1 INTRODUCTION

Though SARS-CoV-2 vaccinations are usually sold as well tolerated, they can cause mild-to-severe side effects in some patients.1 Since the benefit for the global population outweighs these adverse reactions, and since political and pecuniary interests create the image of a “safe and indispensable” tool against the currently dominant global burden, there is only moderate reporting and discussion about them.2 There is also an anti-vaccine movement in the world nowadays that also contributes to the biased assessment of these adverse effects. Usually, single case reports, case series, or registration studies report these side effects but systematic, transnational, multicenter, post-marketing investigations on this matter are infrequently done. This shortage of published information about type, frequency, severity, and therapeutic management of vaccination-related side effects is in contradiction to the daily experience of healthcare workers and affected probands, and may contribute to the individual or organized resistance and reservations against the vaccination from parts of the populations, the only moderate effect of vaccination campaigns, and the tendency to introduce compulsory vaccination.3

Neurological side effects to SARS-CoV-2 vaccinations are usually mild, of short duration, self-limiting, and ambulatorily manageable. However, in some cases, these side effects are severe and require hospitalization or even admission to an intensive care unit (ICU).4 Only, rarely these side effects can be fatal.5 Since the virus and the adverse reactions to vaccinations show a tropism for neuronal structures and tissues this narrative review about the neurological side effects was conducted to collect and discuss published data in order to discover type, frequency, treatment, and outcome of these side effects and to eventually discover if certain patients are prone to experience them, if they can be prevented, and which therapeutic management is the most appropriate.

2 METHODS

A literature search in the databases PubMed and Google Scholar using the search terms “vaccination”, “SARS-CoV-2,” “anti-covid vaccination,” “immunisation” in combination with the terms “side effects,” “adverse reactions,” “neurological,” “brain,” and “nerves” was conducted for the period December 2020 to September 2021. Initially detected were 62 titles in PubMed and 4580 in Google Scholar. Most of them were excluded already after having read the title or the abstract. Included were only original articles which convincingly reported a neurological adverse reaction. Excluded were articles which were repetitive and articles in which a causal relation between the vaccination and the complication could not be convincingly established. Additionally, reference lists were checked for further articles meeting the search criteria. All approved vaccines were considered. Lastly, 28 papers were included.

3 RESULTS

Neurological side effects of SARS-CoV-2 vaccines collected from the literature are listed in Table 1. They include headache, Guillain-Barre syndrome (GBS), venous sinus thrombosis (VST), transverse myelitis, facial nerve palsy, small fiber neuropathy, newly developing multiple sclerosis, and some others that have been reported only in a few patients (Table 1). By far the most frequent of the neurological adverse reactions to SARS-CoV-2 vaccinations is headache, followed by GBS, VST, and myelitis (Table 1). Neurological side effects develop after any of the commercially available anti-COVID-19 vaccines but myelitis predominantly after application of the AstraZeneca vaccine (AZV).

TABLE 1. Neurological side effects of SARS-CoV-2 vaccines as per the end of September 2021 NAR NOP Vaccine type Outcome Reference Headache 3051 AZV, Pfizer CR 6, 7 GBS 389 AZV, Pfizer, JJ CR, PR 4, 9 VST 312 vector-based, AZB, JJ nr 16, 17 Transverse myelitis 11 AZV, Moderna, JJ Sinovac PR, CR, nr 12, 13, 19-26 Facial nerve palsy 4 AZV, Pfizer CR, PR 15, 20, 27 Bharat Biotech 14 Small fiber neuropathy 3 Moderna, Pfizer CRm PR, nr 28 Autoimmune encephalitis 3 ATV PR 29 RCVS 2 Moderna CR [Personal communication] Multiple sclerosis 2 Moderna, Pfizer nr 30 Neuromyelitis optica 2 Pfizer, vector based CR 30, 31 Ischemic stroke 1 AZV PR 20 ICB 1 Pfizer PR 32 Tolosa-Hunt syndrome 1 nr PR 33 Hypophysitis 1 Moderna CR 34 Epilepsy 1 Moderna CR 35 Hyperactive encephalopathy 1 Moderna PR 36 ADEM 1 Pfizer PR 37 Abbreviations: ADEM, acute disseminated encephalomyelitis; AZV, AstraZeneca vaccine; CR, complete recovery; ICB, intracerebral bleeding; JJ, Johnson & Johnson vaccine; NAR, neurological adverse reaction; nr, not reported; PR, partial recovery; RCVS, reversible cerebral vasoconstriction syndrome; VST, venous sinus thrombosis.

In a recent multinational, multicenter observational cohort study by means of a standardized questionnaire, among inhabitants of residential care homes of the elderly and patients from hospitals, 2349 patients reported headache after vaccination with the Pfizer vaccine.6 Headache started on the average 18 h after the shot and lasted on the average for 14 h.6 In two thirds of these cases, headache manifested with a single episode. In 38% and 32% of the cases, headache occurred in a frontal or temporal distribution, respectively.6 Headache was characterized as dull in 40%, and intensity was very severe in 8.2%, severe in 32.1%, and moderate in 46.2%.6 According to one of the registration studies for the AZV, headache was the most frequent neurological complication of SARS-CoV-2 vaccinations without providing an exact figure of the headache frequency.7 In a study of 1480 healthcare workers from Malta undergoing vaccination with the Pfizer vaccine, 655 probands reported headache after the first or second shot.8 Several other studies evaluated the frequency of side effects, why the true figure about headache frequency probably exceeds that provided in Table 1.

In a recent review about Guillain-Barre syndrome (GBS) following a SARS-CoV-2 vaccination, 19 cases were collected as per the end of July 2021.4 Fifteen patients had received the AZV, four patients the Pfizer vaccine, and 2 the Johnson & Johnson vaccine.4 In six of these patients, respiratory muscles were involved why they required mechanical ventilation. Only in a single patient was complete recovery achieved until the last follow-up under standard GBS therapies.4 All other patients in whom the outcome was reported achieved only incomplete recovery. One of the 19 patients had a history of a previous GBS from which he had completely recovered.1 Recently, a further case with post-vaccination GBS after having been vaccinated with the AZV has been reported.9 This patient remained bedridden by the 4-week follow-up.9

Thrombotic events in cerebral veins are another neurological complication of SARS-CoV-2 vaccinations. VST has been most frequently reported after vaccinations with the AZV.10 In most cases, VST occurred already after the first shot. Patients in whom VST was attributed to immune-mediated thrombocytopenia received IVIGs or steroids in addition to heparin.10 Notably, sixty-two patients with post-SARS-CoV-2 vaccination VST died.10 In the study with the highest number of patients experiencing a VST after shots with the AZV (n = 187), Pfizer (n = 25), or Moderna (n = 1) vaccine, concomitant thrombocytopenia was found only among those having received the AZV.11 Of the 117 patients with a reported outcome, 44 (38%) in the AZV group had died, compared to 20% in the Pfizer/Moderna group.11

The fourth most frequent neurological side effect of SARS-CoV-2 vaccinations is transverse myelitis, which has been reported in 11 patients so far (Table 1). In seven of them, transverse myelitis occurred after application of the AZV (Table 1). In the patient having received the Johnson & Johnson vaccine, transverse myelitis was associated with facial palsy.12 The patient who developed transverse myelitis after vaccination with the Moderna vaccine, additionally had vitamin-B12 deficiency, which may have contributed to the development of the neurological compromise.13

Several other neurological abnormalities occurred after SARS-CoV-2 vaccinations, but the number of reported cases was below 5 (Table 1). Facial palsy, for example, was reported in four patients and usually occurred unilaterally but occasionally bilaterally.14, 15 Among the cases so far reported, facial palsy occurred as an isolated condition without being associated with other neurological compromise. We did not include “myalgia” as it is only a symptom and usually the underlying diagnosis is unknown.

4 DISCUSSION

This narrative review shows that the most frequent neurological side effects of SARS-CoV-2 vaccines are headache, GBS, VST, and transverse myelitis. Other neurological side effects occur in a very low frequency as expressed by a number of published cases <5. The worst outcome of these side effects is associated with VST, why it should not be missed and treated appropriately in due time.

Headache is by far the most frequent neurological side effect of SARS-CoV-2 vaccinations and occurs with any of the approved vaccines. In the majority of cases, headache starts within a few hours after the vaccination and resolves spontaneously within 48 h.6 However, a subacute type of headache has been delineated which occurs on the average 8 days after the shot and is frequently associated with VST.16 The cause of headache after SARS-CoV-2 vaccinations remains speculative but generally, it can be tension-type headache due to stress, due to intracerebral bleeding (ICB) or subarachnoid bleeding (SAB), due to vasospasms like in SAB or reversible, cerebral vasoconstriction syndrome (RCVS), or due to VST. As VST is frequently associated with ischemic stroke, ICB, or SAB,17 headache may be multi-causal in patients experiencing VST. Thunderclap headache typically occurs with SAB or RCVS.

The pathophysiological mechanism of GBS post-SARS-CoV-2 vaccination is poorly understood but molecular mimicry is regarded as the most plausible concept. Considering that SARS-CoV-2 vaccines induce immunization against the spike protein and that the SARS-CoV-2 spike protein can bind to sialic acid-containing glycoprotein and gangliosides on cell surfaces, an antibody cross-reaction may be the most likely causal link between GBS and immunization to SARS-CoV-2.9

Venous sinus thrombosis is the third most frequent complication of SARS-CoV-2 vaccinations and explained by hypercoagulability. Hypercoagulability after a SARS-CoV-2 vaccination has been attributed to activation of platelets by the virus or to enhancement of the coagulation system by indirect activation of endothelial cells by SARS-CoV-2, shifting endothelium from an anti-thrombotic to a pro-thrombotic state, and by direct activation of complement pathways, promoting thrombin generation.18

A limitation of the review is that not all patients experiencing side effect may have been included. Patients with side effects may have been missed simply because the side effects were mild and not worth to be reported. It is also conceivable that not each patient with a presumed side effect was also published, as publishing is time-consuming and increasingly expensive.

In conclusion, this study shows that safety concerns against SARS-CoV-2 vaccines are backed by an increasing number of studies reporting neurological side effects. The most frequent of them are headache, GBS, VST, and transverse myelitis. Healthcare professionals, particularly neurologists, involved in the management of patients having undergone SARS-CoV-2 vaccinations, should be aware of these side effects and should stay vigilant to recognize them early and treat them efficiently.

CONFLICT OF INTEREST

None.

AUTHOR CONTRIBUTIONS

JF: literature search, discussion, first draft, critical comments, and final approval.

ETHICAL APPROVAL

The study was approved by the institutional review board.

INFORMED CONSENT

Informed consent was obtained.

All data used for the review are available from the corresponding author.

REFERENCES

1Finsterer J. Exacerbating Guillain-Barré syndrome eight days after vector-based COVID-19 vaccination. Case Rep Infect Dis. 2021; 8(2021): 3619131. doi:10.1155/2021/3619131 2Finsterer J, Scorza FA. SARS-CoV-2 vaccines are not free of neurological side effects. Acta Neurol Scand. 2021; 144(1): 109- 110. doi:10.1111/ane.13451 3Wang MW, Wen W, Wang N, et al. COVID-19 vaccination acceptance among healthcare workers and non-healthcare workers in China: a survey. Front Public Health. 2021; 2(9): 709056. doi:10.3389/fpubh.2021.709056 4Finsterer J, Scorza FA, Scorca CA. Post SARS-CoV-2 vaccination Guillain-Barre syndrome in 19 patients. Clinics. 2021; 76:e3286. doi:10.6061/clinics/2021/e3286 5Wiedmann M, Skattør T, Stray-Pedersen A, et al. Vaccine induced immune thrombotic thrombocytopenia causing a severe form of cerebral venous thrombosis with high fatality rate: a case series. Front Neurol. 2021; 30(12): 721146. doi:10.3389/fneur.2021.721146 6Göbel CH, Heinze A, Karstedt S, et al. Clinical characteristics of headache after vaccination against COVID-19 (coronavirus SARS-CoV-2) with the BNT162b2 mRNA vaccine: a multicentre observational cohort study. Brain Commun. 2021; 3(3): fcab169. doi:10.1093/braincomms/fcab169 7Ramasamy MN, Minassian AM, Ewer KJ, et al. Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial. Lancet. 2021; 396(10267): 1979- 1993. doi:10.1016/S0140-6736(20)32466-1 8Cuschieri S, Borg M, Agius S, Souness J, Brincat A, Grech V. Adverse reactions to Pfizer-BioNTech vaccination of healthcare workers at Malta's state hospital. Int J Clin Pract. 2021; 75(10):e14605. doi:10.1111/ijcp.14605 9Introna A, Caputo F, Santoro C, et al. Guillain-Barré syndrome after AstraZeneca COVID-19-vaccination: a causal or casual association? Clin Neurol Neurosurg. 2021; 208: 106887. doi:10.1016/j.clineuro.2021.106887 10Aladdin Y, Algahtani H, Shirah B. Vaccine-induced immune thrombotic thrombocytopenia with disseminated intravascular coagulation and death following the ChAdOx1 nCoV-19 vaccine. J Stroke Cerebrovasc Dis. 2021; 30: 105938. 11Krzywicka K, Heldner MR, van Sánchez Kammen M, et al. Post-SARS-CoV-2-vaccination cerebral venous sinus thrombosis: an analysis of cases notified to the European Medicines Agency. Eur J Neurol. 2021; 28(11): 3656- 3662. doi:10.1111/ene.15029 12Tahir N, Koorapati G, Prasad S, et al. SARS-CoV-2 vaccination-induced transverse myelitis. Cureus. 2021; 13(7):e16624. doi:10.7759/cureus.16624 13Gao JJ, Tseng HP, Lin CL, Shiu JS, Lee MH, Liu CH. Acute transverse myelitis following COVID-19 vaccination. Vaccines. 2021; 9(9): 1008. doi:10.3390/vaccines9091008 14Ercoli T, Lutzoni L, Orofino G, Muroni A, Defazio G. Functional neurological disorder after COVID-19 vaccination. Neurol Sci. 2021; 42(10): 3989- 3990. doi:10.1007/s10072-021-05504-8 15Burrows A, Bartholomew T, Rudd J, Walker D. Sequential contralateral facial nerve palsies following COVID-19 vaccination first and second doses. BMJ Case Rep. 2021; 14(7):e243829. doi:10.1136/bcr-2021-243829 16García-Azorín D, Do TP, Gantenbein AR, et al. Delayed headache after COVID-19 vaccination: a red flag for vaccine induced cerebral venous thrombosis. J Headache Pain. 2021; 22(1): 108. doi:10.1186/s10194-021-01324-5 17Sharifian-Dorche M, Bahmanyar M, Sharifian-Dorche A, Mohammadi P, Nomovi M, Mowla A. Vaccine-induced immune thrombotic thrombocytopenia and cerebral venous sinus thrombosis post COVID-19 vaccination; a systematic review. J Neurol Sci. 2021; 428: 117607. doi:10.1016/j.jns.2021.117607 18Steadman E, Fandaros M, Yin W. SARS-CoV-2 and plasma hypercoagulability. Cell Mol Bioeng. 2021; 28: 1- 10. doi:10.1007/s12195-021-00685-w 19Notghi AA, Atley J, Silva M. Lessons of the month 1: longitudinal extensive transverse myelitis following AstraZeneca COVID-19 vaccination. Clin Med. 2021; 21(5): e535- e538. doi:10.7861/clinmed.2021-0470 20Corrêa DG, Cañete LAQ, Dos Santos GAC, et al. Neurological symptoms and neuroimaging alterations related with COVID-19 vaccine: cause or coincidence? Clin Imaging. 2021; 7(80): 348- 352. doi:10.1016/j.clinimag.2021.08.021 21Román GC, Gracia F, Torres A, Palacios A, Gracia K, Harris D. Acute Transverse Myelitis (ATM): clinical review of 43 patients with COVID-19-associated ATM and 3 post-vaccination ATM serious adverse events with the ChAdOx1 nCoV-19 vaccine (AZD1222). Front Immunol. 2021; 26(12): 653786. doi:10.3389/fimmu.2021.653786 22Voysey M, Clemens SAC, Madhi SA, et al. Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK. Lancet. 2021; 397(10269): 99- 111. doi:10.1016/S0140-6736(20)32661-1 23Khan E, Shrestha AK, Colantonio MA, Liberio RN, Sriwastava S. Acute transverse myelitis following SARS-CoV-2 vaccination: a case report and review of literature. J Neurol. 2021; 5: 1- 12. doi:10.1007/s00415-021-10785-2 24Vegezzi E, Ravaglia S, Buongarzone G, et al. Acute myelitis and ChAdOx1 nCoV-19 vaccine: casual or causal association? J Neuroimmunol. 2021; 359: 577686. doi:10.1016/j.jneuroim.2021.577686. 25Erdem NŞ, Demirci S, Özel T, et al. Acute transverse myelitis after inactivated COVID-19 vaccine. Ideggyógy Sz. 2021; 74(7-8): 273- 276. doi:10.18071/isz.74.0273 26Pagenkopf C, Südmeyer M. A case of longitudinally extensive transverse myelitis following vaccination against Covid-19. J Neuroimmunol. 2021; 358: 577606. doi:10.1016/j.jneuroim.2021.577606 27Ish S, Ish P. Facial nerve palsy after COVID-19 vaccination – a rare association or a coincidence. Indian J Ophthalmol. 2021; 69(9): 2550- 2552. doi:10.4103/ijo.IJO_1658_21 28Watad A, De Marco G, Mahajna H, et al. Immune-mediated disease flares or new-onset disease in 27 subjects following mRNA/DNA SARS-CoV-2 vaccination. Vaccines. 2021; 9(5): 435. doi:10.3390/vaccines9050435 29Zuhorn F, Graf T, Klingebiel R, Schäbitz WR, Rogalewski A. Postvaccinal encephalitis after ChAdOx1 nCov-19. Ann Neurol. 2021; 90(3): 506- 511. doi:10.1002/ana.26182 30Khayat-Khoei M, Bhattacharyya S, Katz J, et al. COVID-19 mRNA vaccination leading to CNS inflammation: a case series. J Neurol. 2021; 4: 1- 14. doi:10.1007/s00415-021-10780-7 31Chen S, Fan XR, He S, Zhang JW, Li SJ. Watch out for neuromyelitis optica spectrum disorder after inactivated virus vaccination for COVID-19. Neurol Sci. 2021; 42(9): 3537- 3539. doi:10.1007/s10072-021-05427-4 32Finsterer J, Redzic Z. Symptomatic peduncular, cavernous bleeding following SARS-CoV-2 vaccination induced immune thrombocytopenia. Brain Hemorrhages. 2021. doi:10.1016/j.hest.2021.09.001 33Chuang TY, Burda K, Teklemariam E, Athar K. Tolosa-Hunt syndrome presenting after COVID-19 vaccination. Cureus. 2021; 13(7):e16791. doi:10.7759/cureus.16791 34Murvelashvili N, Tessnow A. A case of hypophysitis following immunization with the mRNA-1273 SARS-CoV-2 vaccine. J Investig Med High Impact Case Rep. 2021; 9: 232470962110433. doi:10.1177/23247096211043386 35Šín R, Štruncová D. Status epilepticus as a complication after COVID-19 mRNA-1273 vaccine: a case report. World J Clin Cases. 2021; 9(24): 7218- 7223. doi:10.12998/wjcc.v9.i24.7218 36Al-Mashdali AF, Ata YM, Sadik N. Post-COVID-19 vaccine acute hyperactive encephalopathy with dramatic response to methylprednisolone: a case report. Ann Med Surg. 2021; 69: 102803. doi:10.1016/j.amsu.2021.102803 37Vogrig A, Janes F, Gigli GL, et al. Acute disseminated encephalomyelitis after SARS-CoV-2 vaccination. Clin Neurol Neurosurg. 2021; 208: 106839. doi:10.1016/j.clineuro.2021.106839