Spectrum of neurological complications following COVID-19 vaccination

Authors: Ravindra Kumar Garg1 and Vimal Kumar Paliwal2 Neuro 2022; 43(1): 3–40.Published online 2021 Oct 31. doi: 10.1007/s10072-021-05662-9PMCID: PMC8557950PMID: 34719776

Abstract

COVID-19 vaccines have brought us a ray of hope to effectively fight against deadly pandemic of COVID-19 and hope to save lives. Many vaccines have been granted emergency use authorizations by many countries. Post-authorization, a wide spectrum of neurological complications is continuously being reported following COVID-19 vaccination. Neurological adverse events following vaccination are generally mild and transient, like fever and chills, headache, fatigue, myalgia and arthralgia, or local injection site effects like swelling, redness, or pain. The most devastating neurological post-vaccination complication is cerebral venous sinus thrombosis. Cerebral venous sinus is frequently reported in females of childbearing age, generally following adenovector-based vaccination. Another major neurological complication of concern is Bell’s palsy that was reported dominantly following mRNA vaccine administration. Acute transverse myelitis, acute disseminated encephalomyelitis, and acute demyelinating polyneuropathy are other unexpected neurological adverse events that occur as result of phenomenon of molecular mimicry. Reactivation of herpes zoster in many persons, following administration of mRNA vaccines, has been also recorded. Considering the enormity of recent COVID-19-vaccinated population, the number of serious neurological events is miniscule. Large collaborative prospective studies are needed to prove or disprove causal association between vaccine and neurological adverse events occurring vaccination.

SARS-CoV-2 is a novel coronavirus that can rapidly affect human beings and can result in coronavirus disease (COVID-19). COVID-19 is dominantly characterized by lung damage and hypoxia. The first case of COVID-19, in Wuhan, China, was reported on December 8, 2019. Later, the World Health Organization announced COVID-19 as a worldwide health emergency, on January 30, 2020. On March 11, 2020, COVID-19 was declared a pandemic. As per the latest World Health Organization report, there were 196,553,009 confirmed cases as on August 1, 2021 along with 4,200,412 deaths [1].

Early this year, COVID-19 vaccines has brought a ray of hope to effectively fight against this deadly pandemic and save precious human lives. Currently, four major vaccine types are being used. These vaccine types include viral vector-based vaccines, COVID-19 mRNA-based vaccines, inactivated or attenuated virus vaccine, and protein-based vaccines. In viral vector-based vaccines, adenovirus is used to deliver a part of SARS-COV-2 genome to human cells. Human cells use this genetic material to produce SARS-COV-2 spike protein. Human body recognizes this protein to start a defensive response. The mRNA-based vaccines consist of SARS-COV-2 RNA. Once introduced, genetic material helps in making SARS-COV-2-specific protein. This protein is recognized by human body to start defensive immune reaction. In inactivated or attenuated vaccines, killed or attenuated SARS-COV-2 virus triggers immune response. Protein-based vaccines use the spike protein or its fragments for inciting immune response. These COVID-19 vaccines have received emergency approvals in different countries for human use [2]. As per the latest World Health Organization report, until August 1, 2021, globally, a total of 3,839,816,037 COVID-19 vaccine doses have been globally administered [1].

In fact, all kinds of vaccines are associated with the risk of several serious neurological complications, like acute disseminated encephalomyelitis, transverse myelitis, aseptic meningitis, Guillain-Barré syndrome, macrophagic myofasciitis, and myositis. Influenza vaccine has been found associated with narcolepsy in young persons. Several pathogenic mechanisms, like molecular mimicry, direct neurotoxicity, and aberrant immune reactions, have been ascribed to explain these vaccines associated with neurological complications [3]. Even COVID-19 vaccines are not free from neurological complications. In this article, we have focused on the neurological complications following COVID-19 vaccination that were reported after their emergency use authorizations.

Search strategy

We reviewed available data regarding neurological complications (post-authorization) described following the World Health Organization–approved COVID-19 vaccination. We classified COVID-19 vaccination associated with neurological complications in two broad groups: (1) common but mild and (2) rare but severe. We searched PubMed, Google, and Google Scholar databases using the keywords “COVID‐19” or “SARS‐CoV‐2” and “vaccination” or “vaccine,” to identify all published reports on neurological complications of COVID‐19 vaccines. We in this review will focus on spectrum of published neurological adverse events following COVID-19 vaccination. Last search was done on August 1, 2021.

Mild neurological events

Neurological adverse events following COVID-19 vaccination are generally mild and transient, like fever/chills, headache, fatigue, myalgia and arthralgia, or local injection site effects like swelling, redness, or pain. These mild neurological symptoms are common following administration of all kinds of COVID-19 vaccines.

Anxiety-related events, like feeling of syncope and/or dizziness, are particularly common. For example, Centers for Disease Control and Prevention, in a report published on April 30, 2021, recorded 64 anxiety-related events (syncope in 17) among 8,624 Janssen COVID-19 vaccine recipients. None of the event was labeled as serious [4].

In Mexico (data available in form of preprint) among 704 003 subjects who received first doses of the Pfizer-BioNTech mRNA COVID-19 vaccine, 6536 adverse events following immunization were recorded. Among those, 4258 (65%) had at least one neurologic manifestation, mostly (99.6%) mild and transient. These events included headache (62·2%), transient sensory symptoms (3·5%), and weakness (1%). In this study, there were only 17 serious adverse events, seizures (7), functional syndromes (4), Guillain-Barré syndrome (3), and transverse myelitis (2) [5].

In South Korea, Kim and co-workers collected data of post-vaccination adverse events following first dose of adenovirus vector vaccine ChAdOx1 nCoV-19 (1,403 subjects) and mRNA vaccine BNT162b2 (80 subjects) vaccinations. Data were collected daily for 7 days after vaccination. Authors noted that 91% of adenovirus-vectored vaccine and 53% of mRNA vaccine recipients had mild adverse reactions, like injection-site pain, myalgia, fatigue, headache, and fever [6]. A mobile-based survey among healthcare workers (265 respondents) who received both doses of the BNT162b2 mRNA vaccine was conducted. The most common adverse effects were muscle ache, fatigue, headache, chills, and fever. Adverse reactions were higher after the second dose compared with that after the first dose [7].

Headache

Headache is one of the most frequent mild neurological complaints reported by a large number of COVID-19 vaccine recipients, soon after they receive vaccine.

A review of headache characteristic noted that among 2464 participants, headache begun 14.5 ± 21.6 h after AstraZeneca adenovirus vector vaccine COVID-19 vaccination and persisted for 16.3 ± 30.4 h. Headaches, in majority, were moderate to severe in intensity and generally localized to frontal region. Common accompanying symptoms were fatigue, chills, exhaustion, and fever [8]. In a multicenter observational cohort study, Göbel et al. recorded clinical characteristic of headache occurring after the mRNA BNT162b2 mRNA COVID-19 vaccination. Generally, headache started 18.0 ± 27.0 h after vaccination and persisted for 14.2 ± 21.3 h. In majority, the headaches were bifrontal or temporal, dull aching character and were moderate to severe in intensity. The common accompanying symptoms were fatigue, exhaustion, and muscle pain [8].

Severe neurological adverse events

Serious adverse reaction following immunization is defined as a post-vaccination event that are either life-threatening, requires hospitalization, or result in severe disability. The World Health Organization listed Guillain-Barré syndrome, seizures, anaphylaxis, syncope, encephalitis, thrombocytopenia, vasculitis, and Bell’s palsy as serious neurologic adverse events. Instances of serious adverse events following COVID-19 vaccinations are continuously pouring in the current scientific literature and are source of vaccine hesitancy in many persons [9] (Fig. 1).

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Fig. 1

A flow diagram depicts the spectrum of severe neurological complications following COVID-19 vaccinations (ADEM, acute disseminated encephalomyelitis; CVST, cerebral venous sinus thrombosis; LETM, longitudinally extensive transverse myelitis; MS, multiple sclerosis; NMOSD, neuromyelitis optica spectrum disorders; PRES, posterior reversible encephalopathy syndrome; TIA, transient ischemic attacks)

Functional neurological disorders

Functional neurological disorders are triggered by physical/emotional stress following an injury, medical illness, a surgery, or vaccination. Functional neurological disorders often remain misdiagnosed despite extensive workup.

After availability of COVID-19 vaccine, many YouTube videos depicted continuous limb and trunk movements and difficulty walking immediately after COVID-19 vaccine administration. These videos were of concern as they were the source of “vaccine hesitancy” [10]. Kim and colleagues reviewed several such social media videos demonstrating motor movements consistent with functional motor symptoms occurring after administration of COVID-19 vaccine. Motor movements were bizarre asynchronous and rapidly variable in frequency and amplitude consistent with functional neurological disorder. The Functional Neurological Disorder Society has lately clarified that movement disorder is consistent with functional in nature. The spread of these videos are important because these functional disorders created concerns for vaccine hesitancy [11].

Several other kinds of functional neurological disorders have also been reported. Butler and colleagues described two young ladies, who presented with functional motor deficits mimicking stroke. Both these patients had variability in weakness and had many non-specific symptoms. A detailed workup and neuroimaging failed to demonstrate any specific abnormality [12]. Ercoli and colleagues described a middle-aged man who, immediately after vaccine administration, reported bilateral facial paralysis along with failure to blink. These manifestations resolved quickly within 40 min. Immediately after administration of second dose of vaccine, he complained of respiratory distress and swollen tongue. Again, all these symptoms resolved quickly following treatment with corticosteroids, however, he developed new symptoms in the form of right hemiparesis. Two weeks later, he developed facial hypoesthesia. A detailed workup of the patient failed to demonstrate any abnormality. A diagnosis of functional neurological disorder was, finally, made [13].

Cerebral vascular events

As a matter of concern, increasing number of reports about adenoviral vector vaccine-induced cerebral vascular adverse events, like cerebral venous thrombosis, arterial stroke, and intracerebral hemorrhage, is getting published in leading medical journals. These reports are alarming as post-vaccination vascular events culminate either in severe disability or death. Vaccine-induced cerebral vascular adverse events are generally associated with severe immune-mediated thrombotic thrombocytopenia. Thrombocytopenia generally clinically manifests within 5 to 30 days after administration of adenovirus vector-based vaccines. In post-vaccination thrombotic thrombocytopenia, a picture similar to that of heparin-induced thrombocytopenia is encountered. When heparin binds platelet factor 4, there is generation of antibodies against platelet factor 4. Antibodies against platelet factor 4 result in platelet destruction and trigger the intravascular blood clotting [14]. The post-mortem examination, in patients with vaccine-induced thrombocytopenia, demonstrated extensive involvement of large venous vessels. Microscopic findings showed vascular thrombotic occlusions occurring in the vessels of multiple body organs along with marked inflammatory infiltration [15]. The vector-based vaccines contain genetic material of SARS-COV-2 that is capable of encoding the spike glycoprotein. Possibly, leaked genetic material binds to platelet factor 4 that subsequently activates formation of autoantibodies. These autoantibodies destroy platelets [1617].

Cerebral venous thrombosis

Cerebral venous thrombosis is the one of the most feared devastating COVID-19 vaccine-associated neurological complication. Cerebral venous thrombosis should be suspected in all vaccinated patients, who has persistent headache. Headache is generally unresponsive to the analgesics, and some patients may have focal neurological deficits. Affected patients are generally females of younger ages (Table ​(Table1)1) [1846].

Table 1

Clinical, magnetic resonance imaging findings, and outcome details of patients who developed cerebral venous sinus thrombosis after vaccination against SARS-CoV-2

ReferenceNeurological complicationsCountryAge/sexVaccine typeDuration of onset after vaccinationClinical featuresNeuroimagingTreatment given
Castelli et al. [18]Cerebral venous sinus thrombosisItaly50/MCOVID-19 vaccine AstraZeneca10 daysSevere headache, right hemiparesis, unsteady gait, and visual impairment of 4 days Patient needed ICU care and mechanical ventilationIntra-parenchymal hemorrhage CT angiography = left transverse and sigmoid venous sinuses thrombosisFibrinogen concentrate (10 g total) and platelet (4 units total) a bilateral decompressive craniectomy
D’Agostino et al. [19Cerebral venous thrombosis and disseminated intravascular coagulationItaly54/FThe AstraZeneca vaccine12 daysAltered sensorium and hemiparesis Myocardial infarctionMultiple subacute lobar hemorrhages basilar artery thrombosis associated with the superior sagittal sinus thrombosis Bilateral adrenal hemorrhageIntensive care unit
Scully et al. (report of 23 patients) [20]Thrombocytopenia (23 patients) Cerebral venous thrombosis (13 patients)London12 years (Median)ChAdOx1 nCoV-19 vaccine (AstraZeneca)6 to 24 days13 patients with cerebral venous thrombosisNot availableNot available
Franchini et al. [21]Cerebral venous thrombosisItaly50/MCOVID-19 vaccine AstraZeneca7 daysComa thrombocytopeniaIntra-parenchymal hemorrhage Angiography cerebral venous sinus thrombosisIntensive care unit
Mehta et al. [22]Cerebral venous sinus thrombosisUK32/MVaxzevria vaccine9 daysThunderclap headache Left hemiparesis, left-sided incoordination Thrombocytopenia and rapidly evolving comaSuperior sagittal sinus and cortical vein thrombosis and significant cortical edema with small areas of parenchymal and subarachnoid hemorrhageIntensive care unit
25/MVaxzevria vaccine6 daysHeadache hemiparesis, left hemisensory loss Seizures, agitation, decerebrate posturing, reduced GCS ThrombocytopeniaSuperior sagittal sinus thrombosis with extension into the cortical veins and hemorrhage in lobar and sub-arachnoid locationsIntensive care unit
Bersinger et al. [23]Cerebral venous sinus thrombosisFrance21/FChAdOx1 nCoV-19 vaccine9 daysHeadaches, seizures, hemiplegia, expressive aphasia, and no pupillary abnormalities and altered sensorium The platelet count was 61,000 per cubic millimeterCT of the head showed massive thrombosis in the deep and superficial cerebral veins, thrombosis of the left jugular vein, and left frontoparietal venous hemorrhagic infarctionA selective arterial embolization was performed immediately after decompressive craniectomy IV immunoglobulin Fondaparinux
Ramdeny et al. [24]Cerebral venous sinus thrombosisUnited Kingdom54/MCOVID-19 Vaccine AstraZeneca21 daysWorsening headache, bruising and unilateral right calf swelling Thrombocytopenia D-dimer = 60,000 ng/ml Anti-platelet factor 4Cerebral venous sinus thrombosisIntravenous immunoglobulin
Zakaria et al. [25]Cerebral venous sinus thrombosisMalaysia49/MFirst dose of mRNA SARS-CoV-2 vaccine16 daysNew onset of mild to moderate headache and giddinessCT) of the brain showed cordlike hyperattenuation within the left transverse and sigmoid sinus suggestive of cord or dense clot sign CT cerebral venography a long segment-filling defect and empty delta sign within the superior sagittal sinus extending into the torcula Herophili, left transverse sinus, and sigmoid sinus to proximal internal jugular veinSubcutaneous Clexane improved
Ryan et al. [26]Cerebral venous sinus thrombosisIreland35/FAZD1222 (COVID-19 Vaccine AstraZeneca)10 daysHeadache thrombocytopenia bruising and petechiae Antibody to platelet factor 4MR venogram showed cerebral venous sinus thrombosisApixaban
Graf et al. [27]Cerebral venous sinus thrombosisGermany29/MChAdOx1 nCov-19, AstraZeneca9 daysSevere headache and hematemesis thrombocytopeniaComplete thrombosis of the left transverse and sigmoid sinus down to the left proximal jugular vein Temporo-parietal intracranial hemorrhage CT angiography revealed extensive thrombosis of the mesenteric and portal veinHigh-dose immunoglobulins Argatroban
George et al. [28]Cerebral venous sinus thrombosisUSA40/FChAdOx1 nCov-19, AstraZeneca7 daysHeadache thrombocytopenia Antibody to platelet factor 4Venous thrombosis involving the left transverse sigmoid sinus and internal jugular veinA direct thrombin inhibitor (bivalirudin) Intravenous immune globulin (IVIG)
Jamme et al. [29]Cerebral venous sinus thrombosisFrance69/FFirst dose of Oxford–AstraZeneca vaccine11 daysHeadache associated with behavioral symptomsBilateral frontal hemorrhage cerebral venous thrombosis of the left internal jugular vein, sigmoid sinus, and superior sagittal sinusNone
Tiede et al. (report of 5 patients) [30]Cerebral venous sinus thrombosisGermany41 and 67 years All femalesChAdOx1 COVID-19 vaccine (AZD1222, Vaxzevria)5 to 11 days after first vaccinationCerebral venous sinus thrombosis (CVST), splanchnic vein thrombosis (SVT), arterial cerebral thromboembolism, and thrombotic microangiopathy thrombocytopenia Autoantibodies against platelet factor 4Brain hematomas infarcts, presence of thrombi in major vesselsIntravenous immunoglobulin or corticosteroids Argatroban
Schulz et al. (report of 45 cases) [31]Cerebral venous thrombosisGermany46.5 years (mean)/35 femalesBNT162b2, ChAdOx1, and mRNA-1273Within 30 days of vaccinationThrombocytopenia in all patientsCerebral venous thrombosisIntravenous immunoglobulins, plasmapheresis, corticosteroids, anticoagulants
Bourguignon et al. [32]A report three patients one had cerebral venous sinus thrombosisCanada69/MChAdOx1 nCov-19, AstraZeneca12 daysDiabetes mellitus, hypertension, obstructive sleep apnea, recently diagnosed prostate cancer Headache and confusion left-sided weakness Thrombocytopenia Autoantibodies against platelet factor 4Right middle cerebral-artery stroke with hemorrhagic transformation Right cerebral transverse and sigmoid sinuses, right internal jugular vein, hepatic vein, and distal lower-limb vein; pulmonary embolismIntravenous immunoglobulin Plasmapheresis
Gattringer et al. [33]Cerebral venous sinus thrombosisAustria39/FThe first vaccination with ChAdOx1 nCov-19 (AstraZeneca)8 daysHeadache since 2 days thrombocytopenia (84 × 10 [8]/L)Left sigmoid/transverse sinus thrombosis without brain parenchymal involvementIntravenous immunoglobulin
Ikenberg et al. [34]Cerebral venous sinus thrombosisGermanyearly 30 s/FThe first dose of ChAdOx1 nCov-19 (AstraZeneca)Headache Gait ataxia, and amnestic difficulties as well as aphasia Thrombocytopenia of 37 000/µLCVST of the left transverse and sigmoidal sinus with a left-temporal and left-cerebellar intracerebral hemorrhageIntravenous immunoglobulin argatroban
Clark et al. [35]Cerebral venous sinus thrombosisUSA40/FThe Ad26.COV2.S (Johnson & Johnson/ Jansen) vaccine5 daysWorsening headaches thrombocytopeniaCerebral venous sinus thrombosis involving the left transverse and sigmoid sinuses, extending into the left internal jugular veinBivalirudin infusion Intravenous immunoglobulin
Bonato et al. [36]Cerebral venous sinus thrombosisItaly26/FChAdOx1 nCoV-19 vaccine14 daysheadache non-responsive to drugs right-sided weakness and visual disturbances rapidly deteriorated with decreased consciousnessMultifocal venous thrombosis with bilateral occlusion of parietal cortical veins, straight sinus, vein of Galen, internal cerebral veins, and inferior sagittal sinus. Right parietal and left frontoparietal lobes an extensive venous infarction with hemorrhagic transformation Platelet-factor 4 (PF4)–heparin IgG antibodies – elevated thrombocytopeniaDexamethasone Intravenous immunoglobulin argatroban
Wang et al. [37]Cerebral venous sinus thrombosisTaiwan41/FFirst vaccination with ChAdOx1 nCoV-197 daysFever and headache thrombocytopenia positive anti-PF4 antibodiesMR venography revealed cerebral venous sinus thrombosisIntravenous immunoglobulin
Dutta et al. [38]Cerebral venous sinus thrombosisIndia51/MFirst-dose of COVISHIELD6 daysHeadache double vision papilledema Platelet count was normalMR venography revealed thrombosis in superior sagittal sinus and transverse sinusLow-molecular-weight heparin
Aladdin et al. [39]Cerebral venous sinus thrombosisSaudi Arabia36/FFirst dose of the ChAdOx1 nCoV-19 vaccine14 daysVomiting and severe headache left upper limb weakness thrombocytopenia Disseminated intravascular coagulationBrain computed tomography (CT) scan showed superior sagittal thrombosis with thickened cortical veins and bilateral hypodensities in the parietal lobesLow-molecular-weight heparin ICU care
Lavin et al. (a series of 4 patients) [40]Cerebral venous sinus thrombosisIreland29/F 38/M 50/F 35/FVaxzevria vaccine (ChAdOx1 nCoV-19, AstraZeneca)10 days 16 days 23 days 14 daysVisual disturbance followed by a headache, nausea, vomiting, bruising and petechiae severe thunderclap headache, nausea and vomiting headache, persistent bruising and petechiae all had thrombocytopeniaDural venous sinus thrombosis in one patient only other had abdominal abnormalitiesIntravenous immunoglobulin
Tølbøll Sørensen et al. [41]Cerebral venous sinus thrombosisUK30/FChAdOx1 nCoV-19Headache and general malaise portal vein thrombosis thrombocytopenia and consumption coagulopathy Anti-platelet antibodies were detectedNormalTinzaparin
Fan et al. [42] (a series of 3 patients)Cerebral venous sinus thrombosisSingapore54/M 62/F 60/FBNT162b2 mRNA vaccination1 day 9 days 8 daysSevere headache and vomiting and acute left hemiparesis Headache and vomiting Right ataxic hemiparesis There was no thrombocytopeniaA large right temporo-parietal lobe intraparenchymal hemorrhage Acute right cerebral bleed involving occipital and temporal lobes associated with subarachnoid hemorrhage Venous infarct in bilateral perirolandic gyri Venogram confirmed cerebral venous sinus thrombosis in all threeLow-molecular-weight heparin decompressive craniectomy
Suresh and Petchey  [43]Cerebral venous sinus thrombosisUK27/MChAdOx1 nCOV-19 vaccine2 daysWorsening headache and new homonymous hemianopia Thrombocytopenia Anti-platelet antibodies were detectedAcute parenchymal bleed with subdural extension CT venogram confirmed significant cerebral venous sinus thrombosisDabigatran and intravenous immunoglobulins
Dias et al. (a series of 2 patients) [44]Cerebral venous sinus thrombosisPortugal47/F 67/FBNT162b2 mRNA SARS-CoV-2 vaccine6 days 3 daysHeadache, nausea and photophobia a sudden left motor deficit Sudden right lower limb clonic movements, followed by motor deficit, loss of consciousness and headache There was no thrombocytopenia Anti-platelet antibodies were not detectedMRI with venography revealed thrombosis of superior sagittal, right lateral, transverse, sigmoid sinuses, and jugular vein and left sigmoid sinus, together with right frontal subarachnoid hemorrhage and a cortical venous infarct Brain MRI showed thrombosis of high convexity cortical veins, superior sagittal, right transverse, and sigmoid sinus and jugular veinAcetazolamide and enoxaparin Levetiracetam 500 mg bid and enoxaparin
Guan et al. [45]Cerebral venous sinus thrombosisTaiwan52/MThe first dose of ChAdOx1 nCov-19 (AstraZeneca)10 daysNausea and thunderclap headache thrombocytopenia Platelet factor 4 antibodies detectedHyperdensity of the sinus, including cord sign and dense vein sign at the left transverse and sigmoid sinuses CT venogram revealed CVST at the left transverse sinus and sigmoid sinuses and thrombosis of the left internal jugular veinApixaban Outcome not provided
Varona et al. [46]Cerebral venous sinus thrombosis and primary adrenal insufficiencySpain47/MAdenoviral (ChAdOx1) vector-based COVID-19 vaccine10 daysHeadache, somnolence, and mild confusion Blateral segmentary pulmonary embolism Thrombocytopenia Anti-platelet antibodies were detectedConsistent with cerebral venous thrombosisIntravenous immunoglobulins and subcutaneous fondaparinux hydrocortisone Patient improved

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In Europe, since March 2021, cases of cerebral venous thrombosis started pouring in following COVID-19 vaccination, particularly after administration of viral vector based (AstraZeneca ChAdOx1 nCoV-19 and the Johnson and Johnson Ad26. COV2.S) vaccines [22]. Scully and colleagues recently reported findings of 23 patients, who presented with thrombosis and thrombocytopenia (platelet counts below 10 × 109/L). These patients developed thrombosis and thrombocytopenia 6 to 24 days after they received the first dose of the viral vector-based vaccines. In a significant observation, authors, in majority of patients, demonstrated the presence of autoantibodies against platelet factor 4. Additionally, D-dimer levels were found elevated [20]. Tiede and co-workers reported five German cases of prothrombotic immune thrombocytopenia after vaccination with viral vector-based vaccine (Vaxzevria). In these patients, acute vascular events clinically manifested as cerebral venous sinus thrombosis, splanchnic vein thrombosis, arterial cerebral thromboembolism, and/or thrombotic microangiopathy within 2 weeks post vaccination. All five patients had low platelet counts and markedly raised D-dimer. In all, autoantibodies against platelet factor 4 were also demonstrated [30].

Pottegård et al. in Denmark and Norway evaluated incidence of arterial events, venous thromboembolism, thrombocytopenia, and bleeding among vaccinated population. The vaccinated cohorts comprised of 148,792 Danish people and 132,472 persons from Norway. All has received their first dose of viral vector-based vaccine (ChAdOx1-S). An excess rate of venous thromboembolism (like cerebral venous thrombosis) was observed among vaccine recipients, within 28 days of vaccine administration. Authors estimated an increased rate for venous thromboembolism corresponding to 11 excess events per 100,000 vaccinations with 2.5 excess cerebral venous thrombosis events per 100,000 vaccinations [47].

Krzywicka et al., from the Netherlands, collected data of 213 cases with post-vaccination (187 after adenoviral vector vaccines and 26 after a mRNA vaccine) cerebral venous sinus thrombosis; they noted thrombocytopenia in 107/187 (57%) post-vaccination cerebral venous sinus thrombosis cases. Thrombocytopenia was not recorded in any of patients, who received an mRNA-based vaccine. Cerebral venous sinus thrombosis after adenoviral vector vaccines carried poorer prognosis. Approximately, 38% (44/117) patients in adenoviral vector vaccine group died, while in mRNA vaccine group, 20% (2/10) had died [48].

Recently published National Institute for Health and Care Excellence (NICE) guidelines recommend that the patients with clinical diagnosis of vaccine-induced immune thrombocytopenia and thrombosis should be treated with intravenous administration of human immunoglobulin, at a dose of 1 g/kg. If there is no response or there is further deterioration, second dose of human immunoglobulin should be given. In patients with insufficient response, methylprednisolone 1 g intravenously for 3 days or dexamethasone 20 to 40 mg for 4 days can be used [49].

Heparin needs to be avoided, instead alternative anticoagulants like argatroban, bivalirudin, fondaparinux, rivaroxaban, or apixaban should be used for anticoagulation [4951]. NICE guidelines further recommend that patients with very low platelet count should be treated either alone with a argatroban or a combination of argatroban and platelet transfusion [49].

Arterial events

Several acute arterial events, like arterial thrombosis, intracerebral hemorrhage, transient global amnesia, and spinal artery ischemia, have also been reported following vaccination [31].

Simpson and colleagues, in Scotland, estimated the incidence of vaccine-associated thrombocytopenia and vascular events following administration of first dose of viral vector-based vaccine (ChAdOx1) or mRNA (BNT162b2 Pfizer-BioNTech or mRNA-1273 Moderna) vaccination. First dose of viral vector-based vaccine was associated with small enhanced risk of idiopathic thrombocytopenic purpura; in addition, up to 27 days after vaccination, there was possibility of an increased risk for thromboembolic and hemorrhagic events. No such adverse associations were noted with mRNA vaccines [52]. The reports of COVID-19 vaccine-related intracerebral hemorrhage and ischemic stroke are summarized in Table ​Table22 [5361].

Table 2

Clinical, neuroimaging and outcome details of patients who suffered strokes (other than cerebral venous thrombosis) after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Athyros and Doumas [53]Intracerebral hemorrhageGreece71/FModerna anti-COVID-19 vaccine3 daysRight hemiplegia, aphasia, agnosia Acute hypertensive crisisLeft basal ganglia hemorrhageClonidine, furosemideDied
Bjørnstad-Tuveng [54]Intracerebral hemorrhageNorwayThirties/FAstraZeneca’s vaccine ChAdOx1 nCoV-199 daysSlurred speech, left hemiparesis, and reduced consciousnessRight intracerebral hemorrhage on CT, thrombosis in transverse sinus and pulmonary artery on postmortemICU managementDied
de Mélo Silva et al. [55]Intracerebral hemorrhage with intraventricular extensionBrazil57/FChAdOx1 nCoV-19 vaccine5 daysLeft hemiparesis, vomiting, and somnolenceA large right deep frontal lobe parenchymal hematomaICU management Decompressive craniectomySurvived with disabilities
Bayas et al. [56]Bilateral superior ophthalmic vein thrombosis, ischemic stroke, and immune thrombocytopeniaGermany55/FSARS-CoV-2— ChAdOx1 nCoV-1910 daysFlu-like illness, diplopia, vision loss, a transient, mild, right-sided hemiparesis, and aphasia, focal seizuresMRI showed superior ophthalmic vein thrombosis An MRI showed an ischemic stroke in the left parietal lobe, middle cerebral artery territory, with restricted diffusionIntravenous dexamethasone AnticoagulantsImproved
Al-Mayhani et al. [57Ischemic stroke with thrombocytopeniaLondon35/F 37/F 43/FChAdOx1 nCoV-19 vaccine ChAdOx1 nCoV-19 vaccine ChAdOx1 nCoV-19 vaccine11 days 12 days 21 daysLeft face, arm, leg weakness and drowsiness Headache, left visual field loss, confusion, left arm weakness DysphasiaRight middle-cerebral artery infarct Bilateral acute border zone infarcts Left middle-cerebral artery infarctDecompressive hemicraniectomy Intravenous immunoglobulin Intravenous immunoglobulinDied Improved Stable
Blauenfeldt et al. [58]Ischemic strokeDenmark60/MmRNA-based vaccine BNT162b2 (Pfizer/BIOTECH)7 daysBilateral adrenal hemorrhages A massive right sided ischemic stroke Thrombocytopenia Platelet factor 4 (PF‐4) reactive antibodiesAngiography showed occlusion of the right internal. Carotid arteryIntensive care unitPalliative care
Malik et al. [59]transient ischemic attackUSA43/FJohnson and Johnson COVID-19 Ad26.COV2.S vaccination10 daysHeadache, fever, body aches, chills, mild dyspnea and light-headedness thrombocytopenia numbness and tingling of her face and right armRight internal carotid artery (ICA) thrombusFondaparinuxImproved
Finsterer and Korn [60]AphasiaAustria52/MThe second dose of an mRNA-based SARS-CoV-2 vaccine7 daysSudden-onset reading difficulty and aphasia motor aphasia with paraphasiaA lobar bleeding in the left temporal lobeSupportiveImproved
Walter et al. [61]Ischemic stroke Main stem occlusion of middle cerebral arteryGermanyFirst dose ChAdOx1 nCov-19 vaccineacute headache, aphasia, and hemiparesis Platelet count and fibrinogen level were normalMain stem occlusion of middle cerebral artery A wall-adherent, non-occluding thrombus in the ipsilateral carotid bulb was notedWithin 1 h after start of IV thrombolysisThrombus dissolved and patient improved

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Intracerebral hemorrhage

Athyros and Doumas reported a 71-year-old female. who developed intracerebral hemorrhage after she received the first dose of the Moderna mRNA vaccine.

On the third post-vaccination day, the patient developed right hemiplegia, aphasia, and agnosia along with accelerated hypertension. Computed tomography revealed a hematoma in the left basal ganglia. On the 9th day, she died [53].

In another report, Bjørnstad-Tuveng et al. described a young woman, who had a fatal cerebral event following vaccination with AstraZeneca’s ChAdOx1 nCoV-19 vaccine. She was found to have severe thrombocytopenia. The patient died the next day of the event. Post-mortem examination revealed antibodies against platelet factor 4 and the presence of small thrombi in the transverse sinus, frontal lobe, and pulmonary artery [54].

Acute ischemic stroke

Bayas and co-workers described a case that presented with superior ophthalmic vein thrombosis, ischemic stroke, and immune thrombocytopenia, after administration of viral vector-based vaccine. Intravenous dexamethasone resulted in marked improvement in platelet count [56]. Al-Mayhani et al. described three cases of vaccine-induced thrombotic thrombocytopenia, all presented with arterial strokes. Authors opined that young patients with arterial stroke after receiving the COVID-19 vaccine should always be evaluated for vaccine-induced thrombotic thrombocytopenia. Other laboratory tests, like platelet count, D-dimers, fibrinogen level, and testing for platelet factor 4 antibodies, should also be performed [57].

Blauenfeldt et al. described a 60-year-old woman, who presented with intractable abdominal pain, 7 days after receiving the adenoviral (ChAdOx1) vector-based COVID-19 vaccine. Abdominal computed tomography revealed bilateral adrenal necrosis. Later, a massive right cerebral infarction, secondary to occlusion of the right internal carotid artery, occurred that led to death of the patient. Blood tests showed thrombocytopenia, elevated in D-dimer and platelet factor 4 antibodies [58].

Many reports of acute brain disorders like encephalopathy, seizures, acute disseminated encephalopathy, neuroleptic malignant syndrome, and post-vaccine encephalitis were described secondary to COVID-19 vaccine. These are summarized in Table ​Table33 [6275].

Table 3

Clinical, neuroimaging and outcome details of patients who presented with an acute brain disorder (other than cerebral venous thrombosis and arterial stroke) after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Baldelli et al. [62]Reversible encephalopathyItaly77/MThe first dose of ChAdOx1 nCoV-19 vaccine (AstraZeneca)1 dayDelirium A significant increase of interleukin (IL)-6 in both CSF and serumNormalCorticosteroids
Aladdin and Shirah [63]New-onset refractory status epilepticusSaudi Arabia42/FChAdOx1 nCoV-19 vaccine10 daysHeadache and fever first-ever generalized tonic–clonic seizure lorazepam, levetiracetam, and phenytoin failed to controlIncrease in the signal on FLAIR images at bilateral hippocampi and insulaMidazolam and propofol Plasma exchangeImproved
Ghosh et al. [64]SeizuresIndia68/MCovishield vaccine4 daysFocal onset non-motor seizurePeriventricular leukoaraiosis and cortical atrophybrivaracetamImproved
Liu et al. [65] (two cases)Associated with non-convulsive status epilepticusUSA86/F 73/MModerna COVID-19 vaccine7 days 21 daysDiastolic dysfunction, chronic kidney disease and diabetes mellitus with acute encephalopathy Acute confusion with visual hallucinations EEG demonstrated non-convulsive focal status epilepticus Acute encephalopathy with non-convulsive status epilepticusNormalAntiepileptic therapy and ICU careBoth improved
Naharci and Tasc [66]DeliriumTurkey88/Ffirst dose of CoronaVac–-an inactivated COVID-19 vaccineAcute confusion, hallucinations, agitation, and sleep disturbanceNoneHaloperidol and trazodoneImproved
Salinas et al. [67]Transient akathisiaUSA36/FPfizer-BioNTech vaccineWithin 24 h of second doseRestless body syndrome had fever after 5 h of motor restlessness resolved after 24 hNoneNoneImproved
Zavala-Jonguitud et al. [68]DeliriumMexico89/MThe first dose of BNT162b2 RNA vaccine24 hAcute confusion, fluctuating attention, anxiety and inversion of the sleep–wake cycle History of type 2 diabetes mellitus, hypertension, stage III‐b chronic kidney disease, prostatic hyperplasiaNot doneQuetiapineImproved
Alfishawy et al. [69]Neuroleptic malignant syndromeKuwait74/FBNT162b2 mRNA COVID-19 vaccine16 daysOld case of dementia and bipolar disorder and was receiving memantine, donepezil, and quetiapine presented with fever, delirium, rigidity, and elevated CPKNormalSymptomaticImproved
Ozen Kengngil et al. [70]Acute disseminated encephalomyelitis like MRI lesionsTurkey46/FInactivated SARS-CoV-2 vaccine of Sinovac1 MonthSeizures, normal examinationT2, FLAIR hyperintensity in thalamus, and corona radiataMethyl prednisoloneNo recurrence of seizures
Cao and Ren [71]Acute disseminated encephalomyelitisChina24/FSARS-CoV-2 Vaccine (Vero Cell), Inactivated2 weeksSomnolence and memory decline, MMSE-11 inflammatory changes in CSFT2/FLAIR white matter hyperintensity in both temporal lobesIV immunoglobulinImproved
Raknuzzaman et al. [72]Acute disseminated encephalomyelitisBangladesh55/MBNT162b2 mRNA COVID-19 vaccine3 weeksDelirium followed by loss of consciousnessT2/FLAIR white matter hyperintensities in periventricular regionMethyl prednisoloneImproved
Torrealba-Acosta et al. [73]Acute encephalitis, myoclonus and Sweet syndromeUSA77/MmRNA-1273 vaccine1 dayConfusion, fever and generalized rash; later headache, dizziness and double vision leading to severe encephalopathy Intermittent orofacial movements and upper extremity myoclonus CSF showed increased cells and protein. Skin biopsy showed vasculitis changesNormalMethylprednisoloneImproved
Vogrig et al. [74]Acute disseminated encephalomyelitisItaly56/FPfizer-BioMTech COVID-19 vaccine (Comirnaty)2 weeksHorizontal gaze-evoked nystagmus, Mild weakness on left upper limb, left hemi-ataxic gaitT2/FLAIR white matter hyperintensity in left cerebellar peduncle prednisone improved FLAIR sequences were observed, the largest in the left centrum semiovalePrednisoneImproved
Zuhorn et al. [75]Postvaccinal encephalitis Similar to autoimmune encephalitisGermany21/FChAdOx1 nCov-19 vaccine the first dose5 daysHeadache and progressive neurological symptoms including attention and concentration difficulties and a seizure CSF lymphocytic pleocytosis EEG slow delta rhythmNormalPrednisoneImproved
63/FChAdOx1 nCov-19 vaccine6 daysGait disorder, a vigilance disorder and a twitching all over her body Opsoclonus-myoclonus syndrome CSF lymphocytic pleocytosis EEG slow delta rhythmNormalMethylprednisoloneImproved
63/MChAdOx1 nCov-19 vaccine8 daysIsolated aphasia and fever CSF lymphocytic pleocytosis EEG normalNormalNoneMild improvement despite no treatment

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Encephalopathy

Some patients developed encephalopathy following administration of COVID-19 vaccines. Acute encephalopathy is defined as rapidly evolving disorder of the brain. Acute encephalopathy clinically manifests either with delirium, decreased consciousness, or coma.

Delirium

Delirium is characterized with fluctuating disturbance in attention and awareness. Zavala-Jonguitud and Pérez-García described an 89-year-old man, who developed delirium after mRNA vaccination. Within 24 h, patient developed confusion, fluctuating attention, anxiety, and inversion of the sleep–wake cycle. Patient had many comorbidities (diabetes mellitus, hypertension, and chronic kidney disease). Patient improved after he was treated with quetiapine [68].

Neuroleptic malignant syndrome

Neuroleptic malignant syndrome is a life-threatening complication of many antipsychotic drugs characterized by fever, altered mental status, muscle rigidity, and autonomic dysfunction. In an isolated report, neuroleptic malignant syndrome, in a 74-year-old female with dementia and bipolar disorder 16 days after COVID-19 vaccination, has been described [69].

Acute disseminated encephalomyelitis

Acute disseminated encephalomyelitis (ADEM) is an acute inflammatory demyelinating disorder of the central nervous system. In the majority, ADEM is a post-infectious entity; in many cases, it even develops after vaccination [76]. In two cases, acute disseminated encephalomyelitis following COVID-19 vaccination has been reported. In first such case a 46-year-old woman received Sinovac inactivated SARS-CoV-2 vaccine before onset of clinical manifestations. Patient was presented with seizures, and magnetic resonance imaging revealed multiple, discrete T2/FLAIR periventricular. hyperintense lesions. Patient improved following methylprednisolone treatment [70] Another patient was a 24-year-old female who presented with encephalopathy along with limb weakness of 1-day duration. Two weeks prior, patient was vaccinated with inactivated SARS-CoV-2 vaccine. Magnetic resonance imaging revealed multiple, discrete T2/FLAIR hyperintense lesions in the brain. Patient improved following treatment with antiepileptics and intravenous immunoglobulins [71].

Post-vaccinal encephalitis

Zuhorn et al. reported a case series 3 patients, who presented with post-vaccinal encephalitis, akin to autoimmune encephalitis, 7 to 11 days after administration of adenovirus-based ChAdOx1 nCov-19 vaccine. All patients fulfilled the diagnostic criteria for possible autoimmune encephalitis. One interesting case had presented with opsoclonus-myoclonus syndrome. Two patients presented with cognitive decline, seizures, and gait disorder. Neuroimaging did not reveal any abnormality. CSF pleocytosis was noted in all three patients. All patients responded well to corticosteroids [75].

Transverse myelitis

Acute transverse myelitis is an inflammatory spinal cord disorder that clinically manifests with the paraparesis/quadriparesis, transverse sensory level, and bowel or bladder dysfunction. Acute transverse myelitis usually is a postinfectious disorder. Magnetic resonance imaging demonstrates T2/FLAIR hyperintensity extending several spinal cord segments. Autoimmunity via mechanism of molecular mimicry is usually responsible for spinal cord dysfunction. Adenoviral vector-based COVID-19 vaccines are more frequently associated with causation of transverse myelitis. In isolated cases, even inactivated virus vaccine and mRNA-based vaccines had precipitated acute demyelination spinal cord syndromes, like multiple sclerosis and neuromyelitis optica. Reports of myelitis associated with vaccination for SARS-CoV-2 are summarized in Table ​Table44 [7783].

Table 4

Clinical, neuroimaging, and outcome details of patients who presented with spinal cord involvement after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Malhotra et al. [77]Transverse myelitisIndia36/MViral-vectored, recombinant ChAdOX1 nCoV-19 Covishield vaccine (AstraZeneca vaccine by Serum Institute of India)On the 8th post-vaccination dayAbnormal sensations in lower limbs with truncal levelT2-hyperintense lesion in the dorsal aspect of spinal cord at C6 and C7 vertebral levelsMethylprednisoloneImproved
Fitzsimmons and Nance [78]Transverse myelitisUSA63/MSecond dose of the Moderna vaccineWithin 1 dayLower back pain, paresthesia in both feet, and pain in lower extremities difficulty in walking and urinary retentionIncreased T2 cord signal seen in the distal spinal cord and conusIntravenous immunoglobulin and methylprednisoloneImproved
Tahir et al. [79]Transverse myelitisUSA44/FAd26.COV2.S (Johnson & Johnson) vaccine10 daysCervical cord transverse myelopathy CSF increased cellsIncreased T2 cord signal seen in the spinal cord extending from the C2-3 segment into the upper thoracic regionPlasma exchange and methylprednisoloneImproved
Pagenkopf and Südmeyer [80]Longitudinally extensive transverse myelitisGermany45/MFirst dose COVID-19-vaccine (AZD1222, AstraZeneca)11 daysThoracic back pain and urinary retentionT2 hyperintense signal of the spinal cord with wide axial and longitudinal extent reaching from C3 to Th2PrednisoloneImproved
Helmchen et al. [81]Optic neuritis with longitudinal extensive transverse myelitis in stable multiple sclerosisGermany40/FAstra Zeneca, COVID19 Vaccine®; Vaxzevria2 weeksBlindness paraplegia, with absent tendon reflexes in the legs, incontinence, and a sensory deficit for all qualities below Th5. CSF showed severe pleocytosis and elevated proteinIncreased longitudinal centrally located signal intensities throughout the thoracic spinal cordCorticosteroids and plasmapheresisImproved
Havla et al. [82]First manifestation of multiple sclerosisGermany28/FPfizer-BioNTech COVID-19 vaccine6 days first doseMyelitis oligoclonal bandsMRI revealed multiple (> 20), partially confluent lesions with spatial dissemination but no gadolinium enhancement. Contrast-enhancing lesion at the T6 level, suggestive of myelitisMethylprednisolone and plasma exchangeImproved
Chen et al. [83]Neuromyelitis optica spectrum disorderChinaMiddle-aged femaleThe first dose of inactivated virus vaccine3 daysDizziness and unsteady walking AQP4-positiveMRI scanning of the brain revealed area postrema and bilateral hypothalamus lesionsMethylprednisoloneImproved

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Malhotra and colleagues reported a 36-year-old patient, who had short-segment myelitis 21 days after first dose of adenoviral vector-based (Oxford/AstraZeneca, COVISHIELD™) vaccine. Patient recovered completely after treatment with methylprednisolone [77]. Fitzsimmons and Nance reported another patient of acute transverse myelitis following Moderna vaccine (an mRNA vaccine). The 63-year-old patient developed symptoms of acute myelopathy within 24 h of vaccination. MRI revealed increased T2 cord signal seen in the distal spinal cord and conus. Patient improved considerably following treatment with methylprednisolone and intravenous immunoglobulin [78].

Earlier, in phase III trial of Oxford/AstraZeneca vaccine, 2 patients had developed transverse myelitis. One of the case of transverse myelitis was reported 14 days after booster vaccination. The expert committee considered that this case was the most likely an idiopathic, short segment transverse myelitis. The second case was reported 68 days post-vaccination. Experts believed that in this case, transverse myelitis was not likely to be associated with vaccination. This patient was earlier diagnosed as a case of multiple sclerosis [8485].

The pathogenesis of acute transverse myelitis following COVID-19 vaccination remains unknown. Possibly, SARS-CoV-2 antigens present in the COVID-19 vaccine or its adenovirus adjuvant induce immunological reaction in the spinal cord. The occurrence of 3 reported acute transverse myelitis adverse effects among 11,636 participants in the vaccine trials was considered high and a cause of concern [86].

Bell’s palsy

Several cases of Bell’s palsy have occurred following COVID-19 vaccination. (Table ​(Table5)5) [8795]. The instances of Bell’s palsy are most often associated with mRNA vaccines [96]. Vaccine-associated Bell’s palsy generally responds very well to the oral corticosteroids. The exact pathogenesis remains speculative.

Table 5

Summary of reported patients, who suffered from Bell’s palsy after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Shemer et al. (a report of 9 cases) [87]Bell’s palsyIsrael35–86 (M = 5 and F = 4)BNT162b2 SARS-CoV-2 vaccine4–30 days after first dose 3 received 2nd doseAcute facial weakness One had herpes zoster ophthalmicus and herpes zoster oticusNoneCorticosteroidsNot given
Repajic et al. [88]Bell’s palsyUSA57/FPfizer-BioNTech COVID-19 A messenger RNA (mRNA) vaccine36 h after second dose3 previous episodes of Bell’s palsy ageusia Facial weaknessNonePrednisoneImproved
Colella et al. [89]Bell’s palsyItaly37/MmRNA vaccine BNT162b25 days after first doseAcute facial weaknessNot doneCorticosteroidsImproved
Martin-Villares et al. [90]Bell’s palsySpain34/FModerna COVID-19 vaccine2 daysGrade III facial palsy She developed a right Bell’s palsy in 2012 during pregnancy (5th month)NoneCorticosteroidsImproved
Nishizawa et al. [91]Bell’s palsyJapan62/FAd26.COV2.S vaccination20 daysHouse-Brackmann score 4 Bell’s PalsyNormalNoneNone
Gómez de Terreros et al. [92]Bell’s palsySpain50/MPfizer-BNT162b2 mRNA vaccine9 daysMuscle weakness on the left side of his faceNormalCorticosteroidsImproved
Burrows et al. [93]Sequential contralateral facial nerve palsiesUKFirst and second doses of the Pfizer-BioNTech COVID-19 vaccineRight palsy, 5 h Left palsy after 2 daysTwo discrete contralateral episodes of Bell’s palsyNormalPrednisoloneImproved both the time
Obermann et al. [94]Bell’s palsyGermany21/FFirst dose of SARS-CoV-2 mRNA vaccine Comirnaty (BNT162b2, BioNTech/Pfizer)2 dayFacial muscle paralysis SARS-CoV-2 antibodies were present in blood and CSFNormalPrednisoloneImproved
Iftikhar et al. [95]Bell’s palsyQatar36/MSecond dose of the mRNA-1273 vaccine1 dayFacial palsyNormalPrednisoloneImproved

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In a case–control study, Shemer et al. compared clinical parameters of patients with Bell’s palsy following mRNA vaccination with that of patients with Bell’s palsy without vaccination. Out of 37 patients, 21 had received vaccination. Bell’s palsy developed within 2 weeks following first dose of COVID-19 vaccination. There was no difference in any of the clinical parameter between vaccinated or unvaccinated groups [97].

Earlier, in the Pfizer-BioNTech clinical trial, which included 44,000 participants, 4 people had Bell’s palsy. No case of Bell’s palsy was reported in the placebo arm. In the Moderna trial, which included 30,400 participants, 3 vaccine recipients reported Bell’s palsy. One person was in the placebo arm [98]. An article, published in the Lancet, analyzed the combined phase 3 data of Pfizer and Moderna trials and noted that the rate of Bell’s palsy was higher than expected [98].

Other cranial nerve involvement

In isolated instances, mRNA vaccines were found associated with olfactory dysfunction and sixth cranial nerve palsy (Table ​(Table6)6) [99104].

Table 6

Summary of reported patients, who suffered from cranial nerve involvement (other than Bell’s palsy) after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Konstantinidis et al. [99] Report of 2 patientsOlfactory dysfunctionGreeceBoth femalePfizer-BioNTech BNT162b23 and 5 days after second doseHyposmia after their second doseNoneOlfactory trainingImproved
Keir et al. [100]PhantosmiaUSA57/FPfizer-BioNTech COVID-19 vaccination Second doseNoneFeeling weak, fatigued, with random episodes of ‘‘smelling smoke’’ associated with hyposmiaPostcontrast CT demonstrates faint enhancement left olfactory tract MRI enhancement of the left greater than right olfactory bulb and bilateral olfactory tractsNoneNone
Reyes-Capo et al. [101]Acute abducens nerve palsyUSA59/FPfizer-BioNTech COVID-19 vaccine2 daysFever for 1 day followed by diplopiaNormal MRI of brain and orbitsNot availableSensory-motor examination remained unchanged in recent follow-up
Parrino et al. [102]TinnitusItaly37/F 63/ 30/MBNT162b2 mRNA-vaccine7-h first dose 20 h 7 daysSudden unilateral tinnitusNormal MRICorticosteroids, in twoImproved all
Tseng et al. [103 ] PMID: 34,297,133Reversible tinnitus and cochleopathyTaiwan32/MFirst dosage of the AstraZeneca COVID-19 vaccine5 hHigh-pitch tinnitus and disturbed the normal hearing high fever with chills and myalgiaNot doneCorticosteroidsImproved
Narasimhalu et al. [104]Trigeminal and cervical radiculitisSingapore52/FPfizer-BioNTech vaccination (tozinameran)3 h first doseNumbness, swelling and pain over the left face and neckMRI of trigeminal nerve revealed thickening and perineural sheath enhancement of the V3 segment of the left trigeminal nerve The MRI of the cervical spine revealed spondylotic changesPregabalinImproved

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Olfactory dysfunction

Olfactory dysfunction is the most frequent neurological complication of COVID-19. Konstantinidis and colleagues reported two cases of smell impairment after second dose of the BioNTechBNT162b2 vaccine (Pfizer) administration [51].

Keir and colleagues reported phantosmia following administration of Pfizer COVID-19 vaccine. Patient complained of constantly “smelling smoke” and headaches. MRI of brain of the patient showed enhancement of the olfactory bulbs and bilateral olfactory tracts [100].

Abducens nerve palsy

Reyes-Capo et al. reported a 59-year-old lady, who presented with an abducen nerve palsy 2 days post-vaccination (Pfizer-BioNTech mRNA vaccine). Neuroimaging in this patient was normal..

Otologic manifestations

A variety of otologic manifestations has been noted following COVID-19 vaccination. Parrino and colleagues described three patients with sudden unilateral tinnitus following BNT162b2 mRNA vaccine administration. Tinnitus rapidly resolved in 2 cases. Wichova and colleagues in a retrospective review recorded 30 patients, who either had significantly exacerbated otologic symptoms or had a new symptom after getting mRNA vaccine. Post-vaccination otologic manifestations included hearing loss with tinnitus, dizziness, or with vertigo. In some patients, with Menière’s disease or autoimmune inner ear disease, vaccine led to exacerbation of the pre-existing otologic symptoms [102,105].

Acute vision loss

Santovito and Pinna reported an unusual patient, who developed acute visual impairment following the 2nd dose of the Pfizer-BioNTech COVID-19 vaccine. Prior to visual symptoms, patient experienced unilateral headache. He also reported mild confusion, asthenia, and profound nausea. His symptoms got relieved after taking analgesics. Possibly, patient had an acute attack of migraine with aura that got precipitated by the vaccine [106].

Guillain-Barré syndrome

Guillain-Barré syndrome is a post-infectious disorder of peripheral nerve manifesting with lower motor neuron type of sensory-motor quadriparesis. Acute motor weakness is frequently preceded by an antecedent microbial infection. There are numerous reports indicating that COVID-19 infection can trigger Guillain-Barré syndrome. The US Food and Drug Administration has recently expressed its concern regarding a possible association between the Johnson and Johnson COVID-19 vaccine with Guillain-Barré syndrome [107].

After emergency use approvals, all kinds of COVID-19 vaccines were found associated with Guillain-Barré syndrome. Adenovector-based vaccines were more frequently associated with Guillain-Barré syndrome. Earlier, in phase 3 trial of Johnson and Johnson adenovirus vector-based COVID-19 vaccine, 2 patients developed Guillain-Barré syndrome. One patient belonged to vaccine group and other to placebo group. Both patients had Guillain-Barré syndrome within 2 weeks of receiving injections. The Guillain-Barré syndrome in the vaccine arm was preceded by chills, nausea, diarrhea, and myalgia [108109].

Post-vaccination Guillain-Barré syndrome generally affects older adults within 2 weeks of vaccine administration. Clinical presentation is similar to acute demyelinating neuropathy; nerve conduction studies show demyelinating pattern, and CSF examination shows cyto-albuminic dissociation. Many patients present only with facial diplegia. Response to immunotherapy is generally good. (Table ​(Table7)7) [110126].

Table 7

Summary of reported patients, who developed an acute peripheral nerve disorder after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Waheed et al. [110]Guillain-Barré syndromeUSA82/FPfizer-BioNTech COVID-19 A messenger RNA (mRNA) vaccine2 weeksAreflexic paraparesis with distal sensory loss CSF showed albuminocytologic dissociationenhancement of cauda equina nerve rootsIV immunoglobulinImproved
Márquez Loza et al. [111]Guillain-Barré syndromeUSA60/FJohnson & Johnson, d26.COV2.S, a recombinant adenovirus serotype 26 (Ad26) vector vaccine2 weeksOphthalmoplegia, facial diplegia and Areflexic quadriparesis CSF showed albuminocytologic dissociationEnhancement of cauda equina nerve rootsIV immunoglobulinImproved
Patel et al. [112]Guillain-Barré syndromeUK37/MCOVID-19 ChAdOx1 vaccine adenovirus-vectored vaccine Oxford AstraZeneca2 weeksSymmetrical, progressive ascending muscle weakness areflexic bilaterally in the lower limbsCauda equina nerve root enhancementIntravenous immunoglobulinImproved
Razok et al. [113]Guillain-Barré syndromeQatar73/MPfizer-BioNTech COVID-19 vaccine20 days Second doseAcute bilateral lower limb weaknessNoneIVIGImproved
Ogbebor et al. [114]Guillain-Barré syndromeUS86/3FPfizer-BioNTech COVID-19 vaccine1 dayWeakness in her bilateral lower extremities and by day 6, she could no longer walk CSF = a protein 162 mg/dL and glucose (49 mg/dL)NoneIntravenous immunoglobulinImproved
Finsterer  [115]Exacerbating Guillain-Barré syndromeAustria32/MA vector-based COVID-19 vaccine8 daysParesthesia and dysphagia bilateral frontal and nuchal headacheNoneIntravenous immunoglobulinImproved
Marammatom et al. [116] Report of 7 casesGuillain-Barré syndromeIndiaChAdOx1-S/nCoV-19 adenovector-based vaccineWithin 2 weeks of the first doseAll patients progressed to areflexic quadriplegia 2 cases required mechanical ventilation All 7 cases had bilateral facial paresis Four patients (57%) also developed other cranial neuropathies (4th and 5th)In two patients, MRI brain and spine were normalIntravenous immunoglobulinOne recovered Rest six still bed bound
Allen et al. [117] Report of 4 casesGuillain-Barré syndrome variantUK20–57 all malesOxford-AstraZeneca SARS-CoV2 vaccineWithin 3 weeksFacial weakness in 1 facial diplegia in 3 areflexic quadriparesis in 1 Cyto-albuminic dissociation in allMRI of the brain and whole spine with contrast showed enhancement of the facial nerve within the right internal auditory canalIntravenous immunoglobulin, oral steroids, or no treatmentAll improved
Kohli et al. [118]Guillain-Barré syndromeIndia71/MCovishield, AstraZeneca, University of Oxford6 daysAreflexic quadriparesis with bulbar palsy NCV- demyelinating patternNoneIntravenous immunoglobulin and mechanical ventilationImproved
Azam et al. [119]Guillain-Barré syndromeUK67/MThe first dose of the AstraZeneca COVID-1915 daysAreflexic quadriparesis with facial diplegiaNCV- demyelinating patternNormalIntravenous immunoglobulinImproved
Hasan et al. [120]Guillain-Barré syndromeUK62/FFirst dose of the Oxford/AstraZeneca COVID-19 vaccineWeakness of bilateral lower limbs preceded by paresthesia and numbness a flaccid-type paraplegia NCV- demyelinating pattern CSF-albumin-cytological dissociationNormalIntravenous immunoglobulinThe patient remains in the ICU
Theuriet et al. [121]Guillain-Barré syndromeFrance72/MFirst dose of ChAdOx1 nCoV-19 vaccine (VaxZevria/Oxford-AstraZeneca)3 weeksAreflexic quadriparesis with facial diplegia NCV- demyelinating patternNoneIntravenous immunoglobulinThe patient remains in the ICU
Bonifacio et al. [122] (A series of 5 cases)Guillain-Barré syndromeUK43/M 51 M 53/M 66/m 71/fVaxzevria AstraZeneca, University of Oxford COVID-19 vaccine11 days 7 days 7 days 8 days 12 daysBilateral facial weakness with paresthesia variant of Guillain-Barré syndrome NCV- demyelinating pattern in 4 patientsBilateral contrast enhancement along whole facial nerve in 3 patientsIntravenous immunoglobulin Was given in 2 patientsAll improved
Nasuelli et al. [123]Guillain-Barré syndromeItaly59/MChAdOx1 nCoV-19 vaccine10 daysAreflexic quadriparesis with facial diplegia NCV- demyelinating pattern in 4 patients CSF-albumin-cytological dissociationNormalIntravenous immunoglobulinImproved
Jain et al. [124]Guillain-Barré syndromeUSA65/FAd26.COV2.S (Johnson & Johnson) vaccine19 daysFacial diplegiaNormalIntravenous immunoglobulin And plasmapheresisImproved
McKean and Chircop [125]Guillain-Barré syndromeMalta48/MVaxzevria AstraZeneca, University of Oxford COVID-19 vaccine First dose10 daysFacial diplegia and severe back pain ascending paresthesia and bilateral progressive areflexic lower limb weakness. CSF-albumin-cytological dissociation NCV multifocal sensorimotor demyelinating polyneuropathyNormalIntravenous immunoglobulin and oral prednisoloneImproved
Bonifacio et al. [126] (a report of 5 cases)Guillain-Barré syndromeUK
Waheed et al. [127]Small fiber neuropathyUSA57/FPfizer-BioNTech COVID-19 A messenger RNA (mRNA) vaccine (Second dose)Subacute onsetIntense burning dysesthesias in the feet gradually spreading to the calves and minimally into the hands (Nerve biopsy proved small fiber neuropathy)NoneGabapentinSymptomatic improvement

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Proposed pathogenesis of Guillain-Barré syndrome is an autoantibody-mediated immunological damage of peripheral nerves via mechanism of molecular mimicry between structural components of peripheral nerves and the microorganism. Lately, several cases of Guillain-Barré syndrome following COVID-19 vaccination have also been reported.

Small fiber neuropathy

Waheed et al. described a 57-year-old female, who presented with painful neuropathy following administration of the mRNA COVID-19 vaccine. Patient subacutely presented with intense peripheral burning sensations. Electrodiagnostic studies were normal. Skin biopsy proved small fiber neuropathy. Patient responded to gabapentin.(Table ​gabapentin.(Table7)7) [127].

Parsonage-Turner syndrome

Parsonage-Turner syndrome or neuralgic amyotrophy is clinically manifested with acute unilateral shoulder pain followed by brachial plexopathy. Parsonage-Turner syndrome is usually triggered by any infection, surgery, or rarely vaccination. In many reports, Parsonage-Turner syndrome has been described following COVID-19 vaccination.(Table ​vaccination.(Table8)8) [128130].

Table 8

Summary of reported patients, who developed neuralgic amyotrophy after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Mahajan et al. [128]Parsonage-Turner syndromeUSA50/MCOVID-19 BNT162b2 vaccination7 daysSudden onset of severe left periscapular pain after first dose One week after the second dose, the patient developed left hand grip and left wrist extension weakness. Electromyography showed decreased motor unit recruitmentNormalCorticosteroidsImproved
Diaz-Segarra et al. [129]Painless idiopathic neuralgic amyotrophyUSA35/FPfizer-BioNTech COVID-19 vaccine9 daysNew-onset painless left arm weakness, numbness, and paresthesiasCervical spine computed tomography showed mild degenerative changes without foraminal narrowingHigh-dose prednisoneImproved
Antonio Crespo Burillo et al. [130]Parsonage-Turner syndromeSpain38/MVaxzevria (AstraZeneca)4 daysShoulder and arm pain Electrophysiology suggested brachial plexopathyMRI of the shoulder revealed a mild left subacromial tendinopathyMethylprednisoloneImproved

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Herpes zoster

Herpes zoster occurs following reactivation of varicella zoster virus. Patients with herpes zoster present with the classic maculopapular rash, which is unilateral, confined to a single dermatome. The rash disappears in 7 to 10 days. Postherpetic neuralgia is the frequent complication of herpes zoster, which is noted in 1 in 5 patients. McMahon and co-workers recorded 414 cutaneous reactions to mRNA COVID-19 vaccines, and 5 (1.9%) were diagnosed with herpes zoster [131]. Other types of COVID-19 vaccines are infrequently associated with post-vaccination reactivation of herpes zoster. It has been suggested that vaccine-induced immunomodulation, resulting in dysregulation of T cell function, is responsible for reactivation of herpes zoster virus [132133]. Reports of herpes zoster reactivation after vaccine against SARS-CoV-2 are summarized in Table ​Table99 [134142].

Table 9

Summary of reported patients, who developed Herpes zoster after vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Tessas and Kluger [134]Herpes zosterFinland44/MBNT162b2 mRNA COVID-19 vaccine7 daysHerpetiform vesicular and erythematous rash on the left upper backNoneOral valacyclovirImproved
Rodríguez-Jiménez et al. [135] A report of 5 casesHerpes zosterSpain39–58 F = 3BNT162b2 mRNA COVID-19vaccine (Pfizer)1–16 (4 less than 7 days)Painful herpetiform dermatomal rashNoneNoneNone
Eid et al. [136]Herpes zosterLebanon79/MmRNA COVID vaccine6 daysPainful herpetiform dermatomal rashNoneAntiviral treatmentImproved
Bostan and Yalici-Armagan [137]Herpes zosterTurkey78/MInactivated COVID-19 vaccineErythematous, painful, and pruritic lesions on chest
Furer et al. [138] (a report of 6 cases)Herpes zosterIsrael36–61 All femalesBNT162b2 mRNA vaccination3 -14 daysAll had autoimmune inflammatory rheumatic diseases Herpes zoster ophthalmicus in one Truncal herpes zoster in othersNot doneNANA
Aksu and Öztürk et al. [139]Herpes zosterTurkey68/MThe inactivated COVID-19 vaccine5 daysmultiple pinheaded vesicular lesions upon an erythematous base occupying an area on his right mammary region and back corresponding to T3–T5 dermatomesNot doneValacyclovir paracetamolImproved
Chiu et al. [140] (a report of 3 cases)Herpes zosterTaiwan71/M 46/M 42/MPfizer-BNT162b2 mRNA and Moderna mRNA-12732 days 7 days 2 daysErythematous papules and vesicle in dermatomal patternNot doneOral acyclovirAll improved
Alpalhão and Filipe et al. [141] (a report of 4 cases)Herpes zosterPortugalNAPfizer’s Comirnaty™ vaccine AstraZeneca Vaxzevria™ vaccine3–6 daysErythematous papules and vesicle in dermatomal patternNot doneValacyclovirAll improved
Channa et al. [142]Herpes zosterUSA81/MmRNA-1273 (Moderna) Covid-19 vaccine3 daysA dermatomal rashNot doneNot availableNot available

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Myositis and rhabdomyolysis

There are reports, which have indicated that COVID-19 vaccines have potential to damage the skeletal muscles as well (Table ​(Table10)10) [143147]. Tan and colleagues described a patient with a known carnitine palmitoyltransferase-II deficiency disorder, who developed fever, vomiting, shortness of breath, frank haematuria, myalgia and muscle weakness within four hours of receiving AstraZeneca COVID-19 vaccine [143]. Theodorou and colleagues described a 56-year-old woman who, 8 days after a second dose of vaccine administration, developed severe left upper arm pain along restricted shoulder movements. Her serum creatine kinase was elevated suggesting skeletal muscle damage. MRI revealed severely edematous deltoid muscles. Contrast-enhanced imaging demonstrated enhancement of deltoid muscles suggestive of myositis [146].

Table 10

Summary of reported patients, who developed an acute muscular disorder following vaccination against SARS-CoV-2

ReferenceNeurological complicationCountryAge/sexVaccine typeDuration after vaccinationClinical featuresNeuroimagingTreatmentOutcome
Tan et al. [143]Rhabdomyolysis in a patient with Carnitine palmitoyltransferase II deficiencyUK27/MCOVID-19 vaccine AstraZeneca5 hFever, vomiting, shortness of breath, frank hematuria, and myalgia CK concentration of 105,000 U/L and deranged liver function tests (ALT 300 U/L and AST 1496 U/L)NoneContinuous intravenous dextrose 10% and a high carbohydrate dietImproved
Mack et al. [144]RhabdomyolysisUSA80/MSecond dose of Moderna COVID-19 vaccine2 daysGeneralized body aches, nausea, and vomiting elevated CKNoneIV fluidsImproved
Nassar et al. [145]RhabdomyolysisUSA21/MFirst Pfizer/BioNTech COVID-19 vaccine1 daySevere back pain with radiation to his left lateral thigh Creatinine phosphokinase (CPK) level more than 22,000 U/LNormalIV fluidsImproved
Theodorou et al. [146]MyositisGreece56/FModified mRNA COVID-19 vaccine8 days after second doseThere was tenderness over the deltoid muscle, guarding, and decreased abduction of the shoulder and arm along with elevated CPKOn MRI, the deltoid muscle was edematous. On contrast enhancement, muscle exhibited enhancement indicating inflammationSymptomaticImproved
Godoy et al. [147]Myositis ossificansBrazil51/M3 monthsRight upper arm pain, soreness and palpable massIntramuscular nodule n the proximal fibers of the brachii muscle with perilesional muscle edema One week later, CT showed a hypoattenuating intramuscular nodule with internal calcificationsNSAIDsImproved

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Conclusion

Post-authorization, a wide spectrum of serious neurological complications has been reported following COVID-19 vaccination. The most devastating neurological complication is cerebral venous sinus thrombosis that has been reported in females of childbearing age following adenovector-based vaccines. Another major neurological complication of concern is Bell’s palsy that was reported dominantly following mRNA vaccine administration. Transverse myelitis, acute disseminated encephalomyelitis, and Guillain-Barré syndrome are other severe unexpected post-vaccination complications that can occur as result of molecular mimicry and subsequent neuronal damage. Most of other serious neurological complications are reported in either in form of isolated case reports or small cases series. A causal association of these adverse events is controversial; large collaborative prospective studies are needed to prove causality.

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