (12.8)
23 (59.0)
--
Demography
Mean Age (±SD)
41.5 (7.0)
37.25 (19.0)
23.1 (21.7)
0.566
Age < 25 years (%)
0
2 [40]
4(17.4)
0.111
Age 25–45 years (%)
10(90.9)
2 [40]
11(47.8)
0.038*#
Age 46–60 years (%)
1(9.1)
0
8(34.8)
0.106
Age > 60 years (%)
0
1 [20]
0
–
Gender (Female:Male)
4:7
All females
13:10
–
Vaccine details
COVIShield (ChAdOx1) (%)
11 [100]
3 (60.0)
21 (91.3)
–
COVAXIN (BBV152) (%)
0
2 (40.0)
2 (8.7)
First dose (%)
10 (90.9)
2 (40.0)
17 (73.9)
0.096
Second dose (%)
1 (9.1)
3 (60.0)
6 (26.1)
Timelines
Median latency from last vaccination (IQR) (days)
13 [10–14]
17 [14–36]
14 [4–14]
0.309
Median interval (days) from 1st dose (IQR)
12 [10–14]
29.5(23.3–35.8)
14 [5–14]
0.097
Median interval (days) from 2n dose (IQR)
32
14(7.5–25)
10.5(2.5–14)
0.528
1st week (%)
1(9.1)
1 [20]
7(30.4)
0.379
2nd week (%)
7(63.6)
1 [20]
9(39.1)
0.211
3rd week (%)
2(18.2)
1 [20]
0
0.096
4th week (%)
0
0
1(4.3)
0.700
>4 week (%)
1(9.1)
2 [40]
6(26.1)
0.344
Mean duration of disease (in days ± SD)
20.5 (20.0)
54.6 (32.6)
23.1 (21.7)
0.019*$
Causality label
All probable
All probable
All probable
Investigations
CSF
Pleocytosis (%)
7/9 (77.8)
2/5 (40.0)
10/22 (45.5)
0.217
Protein elevation (%)
4/9 (44.4)
1/5 (20.0)
9/22 (40.9)
0.636
MRI
LETM
6/11 (54.5)
4/5 [80]
9/23 (39.1)
0.228
ON
5/11 (45.5)
–
4/23 (17.4)
0.081
Supratentorial lesion
4/11 (36.4)
2/5 (40.0)
10/23 (43.5)
0.924
Infratentorial lesion
3/11 (27.3)
3/5 (60.0)
9/23 (39.1)
0.457
Outcome
Favourable (mRS 0–1) (%)
7/11 (63.3)
2/5 (40.0)
12/23 (52.2)
0.658
* Denotes p value < 0.05.
$ p value of 0.023 between MOGAD and other demyelination; p value of 0.023 between NMOSD and other demyelination.
# p value of 0.014 between MOGAD and rest of the demyelination group; p value of 0.631 between NMOSD and rest of the demyelination group and 0.111 between other demyelination group and combined NMOSD and MOGAD.
Fig. 1MRI brain T2/FLAIR shows hyperintensities in mid brain, pons, left MCP, bilateral posterior internal capsule, thalamus, bilateral centrum semiovale in a case of MOGAD. (Case 01).
Fig. 2MRI spine T2 weighted image shows longitudinally extensive cervico-dorsal cord hyperintensities in a case of probable post vaccination myelitis. (Case 14).
Patients with a diagnosis of GBS constitutes 10.3 % (3/29) of the total post COVID19 vaccination related neurological diseases. All of them had received ChAdOx-1 vaccine. The mean age of presentation was higher (44.3 ± 10.5 years) than the overall mean age (40.1 ± 14.5 years). Out of three cases, two were female and first clinical symptom started after a mean of 11.0 ± 7.0 days from last vaccination. All three of them had albumin-cytological dissociation with a mean CSF cell of 0 and protein of 115.2 ± 36.2 mg/dl. Nerve conduction studies of sampled nerves were suggestive of motor axonopathy in one case (case 40) and mixed axonal and demyelinating neuropathy (case 41 and 42) in two cases. All patients were treated with large volume plasma exchange for five cycles. One of the patients had favorable mRS at discharge. (Refer to Table 2, Table 3).
4.3 Stroke (patient 43–47)
Out of six cases of stroke, three (50 %) had received ChAdOx-1 and 3 (50 %) were vaccinated with BBV152 vaccine. Based on the [
] criteria for causality labeling four patients were considered as probable vaccine related event. The mean age of presentation (51.1 ± 22.6 years) was higher than the overall mean. Majority of the patients were of male sex (F:M 1:5). They experienced first symptoms after a mean interval of 8.2 ± 5.6 days post vaccination. The spectrum comprised three cases of anterior circulation arterial stroke, and single case each of posterior circulation, watershed infarct and venous stroke. Two cases (Case 47 & 48) were considered to have possible associations since they had vascular risk factors which were well controlled at the time of onset of symptoms. Two cases (33.3 %) had thrombocytopenia and coagulopathy. None of the cases had any definitive evidence of Vaccine induced immune thrombotic thrombocytopenia (VITT) based on American Haematology Society guidelines. Patients were treated as per standard treatment protocols. At discharge, one of the patients (16.7 %) had favorable mRS (0to1). (Refer to Table 3).
4.4 Encephalitis (n = 2)
Patient 49: A 23-year-old lady developed encephalopathy-two days after first dose of ChAdOx 1 vaccination. Brain MRI revealed T2/FLAIR hyperintensities with areas of diffusion restriction predominantly involving cortical grey matter of left parahippocampal gyrus, amygdala, lateral temporal lobe, parieto-temporal junction in a gyriform pattern on left side and deep grey matter of left pulvinar nucleus. (Fig. 3). LP-CSF analysis showed polymorphonuclear cells with predominant pleocytosis with normal protein and sugars. Extensive evaluation for CSF and serum viral markers were unremarkable. Electroencephalogram showed bilateral intermittent slowing (left more than right). Serum and CSF autoimmune mosaic panel were negative. She was empirically treated with antivirals and as there was no response, steroids were started following which she improved completely. Hence a diagnosis of possible post-COVID19 vaccination autoimmune encephalitis was considered.
Fig. 3MRI brain T2/FLAIR hyperintensities with restricted diffusion predominantly involving cortical grey matter of left parahippocampal gyrus, amygdala, lateral temporal lobe, parieto-temporal junction in a gyriform pattern on left side and deep grey matter of left pulvinar nucleus. (Case 28).
Patient 50: A 52-year-old lady presented with pain in the bilateral lower limbs and stiffness, 7 days post vaccination with ChAdOx-1 (second dose). Examination revealed severe spasticity in both the lower limbs and extensor plantar response. Secondary work-ups revealed strong positivity for anti-GAD-65 antibody. Neuroimaging including brain and spine MRI, CSF analysis, serum and CSF NMO/MOG antibody titres were negative. PET-MR brain was normal. She was diagnosed as Stiff person syndrome. She was treated with oral steroids and symptomatic measures. At discharge, she made a mild recovery to mRS of 2.
4.5 Myositis (n = 1)
Patient 51: A 58-year aged male, developed myalgia and progressive weakness of limbs, 15 days post-BBV152 vaccination. He presented to us 2 months after symptom onset and was wheel chair bound at the time of admission. He had Creatine Kinase value of 13786U/L with anti-SRP-antibody positivity, hence diagnosed as definite inflammatory myopathy (ACR/EULAR 2017) [
2017 European League Against Rheumatism/American College of Rheumatology classification criteria for adult and juvenile idiopathic inflammatory myopathies and their major subgroups.
]. Muscle MRI was suggestive of myositis. PET MRI showed increased tracer uptake in the muscles without any sign of malignancy. (Fig. 4) He was treated with intravenous methylprednisolone pulse therapy followed by rituximab 6 monthly regime. At 6 months follow-up, patient was ambulant with mild support. (Refer to Table 3).
Fig. 4Muscle MRI shows T2 hyperintensities in the muscles of the anterior, posterior & adductor compartment of thigh bilaterally. 18FDG-PET shows increased tracer uptake in the muscles of the anterior, posterior & adductor compartment of thigh bilaterally.
In this series of 51 cases, we present multiple neurological diseases which were found to be temporally associated with COVID19 vaccination. Vaccination-associated neurological diseases are well known in the medical literature. Several vaccines, such as influenza, rabies, mumps-measles-rubella (MMR), yellow fever have reported neurological adverse events. [
] However, presence of coexisting confounding factors enhances the risk of false association of any adverse event to a particular vaccine. For instance, several series of post-vaccination GBS were reported following mass vaccination against novel A/NJ/76 (Hsw1N1) influenza, the association which was later refuted in a few observations. [
Antigenic Variability a Potential Factor in Assessing Relationship Between Guillain Barré Syndrome and Influenza Vaccine - Up to Date Literature Review.
Wilson K, Mills E, Ross C, McGowan J, Jadad A. Association of Autistic Spectrum Disorder and the Measles, Mumps, and Rubella Vaccine: A Systematic Review of Current Epidemiological Evidence. Arch Pediatr Adolesc Med [Internet]. 2003;157(7):628–34. Available from: https://doi.org/10.1001/archpedi.157.7.628.
Eggertson L. Lancet retracts 12-year-old article linking autism to MMR vaccines. Vol. 182, CMAJ : Canadian Medical Association journal = journal de l’Association medicale canadienne. 2010. p. E199-200.
Https://www.nytimes.com/. Tracking Coronavirus Vaccinations Around the World [Internet]. Available from: https://www.nytimes.com/interactive/2021/world/covid-vaccinations-tracker.html.
], the coincidental occurrence of a disease, can lead to false labelling of a condition as a vaccine related adverse outcome. Multiple types of vaccines from different manufacturers, different routes of administration, and administration of vaccine candidates in different phases of clinical trials (i.e., phase III or IV) have added to the existing dilemma of causality labelling of AEFIs. (Refer to supplementary appendix). In due course of time, with evolving evidence from larger studies, some of the reports of vaccine-related adverse events get refuted as was seen with sudden sensorineural hearing loss post COVID-19 vaccination. [
Amanzio M, Mitsikostas DD, Giovannelli F, Bartoli M, Cipriani GE, Brown WA. Adverse events of active and placebo groups in SARS-CoV-2 vaccine randomized trials: A systematic review. Lancet Reg Heal - Eur [Internet]. 2022;12:100253. Available from: https://doi.org/10.1016/j.lanepe.2021.100253.
Formeister EJ, Wu MJ, Chari DA, Meek R 3rd, Rauch SD, Remenschneider AK, et al. Assessment of Sudden Sensorineural Hearing Loss After COVID-19 Vaccination. JAMA Otolaryngol Head Neck Surg. 2022 Feb.
] A higher incidence, well and above the background incidence of a given clinical entity can serve as an important surrogate marker of a probable vaccine induced association. Post-vaccination GBS had an approximately-four times the higher incidence among Ad26.COV2.S recipients, with an estimated rate of 9.8 cases per million doses. [
Use of mRNA COVID-19 Vaccine After Reports of Myocarditis Among Vaccine Recipients: Update from the Advisory Committee on Immunization Practices - United States, June 2021.
] are pointed out in many observations. In India, the adenoviral vector vaccine was mostly used. We found three cases of vaccination associated with GBS over 1 year, when a total of 1,48,26,49,754 doses of AstraZeneca, COVIShield (ChAdOx-1), and 28, 80, 80,355 doses of COVAXIN (BBV152) are already administered. This implies the incidence of the event lies within the usual incidence of GBS. [
In contrast to the higher association of the mRNA-based vaccine with demyelination as shown in the systematic review of 32 cases of post-COVID19 vaccination-associated demyelination, we found a majority (16/18, 69.6 %) to be associated with adenoviral vector vaccine (ChAdOx-1). The similar female predominance, the median age of presentation, median interval from the last dose, and clinical presentation as pointed out in the review are also observed in our series. Similar to previous studies, the most common antibody associated with post-vaccination demyelination in our study was MOG. [
Kumar N, Graven K, Joseph NI, Johnson J, Fulton S, Hostoffer R, et al. Case Report: Postvaccination Anti-Myelin Oligodendrocyte Glycoprotein Neuromyelitis Optica Spectrum Disorder: A Case Report and Literature Review of Postvaccination Demyelination. Vol. 22, International journal of MS care. 2020. p. 85–90.
]. MOG associated demyelination has been reported to occur following vaccinations with Japanese encephalitis, tetanus, measles, rubella etc. Various mechanisms proposed are autoantibody production due to molecular mimicry, induction of autoreactive T cells via bystander activation due to ongoing response against vaccine antigen or adjuvant. Vaccines may also cause unmasking of a preexisting autoimmune disorder [
]. Our series on post-vaccination stroke revealed coagulopathy in two cases, wherein vaccine induced thrombocytopenia, could be a potential consideration. The more frequent occurrence of the neurological events among the ChAdOx-1 recipients could probably be the reflection of the more widespread administration of the ChAdOx-1 vaccine in India. [
5.1 Spectrum of COVID vaccine associated neurological symptoms (Co-VAN)
The spectrum of the neurological diseases associated with COVID19 vaccination is yet to be completely explored. Reports of COVID19 vaccine-related adverse events have been tabulated for providing an updated list of neurological diseases attributed to the receipt of COVID-19 vaccine. (Refer to Table 5 Refer to Fig. 5, Fig. 6) (Refer to supplementary appendix for detailed search terms) Although the causality label wasn’t justified in many of these reports, awareness of the smallest possibility of any adverse event could enable prompt recognition in subsequent cases. Presence of clustering or detection of signals of AEFI would prompt further investigations. In the current context, an individual developing any neurological illness after the COVID19 vaccination could potentially satisfy-one or more of the following: a) COVID19 vaccine-associated disorder, b) remote COVID19 infection-related, or “long COVID” with vaccination as a bystander, c) vaccine component induced idiosyncratic reaction, d) occurrence of the disease due to the presence of risk factors and/ or vaccination associated triggering, e) expected occurrence of the disease with vaccination as a bystander, or f) immunization stress-related response. (Refer to Fig. 3 for details) (Refer to Supplementary appendix for vaccination related terms).
Table 5CO-VAN study: scoping review of literature. Spectrum of COVID19 vaccine associated neurological disorders (Co-VAN) – a review of the literature.
Spectrum of COVID19 vaccine associated neurological disorders (Co-VAN)
Miller-Fisher Syndrome and Guillain-Barre Syndrome overlap syndrome
63/M
1st
9 days laterExperienced new-onset lower back pain and 5 days after developed bilateral oculomotor nerve palsy, ataxia, facial diplegia and lower limb weakness. Later developed diplopia on lateral gaze bilaterally. Examination revealed impaired adduction, restricted upward gaze and intorsion with down gaze bilaterally, consistent with partial cranial nerve III palsies.
LP-CSF: Protein- 2.99 g/L Cells- 5/hpf: Albuminocytological dissociation. NCS- long-standing axonal neuropathy with reduced motor and sensory amplitudes. EMG- and length-dependent chronic neurogenic changes. MRI Brain- enhancement of the facial and oculomotor nerves bilaterally. Serum anti-GQ1b antibody- negative. Showed partial improvement with IvIg 2 g/kg over 5 days.
Y. Kim Z. Zhu P. Kochar P. Gavigan D. Kaur A. Kumar A Pediatric Case of Sensory Predominant Guillain-Barré Syndrome Following COVID-19 Vaccination Child Neurol Open. 2022;9:2329048X2210745.
Pediatric Case of Sensory PredominantGuillain-Barré Syndrome
16/F
2nd
2 days afterAscending numbness and paresthesia of her bilateral lower and upper extremities
MRI – mild thickening and enhancement of the anterior and posterior spinal nerve roots of the cauda equine. LP-CSF: 1cell/cmm, Protein- 112 mg/dlNCS- prolonged latency and slowed conduction velocity in multiple sensory and motor nerves
MOG positive = 10Postvaccinial cases were found to have a significantly higher-Mean age, Presence of encephalopathy (p value:0.0007), CSF pleocytosis (p value: 0.0094) andRaised CSF protein (p value: 0.0062).
Chen S, Fan X-R, He S, Zhang J-W, Li S-J. Watch out for neuromyelitis optica spectrum disorder after inactivated virus vaccination for COVID-19. Neurol Sci [Internet]. 2021;42(9):3537–9. Available from: https://doi.org/10.1007/s10072-021-05427-4.
After 3 days of vaccine developed mild fever, vomiting, diarrhoea, cough and unsteadiness and dizziness.
MIR Brain- area postrema and bilateral hypothalamus lesions without Gd enhancement. Investigations: leucopenia of 2.36 × 109/Land positive antibodies for AQP4, ANA, SSA, SSB, Ro-52, and p-ANCA. CSF- Mononuclear pleocytosis with normal protein and negative OCB. Treated with intravenous steroid pulse and patient responded well.
Arnao V, Maimone MB, Perini V, Giudice G Lo, Cottone S. Bilateral optic neuritis after COVID vaccination. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2022. p. 1–2.
First dose of vaccine. Developed headache and painful blurred vision worsened by movement in both eyes, decreased bilateral vision acuity.
MRI of the brain in FLAIR axial showed increased signal of the left optic nerve. LP-CSF analysis normal cells and protein. Aquaporin 4 (AQP4)-IgG and MOG-IgG negative. Treated with intravenous steroid pulse and patient responded well.
2daysp/w- fever, headache and apathy followed by seizure and coma.
MRI Brain- bilateral confluent cortical and subcortical FLAIR hyperintense lesions with haemorrhagic involvement of the basal ganglia. CSF- revealed normal cell counts (1 leukocyte per μl) and moderate disturbance of the blood–brain-barrier. Treated with PLEX and IVMP, poorly responded.
25Y/F
1st
9 days. P/w severe cephalgia, thoracic back pain, mild weakness and ascending numbness in her legs.
MRI- longitudinal edema throughout the thoracic spinal cord exhibiting mild contrast enhancement as well as focal central haemorrhages and brain showed bi-hemispheric white matter lesions with focal contrast enhancement. CSF- granulocytic pleocytosis
VITTS and venous and/or arterial ischemic strokes/ intracerebral haemorrhage
Younger age (median age 46), female preponderance and 12 days as median time after vaccination are reported.
Vaccine-induced immune thrombotic thrombocytopenia (VITT) is mainly reported in adenovirus vector based vaccines, ChAdOx1 CoV-19 vaccine and Ad26.COV2.S. According to VARES data the incidence of VITT is approximately 1 in 263,000 recipients of Ad26.COV2.S. (PMID 35,038,274)
AstraZeneca (ChAdOx1) Jannsen (Ad26.COV2.S) Pfizer-BioNTech (BNT162b2) Moderna (mRNA-1273)
CVST
Vaccine types
Absolute risk of CVST within 28 days of per million of first-dose vaccination
The absolute risk of CVST with thrombocytopenia within 28 days of per million of first-dose vaccination
Age group between 18 and 24 years had the highest absolute risk of CSVT, with thrombocytopenia (7.3 per million, 95 % CI 2.8–18.8) or without thrombocytopenia (3.7 per million, 95 % CI 1.0–13.3).
Ischemic stroke in ICA and MCA territory with haemorrhagic transformation in one patient and another had cortical infarctions and aortic arch thrombi. Both had thrombocytopenia, increased d-dimer level, and positive anti-PF4 antibody.
3 patients with MCA infarct, ICA infarct and CVST, and MCA infarct respectively. All had thrombocytopenia, positive anti-PF4 antibody, and increased d-dimer level.
Complaining of constantly ‘‘smelling smoke’’ and headaches. Associated with hyposmia to additional odorants and was affecting her quality of life.
CTA postcontrast showed a faint enhancement of left olfactory tract. MRI brain – Asymmetric enlargement and increased T2 hyperintensity in the left olfactory bulb and tract extending posteriorly and thickened, clumped olfactory nerve filia.
Jeong J, Choi HS. Sudden sensorineural hearing loss after COVID-19 vaccination. Vol. 113, International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases. 2021. p. 341–3.
Parrino D, Frosolini A, Gallo C, De Siati RD, Spinato G, de Filippis C. Tinnitus following COVID-19 vaccination: report of three cases. Int J Audiol [Internet]. 2021;0(0):1–4. Available from: https://doi.org/10.1080/14992027.2021.1931969.
5 h. Iintermittent, right ear, high-pitch tinnitus which progressed into continuous high-pitch tinnitus and disturbed the normal hearing along with fever and myalgia.
Audiological evaluation s/o cochleopathy. Responded to short course of steroid.
Associated ENT symptoms: Hearing loss = 4 Tinnitus = 6Ear fullness = 2Hypersensitivity to noise = 1
No presence of nystagmus = 7Presence of horizontal or rotatory nystagmus = 9Presence of positive HST/ “central HINTS” or vertical or oblique nystagmus/ “central HINTS”= 17
Probable clinical diagnosis: No presence of vestibular impairment or central etiology of vertigo/dizziness = 7Benign paroxysmal positional vertigo = 9Probable central etiology = 17
1 weekWith sudden-onset diplopia along with severe headache of 1 week’s duration. On examination had left esotropia with limited abduction of the left eye (LE 6th cranial nerve palsy)
MRI and blood investigations were unremarkable. Improved in follow up. H/o 2 episodes of similar 6th nerve palsy, one 5 years back following a febrile illness and another 2 years back following chicken pox.
Third cranial nerve palsy in an 88-year-old man after SARS-CoV-2 mRNA vaccination: Change of injection site and type of vaccine resulted in an uneventful second dose with humoral immune response.
Brain CT scan, CT angiographyand MRI ruled out a vascular accident. Treated with oral steroid, made complete recovery. Later vaccinated again with different vaccine at different injection site.
1 day, Presented with mydriasis, ptosis, and a “down and out” gaze.
MRI Brain (plain) normal. Serum anti AChR Ab, ANA screening and EMG were unremarkable. Treated with prednisone 40 mg daily for 5 days, followed by valacyclovir 500 mg twice daily for 7 days. On 2 months follow up patient improved completely.
1 day afterdeveloped headache and progressive neurological symptoms includingattention and concentration difficulties starting on day 5 after vaccination, resulting in admission to hospital11 days after vaccination. Subsequently had seizure.
MRI Brain- NormalCSF- 46 leukocytes/cmm(lymphocytic). EEG- diffuse abnormally slow thetarhythms without epileptiform activity. Responded to steroid therapy.
63/F
1st
2 days later diagnosed to have DVT in left left- started on anticoagulation. 6 days post vaccination – gait deteriorated, she developed a vigilance disorder and a twitching all over her body. Later developed severe immobilizing opsoclonusmyoclonus syndrome.
MRI Brain- NormalCSF- 115 leukocytes/cmm(lymphocytic). EEG- diffuse abnormally slow theta and delta rhythms without epileptiform activity. No response to initial antibiotic therapy. Later, Responded to steroid therapy.
63/M
8 days afterisolated aphasia and fever.
MRI Brain- NormalCSF- 7 leukocytes/cmm(lymphocytic). Testing for neurotropic viruses in serum and CSF- Negative. EEG- NormalResponded to steroid therapy.
1 day afterConfusion and agitation consistent with delirium with extreme agitation. k/c/osarcoidosis and polymyalgiarheumatica in clinical remission with Methylprednisolone 4 mg/day. Mild COVID-19 five months prior to vaccination.
CRP- elevatedEEG – moderate diffuse slowingCT (contrast)- unremarkableCSF: cell-3, protein-119 mg/dl, glucose-52 mg/dl, IL6-194(high), IL8-162(high) Microbiological testing on CSF-negativeCSFoligoclonal bands, CSF and serum autoimmune encephalitis antibodies, serum onconeural, antinuclear and antineutrophil cytoplasmic antibodies: Negative. Responded to intravenous methylprednisolone pulse therapy.
Moslemi M, Ardalan M, Haramshahi M, Mirzaei H, Sani SK, Dastgir R, et al. Herpes simplex encephalitis following ChAdOx1 nCoV-19 vaccination: a case report and review of the literature. BMC Infect Dis [Internet]. 2022;22(1):22–5. Available from: https://doi.org/10.1186/s12879-022-07186-9.
3 days aftersevere headache and altered mental status began to appear, including slowed psychomotor activity and loss of alertness. Subsequently severeheadache, agitation, delirium, and disorientation
LP-CSF: protein levels (3.05 mg/dl), WBC count of 600 per mm3 (predominance of lymphocyte) CSF HSV PCR- +veMRI brain and EEG- Unremarkable. Treated with antiviral, and improved over 21 days.
Al-Mashdali AF, Ata YM, Sadik N. Post-COVID-19 vaccine acute hyperactive encephalopathy with dramatic response to methylprednisolone: A case report. Ann Med Surg [Internet]. 2021;69(August):102803. Available from: https://doi.org/10.1016/j.amsu.2021.102803.
Zlotnik Y, Gadoth A, Abu-Salameh I, Horev A, Novoa R, Ifergane G. Case Report: Anti-LGI1 Encephalitis Following COVID-19 Vaccination. Vol. 12, Frontiers in immunology. 2021. p. 813487.
2.5 weeks later, Started to have memory deficits and anterograde amnesia. O/E- Montreal Cognitive Assessment (MoCA) score of 18/30
Serum sodiumlevel of 132 mEq/ L (normal range 135–145), Tumor markers (CEA, AFP, CA125, CA19–9, CA15–3) andParaneoplastic neuronal antibodiesincluding anti-Hu, Ri, Yo, Ma/Ta, Amphiphysin, CV2, SOX1, Tr (Euroimmun) were negative. EEG- UnremarkableMRI Brain – intense signal on both medial temporal lobes (more on the left) including theparahyppocampal gyrus on T2/FLAIR and DWI. Whole body CT- liver cyst and adrenal adenoma. CSF- Cell, protein and sugar normal. CSF- LGI-Ab + Treated with methylprednisolone (1gramdailyfor5consecutivedays) with a good response.
18 daysWith headache, fever, paresthesias of the calves and thighs bilaterally and an unsteady gait, diplopia, and urinary retention. O/E: Neck stiffness +
MRI brain- non-enhancing, nonspecific deep white matter lesions. CSF − 200 WBCcells per mm3 with lymphocytic predominance, Mildly elevated protein (65 mg/dl, reference 12–60 mg/dl) and glucose CSF to serum ratio of 0.5. Infection work up and paraneoplastic panel were negative. Treated with IV steroid, responded partially.
Kang HS, Kim JE, Yoo JR, Oh H, Kim M, Kim YR, et al. Aseptic Meningitis Following Second Dose of an mRNA Coronavirus Disease 2019 Vaccine in a Healthy Male: Case Report and Literature Review. Infect Chemother [Internet]. 2022;54. Available from: https://doi.org/10.3947/ic.2021.0131.
5 days after the first dose of vaccine presented with muscle pain of herthigh muscles, radiating to the lower legs, accompanied by an asymmetrical weakness of the lower limbs. Creatine kinase (CPK) was 17,959 U/l (normal range 26–140 U/l).
Myositis profile was negative. MRI muscles- left-dominant edematous signal alterations with contrast enhancement of the quadriceps muscles sparing the M. rectus femoris, and diffuse subcutaneous fluid retention with contrast enhancement, suggestive of fasciitisTreated with steroid, patient improved.
48hoursPresented with a 3-week history of intermittent low-grade fever and polyarthralgia. ESR-123 mm/hr (<15 mm/ hr) CRP-269 (<5mg/L) CPK-24 (25 – 170 U/L) ANCA- negativeANA- negativeMyositis profile- negative
18FDG-PET-CT: a tree-root-like uptake pattern in the lower limbs suggestive of small–medium vessel vasculitis. Whole-body short tau inversion recovery (STIR)-MRI showed diffuse ill-defined muscle hyperintensities suggestive of inflammatory myositis. EMG- fibrillations, positive sharp waves, and complex repetitive discharges in the distal leg muscles. Skin and muscle biopsy showed features of small–medium vessel vasculitis. Remission achieved with oral steroid therapy.
18 FDG-PET CT- Day 25; Diffuse patchy minimallyincreased FDG avidity in skeletal muscles moreevident in lower limb. Arteries show ‘tree root’patterns. MRI – Day 27-Multiple patchy areas of STIRhyperintensity involving the muscles of both thighsincluding all compartments, posterior compartment ofboth legs and pelvic girdle. Treated with Oral Prednisolone 1 mg/ kg + Mycophenolate mofetil. Achieved remission.
1 day afterprogressively worsening pain and swelling in the lower back. O/E- tenderness to the paraspinal lumbar area upon palpation.
CPK- 22000U/LAldolase- 97.8U/LAST-675U/LALT-165U/LCRP-6.4 mg/LLDH-1525U/LUrine blood + Myositis profile- NegativeHydrated with high volume IV normalSaline and pain controlled with morphine. Improved.
1weekPain and left hand grip and left wrist extension weakness with no sensory disturbances or other symptoms. Examination – weaknessof left finger extension and left hand grip. Weak(MRC 3/5) – left dorsal interossei, extensor digitorum, extensorindicis, and flexor carpi ulnaris. DTR- mildly brisk b/l and symmetrical.
MR brachial plexography and NCS- was normal (done early in the disease course). Treated with oral steroid and patient responded significantly.
Mean duration of 17 days (5 days–8 weeks). Initial symptom was pain in the shoulder girdle/upper limb, followed within days by muscle weakness.
Examination and investigation s/o- upper trunk brachial plexopathy in 2 patients, lower trunk plexopathy in 1 patient, posterior cord brachial plexopathy in 1 patient, andanterior/posterior interosseous nerve involvement in 2 patients. All patients either improved or attained complete resolution of the arm pain at follow-up.
Pfizer-BioNTech (BNT162b2) = 1, Moderna (mRNA-1273) = 1
Parsonage Turner Syndrome
49/M
1st
13 hoursPain followed by weakness of left upper limb.
MR Neurography- Within the arm, four severe hourglass- like constrictions and T2-weighted signal hyperintensity of the anteromedially positioned fascicular bundle of the median nerve were detected; this bundle represents the PT/FCR bundle based on the known topographic fascicular arrangement of the median nerve. EDx- severe denervation and no motor unit recruitment within thePT or FCR muscles. 3 month follow up- pain decreased but weakness increased.
44/M
2nd
18 days after developed sudden-onset, Intense, cramping pain in the left lateral deltoid region. Examination- severe weakness in left shoulder abduction (2/5) and external rotation (3/5) Reported hyperesthesias in the left lateral shoulderAnd had diminished sensation to pinprick in the radial nerve distribution.
NCS- mild slowing of the left median and radial sensory responses. EMG- denervation and poor motor unit recruitment in the infraspinatus muscle. MRI- left brachial plexus MR neurography demonstrated enlargement, T2-weighted signal hyperintensity and multiple focal hourglass-like constrictions of the suprascapular nerve with accompanying denervation edemapattern of the supraspinatus and infraspinatus muscles.
1weekWith subacute onset of intense burning dysesthesias in the feet, gradually spreading to the calves and minimally into the hands, unaccompanied by other neurological or constitutional symptoms. Nerve conduction study was unremarkable.
Skin biopsies showed multifocal involvement. Relevent workups for neuropathy were negative. Treated with gabapentin and improved in 2 weeks.
3–4 days after, subacute onset of legs’ weakness, cramping pain and fever (38 °C − 39 °C). O/E: Power LL- 2/5 (b/l) Spastic LLPlantar- equivocalVery brisk patellar, abductor and Achilles tendon reflexes with horizontal and vertical extension, and legs paraesthesia. Tactile and pinpricksensation was decreased from T4 dermatomedownward. Passive and active leg movementselicited rigidity and tenderness.
CSF- Albuminocytological dissociationOCB (CSF and Serum): Pattern IVMRI Brain & Spine- NormalElectromyography and electroneurography – NegativeNear complete recovery in 2 months of steroid therapy.
Chavez A, Pougnier C. A Case of COVID-19 Vaccine Associated New Diagnosis Myasthenia Gravis. J Prim Care \& Community Heal [Internet]. 2021;12:21501327211051932. Available from: https://doi.org/10.1177/21501327211051933.
2 days afterWith intermittent bulbar symptoms, present in the evenings. history of laryngeal cancer status post hemi-laryngectomy 40 years previously, Barrett’s esophagus, and stage 3a chronic kidney disease
Ach receptor binding Ab 11.4 (normal < 0.02) RNST- Decrement patternSecondary evaluation for thymoma was negative. Treated with pyridostigmine and IVIG. Had improving course.
Coincidental Onset of Ocular Myasthenia Gravis Following ChAdOx1 n-CoV-19 Vaccine against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2).
Isr Med Assoc J [Internet].2022; 24 (Available from): 9-10
Lee MA, Lee C, Park JH, Lee JH. Early-Onset Myasthenia Gravis Following COVID-19 Vaccination. J Korean Med Sci [Internet]. 2022 Mar;37(10). Available from: https://doi.org/10.3346/jkms.2022.37.e50.
On the same day: bilateral ptosis and binocular diplopia. On 3rd day: Developed bilateral ptosis. On 4th day: difficulty in raising her arms and moving her neck with a diurnal fluctuation.
RNST- Significant decremental response. CT- Mild thymic hyperplasia. Anti AchR Ab and anti MUSK Ab – NegativeNeostigmine test- Positive. Responded to pyridostigmine.
Salinas MR, Dieppa M. Transient akathisia after the SARS-Cov-2 vaccine. Clin Park Relat Disord [Internet]. 2021;4(May):100098. Available from: https://doi.org/10.1016/j.prdoa.2021.100098.
12 hoursStarted to experience an urge to move which she described as “restless body syndrome.”. k/c/o atopic dermatitis, allergic rhinitis and anxiety (on sertraline 50 mg/day)
She derived temporary relief of symptoms from volitional movement but the internal discomfort and urge to move would soon return. Her movements were alleviated by flexing/extending her trunk and legs as well as getting up and constantly moving. This was followed by fever and myalgia. Her symptoms improved after 24 h.
4 days afterWith intermittent paraesthesia in extremities, which gradually became persistent. Initially was treated with vitamin b12 injection and amitriptyline. 2 months after had increased heart rate, with a significant change when standing (80– 120b.p.m.) vs lying (50–60b.p.m.) and skin colour changes (dark-blue/white/ dark-red) in acral areas (hands/ feet/penis) which is intermittent.
Antinuclear antibody (ANA) was positive at low titre (speckled pattern, 1:40) with elevated IgA level [5.06 g/L (0.60–3.96)]. MRI brain and nerve conduction study was unremarkable. Treated with short course of oral steroid. His postural tachycardia improved, but paraesthesia and skin colour changes persisted at 6-months.
1 week after vaccination presented with sinus tachycardia, dizziness, headaches, and fatigue that are often triggered after a large meal or standing for a longer duration.
Investigations were not remarkable. Treated with life style modification.
Oonk NGM, Ettema AR, van Berghem H, de Klerk JJ, van der Vegt JPM, van der Meulen M. SARS-CoV-2 vaccine-related neurological complications. Neurol Sci [Internet]. 2022;43(4):2295–7. Available from: https://doi.org/10.1007/s10072-022-05898-z.
Laboratory analysis, brain CT and MRI, EEG and CSF analysis including blood pigment and cytologyanalysis were all unremarkable.
AstraZeneca (ChAdOx1)
21/F
1st
2 h afterDeveloped general malaise with subfebrile temperature6hours later experienceda thunderclap headache, with nausea and vomiting
Neurological examination, blood analysis, and brain CT including CTangiography and venography were all normal. Symptoms improved over 1 day with paracetamol, NSAIDs, intravenous morphine, and oxygen therapy
Mattiuzzi C, Lippi G. Headache after COVID-19 vaccination: updated report from the Italian Medicines Agency database. Neurol Sci [Internet]. 2021;42(9):3531–2. Available from: https://doi.org/10.1007/s10072-021-05354-4.
Rate of headache/migraine episodes (per 100,000) voluntarily reported by recipients of COVID-19 vaccines up to May 9, 2021:
Risk of developing headache/migraine episodes(Odds)
AstraZeneca
129
AstraZeneca
3.50; 95 % CI, 3.12–3.93; P < 0.001
Pfizer
103
Pfizer
2.78; 95 % CI, 2.47–3.13; P < 0.001
Moderna
21
Moderna
0.58; 95 % CI, 0.49–0.68; P < 0.001
The cumulative rate of headache/migraine episodes after receiving all COVID-19 vaccines was 2.25-fold higher than the daily frequency of headache disorders (odds ratio, 2.25; 95 % CI, 0.83–6.11).
Interval from vaccination: within the first 24 h: 75 %between 1 and 7d:25 %.
All presented with lateralizedsensory deficits, motor deficits, or both, of 2–14 day duration. Migraine headache occurred in half of the patients.
MRI brain during and after the attacks did not demonstrate any abnormalities suggesting ischemic stroke. All patients showed moderately large regions of hypoperfusion and concurrent smaller regions of hyperperfusion on SPECT imaging while symptomatic. None developed permanent deficits or structural brain injury.
Maldonado MD, Romero-Aibar J. The Pfizer-BNT162b2 mRNA-based vaccine against SARS-CoV-2 may be responsible for awakening the latency of herpes varicella-zoster virus. Brain, Behav Immun - Heal [Internet]. 2021;18(July):100381. Available from: https://doi.org/10.1016/j.bbih.2021.100381.
4 days afterelevated erythematous lesions with vesicles on his right-handsidelumbar area that quickly spread to his lower back, hip, groin, and right-hand-side front and inner thigh, corresponding to L1, L2 and L3 dermatomes. K/c/o Hypercholesterolemia, hyperuricemia and hypertension
Responded to: 800 mg/day of acliclovir for one week; 50 mg of acyclovir applied topically onthe vesicles.
Pfizer-BioNTech (BNT162b2)
56/F
2nd
16 days afterFever, with haemorrhagic vesicles upon an erythematous base spreading on her arm, hand, and left side ofher chest, with chest pain, and pain in her arm on the same side
Treated with 400 mg/8h of gabapentin and 25 mg/12 h of a vitamin B complex.
After twenty minutes of receiving the vaccine, developed an odd sensation that she described as “weakness” around her left ear. During the rest of the day, this weakness spread to her mouth, left arm, and leg.
The next morning, she had difficulty moving the left side of her face and experienced heaviness in her left leg. Her hoover's sign, hip abduction test results, were positive and symptoms were variabile. Investigations including neuroimaging was unremarkable.
Moderna (mRNA-1273)
Functional Neurological disorder
36/F
1st
Few minutes after experienced weakness in her right hand and new right-leg limping, which lasted about 2 h. On the second day after vaccination, she experienced severe bilateral leg heaviness and difficulties in fine movements of the right hand. In addition, she had exertional fatigue after walking short distances.
These symptoms persisted for several days. Examination and neuroimaging, routine investigations were unremarkable.
After a few minutes fromthe injection, reported bilateral facial paralysis withdifficulty to blink and move the facial muscles properly. All the symptoms resolved spontaneously within 40 min. Three weeks later, a few minutes after the second dose, he complained of swollen tongue and respiratory impairment, which was quickly resolved by corticosteroid therapy. Later he developed right-sided weakness, at the same side of the injection, lasting for about 40 min.
Few weeks later, he suddenly manifested left-sided facial hypoesthesia. Examination- midline splitting of sensory deficit in the face with tacto-dolorific hypoesthesia. Brain MRI, CT, & carotid artery Doppler ultrasonography: Normal. Sensory disturbance resolved, and the neurological examination become normal in next 2 weeks.
20 min aftershort episode of generalised tonic–clonic psychogenic non-epileptic seizures (PNES) which was followed byanother episode of-inability to move the whole body with preserved level of consciousness). No post-ictal period followed these episodes.
VEEG during few events- normal.
AstraZeneca (ChAdOx1)
Subjective sensory symptoms- FND
2 weeks afterpersistent dizziness and a subjective loss of tactile sensitivity in the right arm and leg.
18daysdeveloped visual impairment due to scotomas and thunderclapheadache.
Multimodal cerebral MRI: Acute cortical ischemic lesion in the territory of the right PCA on T2- weighted images, DWI,ADC maps and absence of the PCA on MRA. Partially responded to Nimodipine(90 mg/d) and Levetiracetam (1 g/d).
3 daysWith febrile sensation and headache around the eyes and forehead. CSF- Normal cells and protein.
MRI brain- oval shaped restricted diffusion in the corpus callosum with low apparent diffusion coefficient (ADC) values and lack of contrast mediated enhancement
Scott J, Anderson J, Mallak N, Beitinjaneh B, Wei K, Otaki F. Gastroparesis After Pfizer-BioNTech COVID-19 Vaccination. Vol. 116, The American journal of gastroenterology. United States; 2021. p. 2300.
5daysStarted to have nausea, intractable vomiting and hiccups. Treated with metoclopramide, and erythromycin. Recurred again after receiving the second dose.
Investigation showed significant delay in gastric emptying. No response to H2 receptor blocker, but responded to oral steroid.
10 days of vaccination presented with f headache and subjective fever that started one day prior and a rising epigastric, jamais vu and followed by new onset generalized tonic-clonic seizure. Brain MRI showed a subtle increase in the signal on FLAIRimages at bilateral hippocampi and insula that was correlating with Postictal changes.
Cerebrospinal fluid analysis showed normal cell count, normal protein at 0.31 g/L, elevated glucose at 4 mmol/L, and negative microbial cultures and serological tests. EEG showed moderate slowing. Treated with 3 AEDs levetiracetam, phenytoin and lacosamide. Responded to pulse intravenous steroid followed by two sessions of plasma exchange on alternate days.
Liu BD, Ugolini C, Jha P. Two Cases of Post-Moderna COVID-19 Vaccine Encephalopathy Associated With Nonconvulsive Status Epilepticus. Vol. 13, Cureus. 2021. p. e16172.
Encephalopathy Associated With Nonconvulsive Status Epilepticus
86/F
1st
7dayswith acute confusion with visual hallucinations and left frontal headache. k/c/o: diastolic dysfunction, chronic kidney disease stage 3, glaucoma, cataracts, and Type 2 diabetes mellitus.
CSF studies, including meningitis/encephalitis panel NAAT, oligoclonal bands, and Lyme antibody, were negative except for West Nile virus IgG but no IgM antibodies with minimal protein elevation. CT head without contrast and MRI brain with and without contrast showed no acute findings. Continuous EEG –non-convulsive focal status epilepticus treated with lorazepam and fosphenytoin.
73/M
1st
21 dayswith staring episodes, restlessness, and cognitive deficits. K/c/o Crohn’s, hereditary hemochromatosis, hypertension, and hyperlipidemia
CSF studies, including meningitis/encephalitis panel Nucleic Acid Amplification Tests (NAAT), autoimmune encephalitis, and toxoplasma, were negative except for mildly elevated protein and glucose. CT head and MRI brain showed no acute findings. EEG- non-convulsive status epilepticus, which was treated with lorazepam and levetiracetam loading and maintenance.
Moyamoya disease with Sjogren disease and autoimmune thyroiditis presenting with left intracranial hemorrhage after messenger RNA-1273 vaccination: A case report.
Medicine (Baltimore) [Internet].2022; 101 (Available from:)
Triggered Moyamoya disease with Sjogren disease andautoimmune thyroiditis
40/F
2nd
3 days aftersevere headaches with a decreased level ofconsciousness and a tonic-clonic seizure. k/c/o- Sjogren disease andautoimmune thyroiditisO/E- Febrile with high Blood pressure and PR.
Elevated CRP, anti-PF4 Ab, SSA, fibrinogen, CT Brain – left caudate nucleus, temporal lobe IVH and ICH with hydrocephalusDSA- bilateral distal ICAsteno-occlusion with the constricted flow in middle cerebral arteries and anterior cerebral arteries with cortical collateralization pattern from the external carotid artery system that was consistent with typical moyamoya angiopathy (MMA)-Willis and the Suzuki staging system was stage V.
AEFI may occur due to vaccine product-related reaction, vaccine quality defect-related reaction, immunization error-related reaction, immunization stress-related reaction, or an unrelated incidental event. Although the underlying pathomechanisms are yet to be completely elucidated, based on the available limited observations and hypotheses the following possible mechanisms are proposed. (Refer to Fig. 7).
Fig. 7Section A- Enumerates various types of vaccine candidates and their principle components. Se6tion B- Illustrates the post vaccination mechanisms of immunogenicity Section C- Demonstrates the anti-idiotype antibody hypothesis Section D- Explains the role of adjuvants and mast cell activation and mechanism of anaphylaxis. Section E- Depicts the autoantibodies formation and ACE2 down regulation leading to various neurological diseases.
Similarity of vaccine component with human protein can lead to the production of antibodies which are directed against host’s own protein. This mechanism is known as molecular mimicry. [
Kowarz E, Krutzke L, Külp M, Streb P, Larghero P, Reis J, et al. Vaccine-induced COVID-19 mimicry syndrome. Middeldorp S, Barton M, ten Cate H, editors. Elife [Internet]. 2022 Jan;11:e74974. Available from: https://doi.org/10.7554/eLife.74974.
] Genetic predisposition and pre-existing antibodies may recognize the vaccine components and adjuvants which can activate the mast cells leading to degranulation, and hypersensitivity reactions including anaphylaxis. Vaccine adjuvants may also activate the inflammasome pathway leading to interleukin productions and subsequent activation of nuclear factor kB, Th17, and Th1 cells. [
Velikova T, Georgiev T. SARS-CoV-2 vaccines and autoimmune diseases amidst the COVID-19 crisis. Rheumatol Int [Internet]. 2021;41(3):509–18. Available from: https://doi.org/10.1007/s00296-021-04792-9.
SARS-CoV2 virus uses its spike protein (S) to bind to the angiotensin-converting–enzyme 2 (ACE2) receptors on the target cell. Viral infection and its vaccines mount antibodies to the S protein which is called as Ab1. A distinctive sequence in the complementarity-determining region 3 (CDR3), of the idiotype portions of the Ab1 binds and neutralizes the S protein. Subsequently, these antibody-binding regions get down-regulated through generation of antibody responses against themselves which is called anti-idiotype (Ab2) antibodies.
Ab2 antibodies bind to the earlier formed protective neutralizing Ab1 antibody, which results in immune-complex formation and clearance. This impairs the Ab1 efficacy. As the Ab1 is directed against the S protein and the Ab2 is directed against the Ab1, a few binding regions, or paratopes of Ab2 antibodies mirror the S protein. Hence, the Ab2 binds to the same target as the S protein would bind, i.e. the ACE2 receptor. This Ab2-ACE2 interaction blocks the ACE2 function by competitive inhibition of the normal ligand interactions. As Ab2 is an immune response, it may persist even after the original antibody gets cleared off and may lead to the long term adverse events. [
In a prospective study consisting eight patients who experienced post vaccination neurological adverse events, 18F-FDGPET/MRI, and 15O-water PET scans were performed at the baseline (immediately following neurological adverse event after the vaccination) and after 7 days of vaccination. All had hypometabolism in the bilateral parietal lobes on both the first and follow-up scans. Metabolic changes in the bilateral cuneus including hypometabolism in six and hypermetabolism in two patients were observed. One showed mildly significant decreases in perfusion in the bilateral thalamus and bilateral cerebellum, whereas another patient was found to have a diffuse increase in the cerebral white matter perfusion. The areas of metabolic abnormalities indicates towards the involvement of the fear network model which has been implicated in anxiety. [
Retrospective study design and small size are important limitations in this study. Further studies with larger sample size are needed to establish the causal association with these disorders.
6. Conclusion
The advent of newer vaccines raises the possibility of emergence of novel AEFI. While causality may not always be proven, the replication of similar events over a period of time, serve to generate speculations over a new AEFI. Though subject to further investigations, this study will sensitize the neurologists and vaccine stakeholders regarding the spectrum of neurological diseases of probable or possible temporal association with COVID-19 vaccination. It will also enlighten the practitioner regarding the possible underlying pathophysiology of this evolving entity.
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.
Appendix A. Supplementary data
The following are the Supplementary data to this article:
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