Vaccinated Up to 15X MORE LIKELY Than Unvaxxed to Develop Heart Inflammation Requiring Hospitalization: Peer Reviewed Study

Authors:  Julian Conradson Published April 25, 2022 at 4:14pm

A new study out of Europe has revealed that cases of heart inflammation that required hospitalization were much more common among vaccinated individuals compared to the unvaccinated.

A team of researchers from health agencies in Finland, Denmark, Sweden, and Norway found that rates of myocarditis and pericarditis, two forms of potentially life-threatening heart inflammation, were higher in those who had received one or two doses of either mRNA-based vaccine – Pfizer’s or Moderna’s.

In all, researchers studied a total of 23.1 million records on individuals aged 12 or older between December 2020 and October 2021. In addition to the increased rate overall, the massive study confirmed the chances of developing the heart condition increased with a second dose, which mirrors other data that has been uncovered in recent months.

From the *peer-reviewed study, which was published by the Journal of the American Medical Association (JAMA):

“Results of this large cohort study indicated that both first and second doses of mRNA vaccines were associated with increased risk of myocarditis and pericarditis. For individuals receiving 2 doses of the same vaccine, risk of myocarditis was highest among young males (aged 16-24 years) after the second dose. These findings are compatible with between 4 and 7 excess events in 28 days per 100 000 vaccinees after BNT162b2, and between 9 and 28 excess events per 100 000 vaccinees after mRNA-1273.

The risks of myocarditis and pericarditis were highest within the first 7 days of being vaccinated, were increased for all combinations of mRNA vaccines, and were more pronounced after the second dose.”

Also mirroring other data, the study confirmed that young people, especially young males, are the ones who are suffering the worst effects of the experimental jab. Young men, aged 16-24 were an astounding 5-15X more likely to be hospitalized with heart inflammation than their unvaccinated peers.

But it isn’t just young men, all age groups across both sexes – except for men over 40 and girls aged 12-15 – experienced a higher rate of heart inflammation post-vaccination when compared to the unvaxxed.

From The Epoch Times, who spoke with one of the study’s main researchers, Dr. Rickard Ljung:

“‘These extra cases among men aged 16–24 correspond to a 5 times increased risk after Comirnaty and 15 times increased risk after Spikevax compared to unvaccinated,’ Dr. Rickard Ljung, a professor and physician at the Swedish Medical Products Agency and one of the principal investigators of the study, told The Epoch Times in an email.

Comirnaty is the brand name for Pfizer’s vaccine while Spikevax is the brand name for Moderna’s jab.

Rates were also higher among the age group for those who received any dose of the Pfizer or Moderna vaccines, both of which utilize mRNA technology. And rates were elevated among vaccinated males of all ages after the first or second dose, except for the first dose of Moderna’s shot for those 40 or older, and females 12- to 15-years-old.”

Although the peer-reviewed study found a direct link between mRNA based vaccines and increased incident rate of heart inflammation, the researchers claimed that the “benefits” of the experimental vaccines still “outweigh the risks of side effects,” because cases of heart inflammation are “very rare,” in a press conference about their findings earlier this month.

However, while overall case numbers may be low in comparison to the raw numbers and thus technically “very rare,” the rate at which individuals are developing this serious condition has increased by a whopping amount. When considering the fact that 5-15X more, otherwise healthy, young men will come down with the condition – especially since the chances of Covid-19 killing them at that age are effectively zero (99.995% recovery rate) – it’s downright criminal for governments across the world to continue pushing mass vaccinations for everyone.

Dr. Peter McCullough, a world-renowned Cardiologist who has been warning about the long-term horror show that is vaccine-induced myocarditis in young people, certainly thinks so. In his expert opinion, the study does anything but give confidence that the benefits of the vaccine outweigh the risks. In “no way” is that the case, he says. Actually, it’s quite the opposite.

From McCullough, via The Epoch Times:

“In cardiology we spend our entire career trying to save every bit of heart muscle. We put in stents, we do heart catheterization, we do stress tests, we do CT angiograms. The whole game of cardiology is to preserve heart muscle. Under no circumstances would we accept a vaccine that causes even one person to stay sustain heart damage. Not one. And this idea that ‘oh, we’re going to ask a large number of people to sustain heart damage for some other theoretical benefit for a viral infection,’ which for most is less than a common cold, is untenable. The benefits of the vaccines in no way outweigh the risks.”

It’s also worth pointing out that the new study’s findings could be an indicator as to what is driving the massive spike in the excess death rates in the United States and across the world. Correlating exactly with the rollout of the experimental mRNA Covid-19 vaccines, people have been dying at record-breaking rates, especially millennials, who experienced a jaw-dropping 84% increase in excess deaths (compared to pre-pandemic) in the final four months of 2021.

With all the data that has been made available up to this point, there is no denying that the vaccine is at least partially to blame for the spike in severe illness and death, if not entirely. Nevertheless, the CDC, Fauci, Biden, and the rest of the corrupt establishment continue to push mass vaccines, just approved another booster jab (with plans for another already in the works), and are licking their chops to unleash another round of Covid hysteria and crippling restrictions come this fall.

Worse Than the Disease? Reviewing Some Possible Unintended Consequences of the mRNA Vaccines Against COVID-19

Authors: Stephanie Seneff Computer Science and Artificial Intelligence Laboratory, MIT, Cambridge MA, 02139, USA, Greg Nigh Naturopathic Oncology, Immersion Health, Portland, OR 97214, USA International Journal of Vaccine Theory, Practice, and Research

Abstract

Operation Warp Speed brought to market in the United States two mRNA vaccines, produced by Pfizer and Moderna. Interim data suggested high efficacy for both of these vaccines, which helped legitimize Emergency Use Authorization (EUA) by the FDA. However, the exceptionally rapid movement of these vaccines through controlled trials and into mass deployment raises multiple safety concerns. In this review we first describe the technology underlying these vaccines in detail. We then review both components of and the intended biological response to these vaccines, including production of the spike protein itself, and their potential relationship to a wide range of both acute and long-term induced pathologies, such as blood disorders, neurodegenerative diseases and autoimmune diseases. Among these potential induced pathologies, we discuss the relevance of prion-protein-related amino acid sequences within the spike protein. We also present a brief review of studies supporting the potential for spike protein “shedding”, transmission of the protein from a vaccinated to an unvaccinated person, resulting in symptoms induced in the latter. We finish by addressing a common point of debate, namely, whether or not these vaccines could modify the DNA of those receiving the vaccination. While there are no studies demonstrating definitively that this is happening, we provide a plausible scenario, supported by previously established pathways for transformation and transport of genetic material, whereby injected mRNA could ultimately be incorporated into germ cell DNA for transgenerational transmission. We conclude with our recommendations regarding surveillance that will help to clarify the long-term effects of these experimental drugs and allow us to better assess the true risk/benefit ratio of these novel technologies.

How Vaccine Messaging Confused The Public

Authors: John Gibson the Brownstone Institute 

Pivotal randomized control trials (RCTs) underpinning approval of Covid-19 vaccines did not set out to, and did not, test if the vaccines prevent transmission of the SARS-CoV-2 virus. Nor did the trials test if the vaccines reduce mortality risk. A review of seven phase III trials, including those for Moderna, Pfizer/BioNTech and AstraZeneca vaccines, found the criterion the vaccines were trialled against was just reduced risk of Covid-19 symptoms

There should be no secret about these facts, as they were discussed in August 2020 in the BMJ (formerly the British Medical Journal); one of the oldest and most widely cited medical journals in the world. Moreover, this was not an isolated article, as the editor-in-chief also gave her own summary of the vaccine-testing situation, which has proved very prescient:

“…we are heading for vaccines that reduce severity of illness rather than protect against infection [and] provide only short-lived immunity, … as well as damaging public confidence and wasting global resources by distributing a poorly effective vaccine, this could change what we understand a vaccine to be. Instead of long-term, effective disease prevention it could become a suboptimal chronic treatment.”It was not just the BMJ covering these features of the RCTs. When health bureaucrats Rochelle Walensky, Henry Walke and Anthony Fauci claimed (in the Journal of the American Medical Association) that “clinical trials have shown that the vaccines authorized for use in the US are highly effective against Covid-19 infection, severe illness and death” this was felt sufficiently false that the journal published a comment simply titled “Inaccurate Statement.”

The basis of the comment was that the primary endpoint for the RCTs was symptoms of Covid-19; a less exacting standard than testing to show efficacy against infection, severe illness, and death.

Yet these aspects of the vaccine trials discussed in medical journals are largely unknown by the general public. To measure public understanding of the Covid-19 vaccine trials I added a question about the vaccine testing to an ongoing nationally representative survey of adult New Zealanders.

While not top-of-mind for most readers, New Zealand is a useful place for finding out about public understanding of the vaccine trials. Until recently, when a few doses of AstraZeneca and Novavax vaccines were allowed, it was 100% Pfizer, making it easy to word the survey question very specifically about the Pfizer vaccine trials.

Also, New Zealanders were vaccinated in a very short period, just prior to the survey. In late August 2021 New Zealand was last in the OECD in dosing rates but by December, when the survey was fielded, it had jumped into the top half of the OECD, with vaccinations rising by an average of 110 doses per 100 people in just over three months. 

This rapid rise in vaccination was partly driven by mandates, for health, education, police, and emergency workers and also by a vaccine passport system that blocked the unvaccinated from most places. The mandates were strictly applied, and even people suffering adverse reactions after their first shot, such as Bell’s Palsy and pericarditis, still had to get the second shot. The vaccine passport law had gone through Parliament just prior to the survey, so the vaccines, and what was expected of them, should have been utmost in peoples’ minds. 

The other relevant factor about New Zealand is the government-dominated media, which is either publicly funded, or is heavily subsidized by a “public interest journalism fund” and by generous government advertising of the Covid-19 vaccines. Also, supposedly independent commentators prominent in the media got their talking points about the vaccines from the government in a carefully orchestrated public relations campaign. 

Thus, it was mainly overseas journalists who expressed concern when New Zealand’s Prime Minister made the Orwellian claim that in matters of Covid-19 and vaccines: “Dismiss anything else, we will continue to be your single source of truth.”

Yet a government-controlled media and a vaccine advertising blitz yielded widespread public misunderstanding about the testing the vaccines underwent in pivotal trials. The survey asked if the Pfizer vaccine had been trialled against: (a) preventing infection and transmission of SARS-CoV-2, or (b) reducing risk of getting symptoms of Covid-19, or (c) reducing risk of getting serious sick or dying, or (d) all of the above. The correct answer is (b), the trials only set out to test if the vaccines reduced the risk of getting Covid-19 symptoms.

Only four percent of respondents got the right answer. In other words, 96 percent of adult New Zealanders thought the Covid-19 vaccines were tested against more demanding criteria than is actually the case. 

Currently, most Covid-19 cases in New Zealand are post-vaccination. And despite almost everyone being vaccinated, and most boosted, the rate of new confirmed Covid-19 cases is one of the highest in the world. As people see with their own eyes that one can still get infected they may question what they have been led to (mis)understand about the vaccines.

Elsewhere it is noted that vaccine fanaticism—especially denying natural immunity—fuels vaccine scepticism. As people see that public health authorities lied about natural immunity they will wonder if they also lied about vaccine efficacy. Likewise, as they realise they were given a misleading impression about what the vaccines were trialled against they might doubt other claims about vaccines.

In particular, by believing the vaccines were tested against more demanding criteria than was actually so, public expectations of what vaccination would achieve were likely too high. As the public witnesses a failure of mass vaccination to prevent SARS-CoV-2 infections, and a failure to reduce overall mortality, scepticism about these and other vaccines will grow.

In New Zealand this issue is exacerbated by the Prime Minister creating a false equivalence between Covid-19 vaccines and measles vaccines. Currently the paediatric vaccination rate (which includes the measles vaccine) for indigenous Maori has dropped 12 percentage points in two years and 0.3 million measles vaccines had to be discarded after expiring due to lack of demand. The advertising for Covid-19 vaccines particularly targets Maori, with claims that boosters will protect them against Omicron. The progress of infections is likely to prove this claim to be largely untrue, and so Maori are likely to be even more sceptical about future vaccination, even for vaccines that truly can be described as ‘safe and effective.’

If politicians and health bureaucrats had been honest with the public, setting out the criteria the Covid-19 vaccines were trialed against, and what could and could not be expected of the vaccines, then this widespread misunderstanding need not have occurred. Instead, their lack of honesty is likely to damage future vaccination efforts and harm public health.

Extensive thrombosis after COVID-19 vaccine: cause or coincidence

Authors: Luís Lourenço Graça ,1 Maria João Amaral ,2 Marco Serôdio,3 Beatriz Costa2

SUMMARY
A 62-year-old Caucasian female patient presented with abdominal pain, vomiting and fever 1 day after administration of COVID-19 vaccine. Bloodwork revealed anaemia and thrombocytosis. Abdominal CT angiography showed a mural thrombus at the emergence of the coeliac trunk, hepatic and splenic arteries, and extensive thrombosis of the superior and inferior mesenteric veins, splenic and portal veins, and the inferior vena cava, extending to the
left common iliac vein. The spleen displayed extensive areas of infarction. Etiological investigation included assessment of congenital coagulation disorders and acquired causes with no relevant findings. Administration of COVID-19 vaccine was considered a possible cause of the extensive multifocal thrombosis. After reviewing relevant literature, it was considered
that other causes of this event should be further investigated. Thrombosis associated with COVID-19vaccine is rare and an etiological relationship should only be considered in the appropriate context and after investigation of other, more frequent, causes.

BACKGROUND
During the COVID-19 pandemic, the pharmaceutical industry is under immense pressure to develop effective and safe vaccines, and as such clinical trials have been expedited in order to make them available to help fight this health crisis. In this context, timely communication between healthcare institutions and regulatory entities is especially important. Reports of thrombosis due to administration of these vaccines have been causing an important
discussion in the scientific community as well as social alarm. However, it is important to note that this is a rare complication and more frequent causes of extensive arterial and venous thrombosis should be considered and investigated.1

CASE PRESENTATION
A 62-year-old Caucasian female patient, with personal history of obesity (body mass index of
30kg/m2), asthma and rhinitis, presented to the emergency department with abdominal pain,
nausea, vomiting and fever (38°C) 1day after administration of the first dose of COVID-19 vaccine(from AstraZeneca). On physical examination, she presented epigastric and left iliac fossa tenderness as the only abnormal finding. The patient denied recent epistaxis and gastrointestinal or genitourinary blood loss.

INVESTIGATIONS
Blood tests revealed microcytic hypochromic anemia (hemoglobin 7g/L), thrombocytosis (780×109/L),increased levels of inflammatory parameters (leucocytes 13×109/L; C reactive protein 31.07mg/dL) and slightly increased levels of liver enzymes and function (AST 36, ALP 126U/L, GGT 72U/L, LDH 441U/L, total bilirubin 1.3mg/dL, direct bilirubin 0.5mg/dL). The patient was tested for COVID-19 with nasopharyngeal PCR tests at admission and on the fifth day of hospitalization. Both tests were negative. Abdominal CT angiography (CTA) showed a mural thrombus at the emergence of the coeliac trunk, with total occlusion (figure 1), as well as at the hepatic and splenic arteries. There was also extensive thrombosis of the superior and inferior mesenteric veins and its tributaries, splenic and portal veins, including the splenoportal confluent (figure 2). There was a filiform thrombus at the distal portion of the inferior vena cava, extending to the left common iliac vein, non-occlusive (figure 3). Spleen presented extensive areas of infarction (figure 1). Coeliac trunk occlusion due to paradoxical embolism was excluded by transthoracic echocardiogram. No interatrial communication was detected. Re-evaluation CTA 5days after the diagnosis was identical. Etiological investigation included assessment of congenital coagulation disorders and acquired causes. Regarding congenital disorders, personal and family history of important thrombotic events, thrombosis in unusual sites and abortions were assessed with no relevant findings. Molecular testing for factor V Leiden mutation and prothrombin gene20210 G/A mutation were both negative. Acquired causes of a coagulation disorder, such as neoplastic, infectious and autoimmune disorders, like antiphospholipid syndrome (APS), were also investigated. Thorax, abdomen, pelvic and brain CT did not detect any suspicious lesions. Tumor biomarkers—carcinoembryonic antigen, alpha fetoprotein, carbohydrate antigen 19-9, cancer antigen 125, cancer antigen 15-3, neuron-specific enolase and chromogranin A—were negative. The patient refused to undergo upper digestive endoscopy and colonoscopy. Despite increased levels of inflammatory parameters at admission (leukocytosis and C reactive protein), these values decreased during the hospitalization period. Blood and urine cultures were also negative. Anticardiolipin IgG and IgM and antibeta-2-glycoprotein IgG and IgM were negative, excluding APS.

DIFFERENTIAL DIAGNOSIS
In the presence of venous and arterial thrombosis, the etiological investigation should include

assessment of congenital and acquired coagulation disorders, as well as the presence of interatrial communication that could explain the coeliac trunk occlusion due to paradoxical embolism. As previously stated, these etiological factors were assessed with no specific findings, with the exception of digestive endoscopic study, which was refused by the patient. In this context, and given the fact that the presentation took place 1day after administration of the first dose of COVID-19 vaccine, we hypothesize that the vaccine might be the cause of the extensive arterial and venous thrombosis. This case was immediately reported to INFARMED, the Portuguese authority for drugs and health products. Vaccine-induced thrombotic thrombocytopenia (VITT) was also considered a differential diagnosis. However, the patient did
not present with thrombocytopenia, which is a key criteria for VITT, and therefore the presence of this syndrome was unlikely.COVID-19 tests at admission and on the fifth day of hospitalization were negative; however, she was not tested prior to the onset of the event and therefore it was not possible to exclude

recent COVID-19 infection, which may predispose to thrombosis, even during the convalescent phase.
TREATMENT
At presentation, there were no signs of organ ischemia that required revascularization procedure or intestinal resection. Considering the anemia, the patient was not a candidate for
fibrinolysis. The treatment was empiric endovenous antibiotherapy and transfusion of two units of red blood cells. Anticoagulation with low molecular weight heparin (LMWH) 1mg/kg
two times per day was initiated and maintained during hospitalisation, with monitoring of anti-Xa levels. After hospitalization,in an outpatient setting, the patient was initiated on edoxaban.

OUTCOME AND FOLLOW-UP
Re-evaluation CTA 28 days after presentation revealed a portal vein with a filiform caliber, with a cavernomatous transformation. There was only permeability of the left branch of the portal
vein, with venous collateralization in the hepatic hilum. Coeliac trunk was still occluded, with permeability of the gastroduodenal artery and the right hepatic artery, and apparent occlusion at the emergence of the left hepatic artery, although with distal repermeabilisation. Partial thrombus persisted in the lumen of the left common iliac vein and inferior infrarenal vena cava. At the follow-up consultation, 1month after discharge, the patient was clinically asymptomatic.

DISCUSSION
Venous and arterial thrombotic disorders have long been considered separate pathophysiological entities due to their anatomical differences and distinct clinical presentations. In particular, arterial thrombosis is seen largely as a phenomenon of platelet
activation, whereas venous thrombosis is mostly a matter of activation of the clotting system.2
There is increasing evidence regarding a link between venous and arterial thromboses. These two vascular complications share several risk factors, such as age, obesity, diabetes mellitus, blood Figure 1 CT angiography arterial phase, axial image: a mural thrombus is observed at the coeliac trunk emergence, with total occlusion. Splenic parenchyma without enhancement after contrast administration can also be observed, translating to extensive infarct areas.
Figure 2 CT angiography portal phase, coronal image: portal vein thrombosis (A) extending to the splenoportal confluent (B) can be observed. Figure 3 CT angiography portal phase, coronal image: a non-occlusive filiform thrombus at the distal portion of the inferior vena cava can be observed, extending to the left common iliac vein. on April 13, 2022 by guest. Protected by copyright. http://casereports.bmj.com/ BMJ Case Rep: first published as 10.1136/bcr-2021-244878 on 16 August 2021. Downloaded from Graça LL, et al. BMJ Case Rep 2021;14:e244878. doi:10.1136/bcr-2021-244878 3

Case report hypertension, hypertriglyceridaemia and metabolic syndrome.3 Moreover, there are many examples of conditions accounting for both venous and arterial thromboses, such as APS, hyperhomocysteinaemia, malignancies, infections and use of hormonal treatment.3 In this case, in accordance with the literature, the patient is 62 years old and obese, with no other findings. Hyperhomocysteinaemia and digestive tract malignancies were not excluded. Recent studies have shown that patients with venous thromboembolism are at a higher risk of arterial thrombotic complications than matched control individuals. Therefore, it is speculated that
the two vascular complications may be simultaneously triggered by biological stimuli responsible for activating coagulation and inflammatory pathways in both the arterial and the venous system.3 The modified adenovirus vector COVID-19 vaccines (ChAdOx1nCoV-19 by Oxford/AstraZeneca and Ad26.COV2.S by Johnson & Johnson/Janssen) and mRNA-based COVID-19 vaccines(BNT162b2 mRNA by Pfizer/BioNTech and mRNA-1273 by Moderna) have shown both safety and efficacy against COVID-19 in phase III clinical trials and are now being used in global vaccination programmes.4Rare cases of postvaccine-associated cerebral venous thrombosis(CVT) from use of COVID-19 vaccines which use a viral vector, including the mechanism of VITT, have emerged in real-worldvaccination.4 On the other hand, the incidence and pathogenesis of CVT after mRNA COVID-19 vaccines remain unknown. However Fan et al4
presented three cases and Dias et al5reported two cases of CVT in patients who took an mRNA vaccine (BNT162b2 mRNA by Pfizer/BioNTech). In both cases, causality has not been proven.
In a recent editorial, three independent descriptions of persons with a newly described syndrome, VITT, were highlighted, characterized by thrombosis and thrombocytopenia that developed 5–24 days after initial vaccination with ChAdOx1 nCoV-19 (AstraZeneca), a recombinant adenoviral vector encoding the spike protein of SARS-CoV-2.6VITT is also characterized by the presence of CVT, thrombosis in the portal, splanchnic and hepatic veins, as well as acute arterial thromboses, platelet counts of 20–30×109 /L, high levels of D-dimers and low levels of fibrinogen, suggesting systemic activation of coagulation.6 In our case, similarities were found with VITT regarding thrombosis in the portal, splanchnic and hepatic veins, as well as acute arterial thromboses and high levels of D-dimers. On the other hand, timing of the event (1day after vaccination), high levels of fibrinogen and absence of thrombocytopenia, which is a key criteria for VITT, point to a different direction. Moreover, the
presence of thrombocytosis allowed for a safe use of LMWH for anticoagulation, with monitoring of anti-Xa levels. Most of the cases reported so far of venous and arterial thrombosis as a complication of AstraZeneca’s COVID-19 vaccine have occurred in women under the age of 60 years, associated with thrombocytopenia, within 2weeks of receiving their first dose of the vaccine.7As for the mechanism, it is thought that the vaccine may trigger an immune response leading to an atypical heparin-induced thrombocytopenia-like disorder. In contrast with the literature, our patient presented with thrombocytosis, not thrombocytopaenia.7 Smadja et al8reported that between 13 December 2020 and
16 March 2021 (94 days), 361734967 people in the international COVID-19 vaccination data set received vaccination and795 venous and 1374 arterial thrombotic events were reported in
Vigibase on 16 March 2021. Spontaneous reports of thrombotic events are shared in 1197 for Pfizer/BioNtech’s COVID-19 vaccine,325 for Moderna’s COVID-19 vaccine and 639 for AstraZeneca’sCOVID-19 vaccine.7 The reporting rate for cases of venous (VTE) and arterial (ATE) thrombotic events during this time period among the total number of people vaccinated was 0.21 cases of thrombotic events per 1million person vaccinated-days.7For VTE and ATE, the rates were 0.075 and 0.13 cases per 1million persons vaccinated, respectively, and the timeframe between vaccinationand ATE is the same for the three vaccines (median of 2days),
although a significant difference in terms of VTE was identified between AstraZeneca’s COVID-19 vaccine (median of 6days) and both mRNA vaccines (median of 4days).8 The first paper addressing this issue was published in the New England Journal of Medicine and described 11 patients, 9 of themwomen.9 Nine patients had cerebral venous thrombosis, three had
splanchnic vein thrombosis, three had pulmonary embolism and four had other thromboses. All 11 patients, as well as another 17 for whom the researchers had blood samples, tested positive for antibodies against platelet factor 4 (PF4). These antibodies are also observed in people who develop heparin-induced thrombocytopenia. However, none of the patients had received heparin before their symptoms started.9Our patient did not present thrombocytopenia, so anti-PF4 antibodies were not tested. Thus, considering the anemia, thrombocytosis and thrombosis diagnosed 1day after the first dose ofCOVID-19 vaccine, it seems prudent to continue investigation for other causes of this event, such as hematological malignancies or others.

REFERENCES
1 Burch J, Enofe I. Acute mesenteric ischaemia secondary to portal, splenic and superior
mesenteric vein thrombosis. BMJ Case Rep 2019;12:e230145.
2 Singer DE, Albers GW, Dalen JE, et al. Antithrombotic therapy in atrial fibrillation:
American College of chest physicians evidence-based clinical practice guidelines (8th
edition). Chest 2008;133:546S–92.
3 Ageno W, Becattini C, Brighton T, et al. Cardiovascular risk factors and venous
thromboembolism: a meta-analysis. Circulation 2008;117:93–102.
4 Fan BE, Shen JY, Lim XR, et al. Cerebral venous thrombosis post BNT162b2 mRNA
SARS-CoV-2 vaccination: a black Swan event. Am J Hematol 2021. doi:10.1002/
ajh.26272. [Epub ahead of print: 16 Jun 2021].
5 Dias L, Soares-Dos-Reis R, Meira J, et al. Cerebral venous thrombosis after BNT162b2
mRNA SARS-CoV-2 vaccine. J Stroke Cerebrovasc Dis 2021;30:105906.
6 Cines DB, Bussel JB. SARS-CoV-2 vaccine-induced immune thrombotic
thrombocytopenia. N Engl J Med 2021;384:2254–6.
7 AstraZeneca’s COVID-19 vaccine: EMA finds possible link to very rare cases of unusual
blood clots with low blood platelets. Available: https://www.ema.europa.eu/en/news/
astrazenecas-covid-19-vaccine-ema-finds-possible-link-very-rare-cases-unusual-bloodclots-low-blood [Accessed Apr 2021].
8 Smadja DM, Yue Q-Y, Chocron R, et al. Vaccination against COVID-19: insight from
arterial and venous thrombosis occurrence using data from VigiBase. Eur Respir J
2021;58:2100956.
9 Wise J. Covid-19: rare immune response may cause clots after AstraZeneca vaccine, say
researchers. BMJ 2021;373:n954.

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).

An external file that holds a picture, illustration, etc.
Object name is 10072_2021_5662_Fig1_HTML.jpg

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

Open in a separate window

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

Open in a separate window

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

Open in a separate window

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

Open in a separate window

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

Open in a separate window

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

Open in a separate window

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

Open in a separate window

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

Open in a separate window

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

Open in a separate window

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

Open in a separate window

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.

References

1. World Health Organization. 12 January 2021. WHO Coronavirus (COVID-19) Dashboard. &It; The World Health Organization https://covid19.who.int/. Accessed 1 Aug 2021.

2. Jeff Craven. 10 June 2021. COVID-19 vaccine tracker. &It; https://www.raps.org/news-and-articles/news-articles/2020/3/covid-19-vaccine-tracker. Accessed 16 June 2021.

3. Piyasirisilp S, Hemachudha T. Neurological adverse events associated with vaccination. Curr Opin Neurol. 2002;15(3):333–338. doi: 10.1097/00019052-200206000-00018. [PubMed] [CrossRef] [Google Scholar]

4. Hause AM, Gee J, Johnson T, et al. Anxiety-related adverse event clusters after Janssen COVID-19 vaccination – five U.S. mass vaccination sites, April 2021. MMWR Morb Mortal Wkly Rep. 2021;70(18):685–688. doi: 10.15585/mmwr.mm7018e3. [PubMed] [CrossRef] [Google Scholar]

5. García-Grimshaw M, Ceballos-Liceaga SE, Hernández-Vanegas LE, et al. Neurologic adverse events among 704,003 first-dose recipients of the BNT162b2 mRNA COVID-19 vaccine in Mexico: a nationwide descriptive study. Clin Immunol. 2021;229:108786. doi: 10.1016/j.clim.2021.108786. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

6. Kim SH, Wi YM, Yun SY, et al. Adverse events in healthcare workers after the first dose of ChAdOx1 nCoV-19 or BNT162b2 mRNA COVID-19 vaccination: a single center experience. J Korean Med Sci. 2021;36(14):e107. doi: 10.3346/jkms.2021.36.e107. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

7. Lee YW, Lim SY, Lee JH, et al. Adverse reactions of the second dose of the BNT162b2 mRNA COVID-19 vaccine in healthcare workers in Korea. J Korean Med Sci. 2021;36(21):e153. doi: 10.3346/jkms.2021.36.e153. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

8. Göbel CH, Heinze A, Karstedt S, et al. 2021 Headache attributed to vaccination against COVID-19 (coronavirus SARS-CoV-2) with the ChAdOx1 nCoV-19 (AZD1222) vaccine: a multicenter observational cohort study [published online ahead of print, 2021 Jul 27]. Pain Ther. 1–22. [PMC free article] [PubMed]

9. Module 3. Adverse events following immunization. https://www.who.int/vaccine_safety/initiative/tech_support/Part-3.pdf?ua=1. Accessed 19 June 2021.1

0. Ng JH, Chaudhuri KR, Tan EK. Functional neurological disorders and COVID-19 vaccination. Ann Neurol. 2021;90(2):328. doi: 10.1002/ana.26160. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

11. Kim DD, Kung CS, Perez DL. Helping the public understand adverse events associated with COVID-19 vaccinations: lessons learned from functional neurological disorder. JAMA Neurol. 2021;78(7):789–790. doi: 10.1001/jamaneurol.2021.1042. [PubMed] [CrossRef] [Google Scholar]

12. Butler M, Coebergh J, Safavi F, et al. 2021 Functional neurological disorder after SARS-CoV-2 vaccines: two case reports and discussion of potential public health implications [published online ahead of print, 2021 Jul 15]. J Neuropsychiatry Clin Neurosci. appineuropsych21050116. 10.1176/appi.neuropsych.21050116 [PMC free article] [PubMed]

13. Ercoli T, Lutzoni L, Orofino G, Muroni A, Defazio G. 2021 Functional neurological disorder after COVID-19 vaccination [published online ahead of print, 2021 Jul 29]. Neurol Sci.;1–2. 10.1007/s10072-021-05504-8 [PMC free article] [PubMed]

14. Iba T, Levy JH, Warkentin TE. 2021 Recognizing vaccine-induced immune thrombotic thrombocytopenia [published online ahead of print, 2021 Jul 13]. Crit Care Med. 10.1097/CCM.0000000000005211 [PMC free article] [PubMed]

15. Pomara C, Sessa F, Ciaccio M, et al. 2021 Post-mortem findings in vaccine-induced thrombotic thombocytopenia [published online ahead of print, 2021 May 20]. Haematologica. 10.3324/haematol.2021.279075. [PMC free article] [PubMed]

16. Ledford H. COVID vaccines and blood clots: five key questions. Nature. 2021;592(7855):495–496. doi: 10.1038/d41586-021-00998-w. [PubMed] [CrossRef] [Google Scholar]

17. McGonagle D, De Marco G, Bridgewood C. Mechanisms of Immunothrombosis in vaccine-induced thrombotic thrombocytopenia (VITT) compared to natural SARS-CoV-2 Infection. J Autoimmun. 2021;121:102662. doi: 10.1016/j.jaut.2021.102662. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

18. Castelli GP, Pognani C, Sozzi C, Franchini M, Vivona L. Cerebral venous sinus thrombosis associated with thrombocytopenia post-vaccination for COVID-19. Crit Care. 2021;25(1):137. doi: 10.1186/s13054-021-03572-y. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

19. D’Agostino V, Caranci F, Negro A, et al. A rare case of cerebral venous thrombosis and disseminated intravascular coagulation temporally associated to the COVID-19 vaccine administration. J Pers Med. 2021;11(4):285. doi: 10.3390/jpm11040285. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

20. Scully M, Singh D, Lown R, et al. Pathologic antibodies to platelet factor 4 after ChAdOx1 nCoV-19 vaccination. N Engl J Med. 2021;384(23):2202–2211. doi: 10.1056/NEJMoa210538512. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

21. Franchini M, Testa S, Pezzo M, et al. Cerebral venous thrombosis and thrombocytopenia post-COVID-19 vaccination. Thromb Res. 2021;202:182–183. doi: 10.1016/j.thromres.2021.04.001. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

22. Mehta PR, Apap Mangion S, Benger M, et al. Cerebral venous sinus thrombosis and thrombocytopenia after COVID-19 vaccination – a report of two UK cases. Brain Behav Immun. 2021;95:514–517. doi: 10.1016/j.bbi.2021.04.006.11. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

23. Bersinger S, Lagarde K, Marlu R, Pernod G, Payen JF. Using nonheparin anticoagulant to treat a near-fatal case with multiple venous thrombotic lesions during ChAdOx1 nCoV-19 vaccination-related vaccine-induced immune thrombotic thrombocytopenia. Crit Care Med. 2021;49(9):e870–e873. doi: 10.1097/CCM.0000000000005105. [PubMed] [CrossRef] [Google Scholar]

24. Ramdeny S, Lang A, Al-Izzi S, Hung A, Anwar I, Kumar P. Management of a patient with a rare congenital limb malformation syndrome after SARS-CoV-2 vaccine-induced thrombosis and thrombocytopenia (VITT) [published online ahead of print, 2021 Jun 7]. Br J Haematol. 2021. 10.1111/bjh.17619. [PMC free article] [PubMed]

25. Zakaria Z, Sapiai NA, Ghani ARI. Cerebral venous sinus thrombosis 2 weeks after the first dose of mRNA SARS-CoV-2 vaccine. Acta Neurochir (Wien) 2021;163(8):2359–2362. doi: 10.1007/s00701-021-04860-w. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

26. Ryan E, Benjamin D, McDonald I, et al. AZD1222 vaccine-related coagulopathy and thrombocytopenia without thrombosis in a young female. Br J Haematol. 2021;194(3):553–556. doi: 10.1111/bjh.17530. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

27. Graf T, Thiele T, Klingebiel R, Greinacher A, Schäbitz WR, Greeve I. 2021 Immediate high-dose intravenous immunoglobulins followed by direct thrombin-inhibitor treatment is crucial for survival in Sars-Covid-19-adenoviral vector vaccine-induced immune thrombotic thrombocytopenia VITT with cerebral sinus venous and portal vein thrombosis [published online ahead of print, May 22]. J Neurol. 2021;1–3. 10.1007/s00415-021-10599-2 [PMC free article] [PubMed]

28. George G, Friedman KD, Curtis BR, Lind SE. 2021 Successful treatment of thrombotic thrombocytopenia with cerebral sinus venous thrombosis following Ad26.COV2.S vaccination [published online ahead of print, 2021 May 14]. Am J Hematol. 10.1002/ajh.26237. [PubMed]

29. Jamme M, Mosnino E, Hayon J, Franchineau G. Fatal cerebral venous sinus thrombosis after COVID-19 vaccination. Intensive Care Med. 2021;47(7):790–791. doi: 10.1007/s00134-021-06425-y. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

30. Tiede A, Sachs UJ, Czwalinna A, et al. Prothrombotic immune thrombocytopenia after COVID-19 vaccine [published online ahead of print, 2021 Apr 28]. Blood. 2021;blood.2021011958. 10.1182/blood.2021011958. 13

31. Schulz JB, Berlit P, Diener HC, Gerloff C, Greinacher A, Klein C. 2021 COVID-19 vaccine-associated cerebral venous thrombosis in Germany. medRxiv.04.30.21256383; doi: 10.1101/2021.04.30.21256383. 14 [PMC free article] [PubMed]

32. Bourguignon A, Arnold DM, Warkentin TE, et al. 2021 Adjunct immune globulin for vaccine-induced thrombotic thrombocytopenia [published online ahead of print, 2021 Jun 9]. N Engl J Med. 10.1056/NEJMoa2107051. [PMC free article] [PubMed]

33. Gattringer T, Gressenberger P, Gary T, Wölfler A, Kneihsl M, Raggam RB. 2021 Successful management of vaccine-induced immune thrombotic thrombocytopenia-related cerebral sinus venous thrombosis after ChAdOx1 nCov-19 vaccination [published online ahead of print, 2021 Jul 8]. Stroke Vasc Neurol.svn-2021–001142. 10.1136/svn-2021-001142 [PMC free article] [PubMed]

34. Ikenberg B, Demleitner AF, Thiele T, et al. Cerebral venous sinus thrombosis after ChAdOx1 nCov-19 vaccination with a misleading first cerebral MRI scan. Stroke Vasc Neurol. 2021;8:svn-2021–001095. doi: 10.1136/svn-2021-001095. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

35. Clark RT, Johnson L, Billotti J, et al. Early outcomes of bivalirudin therapy for thrombotic thrombocytopenia and cerebral venous sinus thrombosis after Ad26.COV2.S vaccination. Ann Emerg Med. 2021;S0196 0644(21):00342 5. doi: 10.1016/j.annemergmed.2021.04.035. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

36. Bonato S, Artoni A, Lecchi A, et al. 2021 Massive cerebral venous thrombosis due to vaccine-induced immune thrombotic thrombocytopenia [published online ahead of print, 2021 Jul 15]. Haematologica. 10.3324/haematol.2021.279246 [PMC free article] [PubMed]

37. Wang RL, Chiang WF, Shyu HY, et al. COVID-19 vaccine-associated acute cerebral venous thrombosis and pulmonary artery embolism. QJM. 2021;10:hcab185. doi: 10.1093/qjmed/hcab185. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

38. Dutta A, Ghosh R, Bhattacharya D, et al. Anti-PF4 antibody negative cerebral venous sinus thrombosis without thrombocytopenia following immunization with COVID-19 vaccine in an elderly non-comorbid Indian male, managed with conventional heparin-warfarin based anticoagulation. Diabetes Metab Syndr. 2021;15(4):102184. doi: 10.1016/j.dsx.2021.06.021. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

39. Aladdin 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(9):105938. doi: 10.1016/j.jstrokecerebrovasdis.2021.105938. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

40. Lavin M, Elder PT, O’Keeffe D, et al. Vaccine-induced immune thrombotic thrombocytopenia (VITT) – a novel clinico-pathological entity with heterogeneous clinical presentations [published online ahead of print, 2021 Jun 22]. Br J Haematol. 2021. 10.1111/bjh.17613. [PMC free article] [PubMed]

41. Tølbøll Sørensen AL, Rolland M, Hartmann J, et al. A case of thrombocytopenia and multiple thromboses after vaccination with ChAdOx1 nCoV-19 against SARS-CoV-2. Blood Adv. 2021;5(12):2569–2574. doi: 10.1182/bloodadvances.2021004904. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

42. Fan BE, Shen JY, Lim XR, et al. Cerebral venous thrombosis post BNT162b2 mRNA SARS-CoV-2 vaccination: a black swan event. Am J Hematol. 2021;96(9):E357–E361. doi: 10.1002/ajh.26272. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

43. Suresh P, Petchey W. ChAdOx1 nCOV-19 vaccine-induced immune thrombotic thrombocytopenia and cerebral venous sinus thrombosis (CVST) BMJ Case Rep. 2021;14(6):e243931. doi: 10.1136/bcr-2021-243931. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

44. Dias L, Soares-Dos-Reis R, Meira J, et al. Cerebral venous thrombosis after BNT162b2 mRNA SARS-CoV-2 vaccine. J Stroke Cerebrovasc Dis. 2021;30(8):105906. doi: 10.1016/j.jstrokecerebrovasdis.2021.105906. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

45. Guan CY, Tsai SH, Fan JS, Lin YK, Kao CC. 2021 A rare case of a middle-age Asian male with cerebral venous thrombosis after COVID-19 AstraZeneca vaccination [published online ahead of print, Jul 8]. Am J Emerg Med. 2021;S0735–6757(21)00571–4. 10.1016/j.ajem.2021.07.011 [PMC free article] [PubMed]

46. Varona JF, García-Isidro M, Moeinvaziri M, Ramos-López M, Fernández-Domínguez M. 2021 Primary adrenal insufficiency associated with Oxford-AstraZeneca ChAdOx1 nCoV-19 vaccine-induced immune thrombotic thrombocytopenia (VITT) [published online ahead of print, Jul 10]. Eur J Intern Med. 2021;S0953–6205(21)00236–3. 10.1016/j.ejim.2021.06.025 [PMC free article] [PubMed]

47. Pottegård A, Lund LC, Karlstad Ø, et al. Arterial events, venous thromboembolism, thrombocytopenia, and bleeding after vaccination with Oxford-AstraZeneca ChAdOx1-S in Denmark and Norway: population based cohort study. BMJ. 2021;373:n1114. doi: 10.1136/bmj.n1114. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

48. Krzywicka K, Heldner MR, Sánchez van 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. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

49. National Institute for Health and Care Excellence. 29 July 2021. COVID-19 rapid guideline: vaccine-induced immune thrombocytopenia and thrombosis (VTT). &It; https://www.nice.org.uk/guidance/ng200/resources/covid19-rapid-guideline-vaccineinduced-immune-thrombocytopenia-and-thrombosis-vitt-pdf-51036811744. Accessed 2 Aug 2021.

50. Krzywicka K, Heldner MR, Sánchez van 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. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

51. Bersinger S, Lagarde K, Marlu R, Pernod G, Payen JF. Using nonheparin anticoagulant to treat a near-fatal case with multiple venous thrombotic lesions during ChAdOx1 nCoV-19 vaccination-related vaccine-induced immune thrombotic thrombocytopenia. Crit Care Med. 2021;49(9):e870–e873. doi: 10.1097/CCM.0000000000005105. [PubMed] [CrossRef] [Google Scholar]

52. Simpson CR, Shi T, Vasileiou E, et al. First-dose ChAdOx1 and BNT162b2 COVID-19 vaccines and thrombocytopenic, thromboembolic and hemorrhagic events in Scotland. Nat Med. 2021;27(7):1290–1297. doi: 10.1038/s41591-021-01408-4. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

53. Athyros VG, Doumas M. 2021 A possible case of hypertensive crisis with intracranial haemorrhage after an mRNA Anti-COVID-19 vaccine [published online ahead of print, 2021 May 21]. Angiology.;33197211018323. 10.1177/00033197211018323 [PubMed]

54. Bjørnstad-Tuveng TH, Rudjord A, Anker P. 2021 Fatal cerebral haemorrhage after COVID-19 vaccine. Fatal hjerneblødning etter covid-19-vaksine. Tidsskr Nor Laegeforen. 2021;141. 10.4045/tidsskr.21.0312. [PubMed]

55. de Mélo Silva ML Jr, Lopes DP. 2021 Large hemorrhagic stroke after ChAdOx1 nCoV-19 vaccination: a case report [published online ahead of print, 2021 Jul 17]. Acta Neurol Scand. 10.1111/ane.13505. [PMC free article] [PubMed]

56. Bayas A, Menacher M, Christ M, Behrens L, Rank A, Naumann M. Bilateral superior ophthalmic vein thrombosis, ischaemic stroke, and immune thrombocytopenia after ChAdOx1 nCoV-19 vaccination. Lancet. 2021;397(10285):e11. doi: 10.1016/S0140-6736(21)00872-2. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

57. Al-Mayhani T, Saber S, Stubbs MJ, et al. Ischaemic stroke as a presenting feature of ChAdOx1 nCoV-19 vaccine-induced immune thrombotic thrombocytopenia. J Neurol Neurosurg Psychiatry. 2021;92(11):1247–1248. doi: 10.1136/jnnp-2021-326984. [PubMed] [CrossRef] [Google Scholar]

58. Blauenfeldt RA, Kristensen SR, Ernstsen SL, Kristensen CCH, Simonsen CZ, Hvas AM. Thrombocytopenia with acute ischemic stroke and bleeding in a patient newly vaccinated with an adenoviral vector-based COVID-19 vaccine. J Thromb Haemost. 2021;19(7):1771–1775. doi: 10.1111/jth.15347. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

59. Malik B, Kalantary A, Rikabi K, Kunadi A. Pulmonary embolism, transient ischaemic attack and thrombocytopenia after the Johnson & Johnson COVID-19 vaccine. BMJ Case Rep. 2021;14(7):e243975. doi: 10.1136/bcr-2021-243975. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

60. Finsterer J, Korn M. 2021 Aphasia seven days after second dose of an mRNA-based SARS-CoV-2 vaccine [published online ahead of print, 2021 Jun 24]. Brain Hemorrhages. 10.1016/j.hest.2021.06.001. [PMC free article] [PubMed]

61. Walter U, Fuchs M, Grossmann A, et al. 2021 Adenovirus-vectored COVID-19 vaccine-induced immune thrombosis of carotid artery: a case report [published online ahead of print, 2021 Jul 26]. Neurology. 10.1212/WNL.0000000000012576. [PubMed]

62. Baldelli L, Amore G, Montini A, et al. Hyperacute reversible encephalopathy related to cytokine storm following COVID-19 vaccine. J Neuroimmunol. 2021;358:577661. doi: 10.1016/j.jneuroim.2021.577661. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

63. Aladdin Y, Shirah B. New-onset refractory status epilepticus following the ChAdOx1 nCoV-19 vaccine. J Neuroimmunol. 2021;357:577629. doi: 10.1016/j.jneuroim.2021.577629. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

64. Ghosh R, Dubey S, Roy D, Mandal A, Naga D, Benito-León J. Focal onset non-motor seizure following COVID-19 vaccination: a mere coincidence? Diabetes Metab Syndr. 2021;15(3):1023–1024. doi: 10.1016/j.dsx.2021.05.003. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

65. Liu BD, Ugloini C, Jha P. Two cases of post-Moderna COVID-19 vaccine encephalopathy associated with nonconvulsive status epilepticus. Cureus. 2021;13(7):e16172. doi: 10.7759/cureus.16172. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

66. Naharci MI, Tasci I. 2021 Delirium in a patient with Alzheimer’s dementia following COVID-19 vaccination [published online ahead of print, 2021 Jul 10]. Psychogeriatrics. 10.1111/psyg.12747. [PMC free article] [PubMed]

67. Salinas MR, Dieppa M. Transient akathisia after the SARS-Cov-2 vaccine. Clin Park Relat Disord. 2021;4:100098. doi: 10.1016/j.prdoa.2021.100098. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

68. Zavala-Jonguitud LF, Pérez-García CC. Delirium triggered by COVID-19 vaccine in an elderly patient. Geriatr Gerontol Int. 2021;21(6):540. doi: 10.1111/ggi.14163. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

69. Alfishawy M, Bitar Z, Elgazzar A, Elzoueiry M. 2021 Neuroleptic malignant syndrome following COVID-19 vaccination [published online ahead of print, Feb 20]. Am J Emerg Med. 2021;S0735–6757(21)00117–0. 10.1016/j.ajem.2021.02.011 [PMC free article] [PubMed]

70. Ozgen Kenangil G, Ari BC, Guler C, Demir MK. Acute disseminated encephalomyelitis-like presentation after an inactivated coronavirus vaccine. Acta Neurol Belg. 2021;121(4):1089–1091. doi: 10.1007/s13760-021-01699-x. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

71. Cao L, Ren L. Acute disseminated encephalomyelitis after severe acute respiratory syndrome coronavirus 2 vaccination: a case report. Acta Neurol Belg. 2021;1:1–3. doi: 10.1007/s13760-021-01608-2. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

72. Raknuzzaman M, Jannaty T, Hossain MB, Saha B, Dey SK, Shahidullah M. 2021 Post Covid 19 vaccination acute disseminated encephalomyelitis: a case report in Bangladesh. Int J Med Sci Clin Res Studies 3. 10.47191/ijmscrs/v1-i3-01

73. Torrealba-Acosta G, Martin JC, Huttenbach Y, et al. Acute encephalitis, myoclonus and Sweet syndrome after mRNA-1273 vaccine. BMJ Case Rep. 2021;14(7):e243173. doi: 10.1136/bcr-2021-243173. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

74. Vogrig A, Janes F, Gigli GL. Acute disseminated encephalomyelitis after SARS-CoV-2 vaccination. Clin Neurol Neurosurg. 2021;208:106839. doi: 10.1016/j.clineuro.2021.106839. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

75. Zuhorn 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. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

76. Pellegrino P, Carnovale C, Perrone V, et al. Acute disseminated encephalomyelitis onset: evaluation based on vaccine adverse events reporting systems. PLoS One. 2013;8(10):e77766. doi: 10.1371/journal.pone.0077766. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

77. Malhotra SH, Gupta P, Prabhu V, Garg RK, Dandu H, Agarwal V. COVID-19 vaccination-associated myelitis [published online ahead of print, 2021 Mar 31]. QJM. 2021;hcab069. 10.1093/qjmed/hcab069 [PMC free article] [PubMed]

78. Fitzsimmons, William and Nance, Christopher S., Sudden onset of myelitis after COVID-19 vaccination: an under-recognized severe rare adverse event (May 5, 2021). Available at SSRN: https://ssrn.com/abstract=3841558 or 10.2139/ssrn.3841558

79. Tahir N, Koorapati G, Prasad S, et al. SARS-CoV-2 vaccination-induced transverse myelitis. Cureus. 2021;13(7):e16624. doi: 10.7759/cureus.16624. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

80. Pagenkopf 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. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

81. Helmchen C, Buttler GM, Markewitz R, Hummel K, Wiendl H, Boppel T. 2021 Acute bilateral optic/chiasm neuritis with longitudinal extensive transverse myelitis in longstanding stable multiple sclerosis following vector-based vaccination against the SARS-CoV-2 [published online ahead of print, Jun 15]. J Neurol. 2021;1–6. 10.1007/s00415-021-10647-x [PMC free article] [PubMed]

82. Havla J, Schultz Y, Zimmermann H, Hohlfeld R, Danek A, Kümpfel T. 2021 First manifestation of multiple sclerosis after immunization with the Pfizer-BioNTech COVID-19 vaccine [published online ahead of print, 2021 Jun 11]. J Neurol. 1–4. 10.1007/s00415-021-10648-w [PMC free article] [PubMed]

83. Chen 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. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

84. Chagla Z. In adults, the Oxford/AstraZeneca vaccine had 70% efficacy against COVID-19 >14 d after the 2nd dose. Ann Intern Med. 2021;174(3):JC29. doi: 10.7326/ACPJ202103160-029. [PubMed] [CrossRef] [Google Scholar]

85. Knoll MD, Wonodi C. Oxford-AstraZeneca COVID-19 vaccine efficacy. Lancet. 2021;397(10269):72–74. doi: 10.1016/S0140-6736(20)32623-4. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

86. Román 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.2021.6537

86. PMID:33981305;PMCID:PMC8107358. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

87. Shemer A, Pras E, Hecht I. Peripheral facial nerve palsy following BNT162b2 (COVID-19) vaccination. Isr Med Assoc J. 2021;23(3):143–144. [PubMed] [Google Scholar]

88. Repajic M, Lai XL, Xu P, Liu A. Bell’s Palsy after second dose of Pfizer COVID-19 vaccination in a patient with history of recurrent Bell’s palsy. Brain Behav Immun Health. 2021;13:100217. doi: 10.1016/j.bbih.2021.100217. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

89. Colella G, Orlandi M, Cirillo N. 2021 Bell’s palsy following COVID-19 vaccination [published online ahead of print, 2021 Feb 21]. J Neurol. 1–3. doi:10.1007/s00415-021-10462-4 [PMC free article] [PubMed]

90. Martin-Villares C, Vazquez-Feito A, Gonzalez-Gimeno MJ, de la Nogal-Fernandez B. 2021 Bell’s palsy following a single dose of mRNA SARS-CoV-2 vaccine: a case report [published online ahead of print, 2021 May 25]. J Neurol. 1–2. doi:10.1007/s00415-021-10617-3 [PMC free article] [PubMed]

91. Nishizawa Y, Hoshina Y, Baker V. 2021 Bell’s palsy following the Ad26.COV2.S COVID-19 vaccination [published online ahead of print, 2021 May 20]. QJM.;hcab143. doi:10.1093/qjmed/hcab143 [PMC free article] [PubMed]

92. Gómez de Terreros Caro G, Díaz SG, Alé MP, Gimeno LM. 2021 PARÁLISIS DE BELL TRAS VACUNACIÓN COVID19: A PROPÓSITO DE UN CASO [BELL´S PALSY FOLLOWING COVID-19 VACCINATION: A CASE REPORT] [published online ahead of print, 2021 Apr 12]. Neurologia (Engl Ed). 10.1016/j.nrl.2021.04.004. [PMC free article] [PubMed]

93. Burrows 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. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

94. Obermann M, Krasniqi M, Ewers N, Fayad J, Haeberle U. Bell’s palsy following COVID-19 vaccination with high CSF antibody response. Neurol Sci. 2021;42(11):4397–4399. doi: 10.1007/s10072-021-05496-5. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

95. Iftikhar H, Noor SU, Masood M, et al. Bell’s palsy after 24 hours of mRNA-1273 SARS-CoV-2 vaccine. Cureus. 2021;13(6):e15935. doi: 10.7759/cureus.15935. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

96. Ozonoff A, Nanishi E, Levy O. 2021 Bell’s palsy and SARS-CoV-2 vaccines-an unfolding story – authors’ reply [published online ahead of print, 2021 Jun 7]. Lancet Infect Dis S1473–3099(21)00323–6. doi:10.1016/S1473-3099(21)00323-6 [PMC free article] [PubMed]

97. Shemer A, Pras E, Einan-Lifshitz A, Dubinsky-Pertzov B, Hecht I. Association of COVID-19 vaccination and facial nerve palsy: a case-control study. JAMA Otolaryngol Head Neck Surg. 2021;147(8):739–743. doi: 10.1001/jamaoto.2021.1259. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

98. Ozonoff A, Nanishi E, Levy O. Bell’s palsy and SARS-CoV-2 vaccines. Lancet Infect Dis. 2021;21(4):450–452. doi: 10.1016/S1473-3099(21)00076-1. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

99. Konstantinidis I, Tsakiropoulou E, Hähner A, de With K, Poulas K, Hummel T. 2021 Olfactory dysfunction after coronavirus disease 2019 (COVID-19) vaccination [published online ahead of print, 2021 May 28]. Int Forum Allergy Rhinol. 10.1002/alr.22809. [PMC free article] [PubMed]

100. Keir G, Maria NI, Kirsch CFE. Unique imaging findings of neurologic phantosmia following Pfizer-BioNtech COVID-19 vaccination: a case report. Top Magn Reson Imaging. 2021;30(3):133–137. doi: 10.1097/RMR.0000000000000287. [PubMed] [CrossRef] [Google Scholar]

101. Reyes-Capo DP, Stevens SM, Cavuoto KM. 2021 Acute abducens nerve palsy following COVID-19 vaccination [published online ahead of print, 2021 May 24]. J AAPOS S1091–8531(21)00109–9. doi:10.1016/j.jaapos.2021.05.003 [PMC free article] [PubMed]

102. 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. 2021;13:1–4. doi: 10.1080/ 14992027.2021.1931969. [PubMed] [CrossRef] [Google Scholar]

103. Tseng PT, Chen TY, Sun YS, Chen YW, Chen JJ. 2021 The reversible tinnitus and cochleopathy followed first-dose AstraZeneca COVID-19 vaccination [published online ahead of print, 2021 Jul 23]. QJM hcab210. doi:10.1093/qjmed/hcab210 [PMC free article] [PubMed]

104. Narasimhalu K, Lee WC, Salkade PR, De Silva DA. Trigeminal and cervical radiculitis after tozinameran vaccination against COVID-19. BMJ Case Rep. 2021;14(6):e242344. doi: 10.1136/bcr-2021-242344. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

105. Wichova H, Miller ME, Derebery MJ. Otologic manifestations after COVID-19 vaccination: the house ear clinic experience. Otol Neurotol. 2021;42(9):e1213–e1218. doi: 10.1097/MAO.0000000000003275. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

106. Santovito LS, Pinna G. Acute reduction of visual acuity and visual field after Pfizer-BioNTech COVID-19 vaccine 2nd dose: a case report. Inflamm Res. 2021;70(9):931–933. doi: 10.1007/s00011-021-01476-9. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

107. Dyer O. Covid-19: Regulators warn that rare Guillain-Barré cases may link to J&J and AstraZeneca vaccines. BMJ. 2021;374:n1786. doi: 10.1136/bmj.n1786. [PubMed] [CrossRef] [Google Scholar]

108. Márquez Loza AM, Holroyd KB, Johnson SA, Pilgrim DM, Amato AA. Guillain- Barré syndrome in the placebo and active arms of a COVID-19 vaccine clinical trial: temporal associations do not imply causality [published online ahead of print, 2021 Apr 6]. Neurology. 2021. 10.1212/WNL.0000000000011881. [PubMed]

109. FDA Briefing Document Janssen Ad26.COV2.S Vaccine for the prevention of COVID-1.26 February 2021. Vaccines and Related Biological Products Advisory Committee Meeting. &It; https://www.fda.gov/media/146217/download. Accessed 24 June 2021

110. Waheed S, Bayas A, Hindi F, Rizvi Z, Espinosa PS. Neurological complications of COVID-19: Guillain-Barre syndrome following Pfizer COVID-19 vaccine. Cureus. 2021;13(2):e13426. doi: 10.7759/cureus.13426. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

111. Márquez Loza AM, Holroyd KB, Johnson SA, Pilgrim DM, Amato AA. 2021 Guillain-Barré syndrome in the placebo and active arms of a COVID-19 vaccine clinical trial: temporal associations do not imply causality [published online ahead of print, 2021 Apr 6]. Neurology. 10.1212/WNL.0000000000011881. [PubMed]

112. Patel SU, Khurram R, Lakhani A, Quirk B. Guillain-Barre syndrome following the first dose of the chimpanzee adenovirus-vectored COVID-19 vaccine, ChAdOx1. BMJ Case Rep. 2021;14(4):e242956. doi: 10.1136/bcr-2021-242956. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

113. Razok A, Shams A, Almeer A et al. 2021 Post-COVID-19 vaccine Guillain-Barré syndrome; first reported case from Qatar. Authorea. May 07,. DOI: 10.22541/au.162041666.65803989/v1 [PMC free article] [PubMed]

114. Ogbebor O, Seth H, Min Z, Bhanot N. Guillain-Barré syndrome following the first dose of SARS-CoV-2 vaccine: a temporal occurrence, not a causal association. IDCases. 2021;24:e01143. doi: 10.1016/j.idcr.2021.e01143. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

115. Finsterer J. Exacerbating Guillain-Barré syndrome eight days after vector-based COVID-19 vaccination. Case Rep Infect Dis. 2021;2021:3619131. doi: 10.1155/2021/3619131. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

116. Maramattom BV, Krishnan P, Paul R, et al. Guillain-Barré syndrome following ChAdOx1-S/nCoV-19 vaccine. Ann Neurol. 2021;90(2):312–314. doi: 10.1002/ana.26143. [PubMed] [CrossRef] [Google Scholar]

117. Allen CM, Ramsamy S, Tarr AW, Tighe PJ, Irving WL, Tanasescu R, Evans JR. Guillain-Barré syndrome variant occurring after SARS-CoV-2 vaccination. Ann Neurol. 2021 doi: 10.1002/ ana.26144. [PubMed] [CrossRef] [Google Scholar]

118. Kohli S, Varshney M, Mangla S, Jaiswal B, Chhabra PH. Guillain-Barré syndrome after COVID-19 vaccine: should we assume a causal Link? International Journal of Medical and Pharmaceutical Case Reports. 2021;14(1):20–24. doi: 10.9734/ijmpcr/2021/ v14i130124. [CrossRef] [Google Scholar]

119. Azam S, Khalil A, Taha A. Guillain-Barré syndrome in a 67-year-old male post COVID-19 vaccination (Astra Zeneca) American Journal of Medical Case Reports. 2021;9(8):424–427. doi: 10.12691/ajmcr-9-8-10. [CrossRef] [Google Scholar]

120. Hasan T, Khan M, Khan F, Hamza G. Case of Guillain-Barré syndrome following COVID-19 vaccine. BMJ Case Rep. 2021;14(6):e243629. doi: 10.1136/bcr-2021-243629. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

121. Theuriet J, Richard C, Becker J, Pegat A, Bernard E, Vukusic S. 2021 Guillain-Barré syndrome following first injection of ChAdOx1 nCoV-19 vaccine: First report. Rev Neurol (Paris) S0035–3787(21)00585–3 doi:10.1016/j.neurol.2021.04.005 [PubMed]

122. Bonifacio GB, Patel D, Cook S, et al. 2021 Bilateral facial weakness with paraesthesia variant of Guillain-Barré syndrome following Vaxzevria COVID-19 vaccine [published online ahead of print, 2021 Jul 14]. J Neurol Neurosurg Psychiatry jnnp-2021–327027. doi:10.1136/jnnp-2021-327027 [PubMed]

123. Nasuelli NA, De Marchi F, Cecchin M, et al. A case of acute demyelinating polyradiculoneuropathy with bilateral facial palsy after ChAdOx1 nCoV-19 vaccine. Neurol Sci. 2021;42(11):4747–4749. doi: 10.1007/s10072-021-05467-w. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

124. Jain E, Pandav K, Regmi P, et al. Facial diplegia: a rare, atypical variant of Guillain-Barré syndrome and Ad26.COV2.S Vaccine. Cureus. 2021;13(7):e16612. doi: 10.7759/cureus.16612. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

125. McKean N, Chircop C. Guillain-Barré syndrome after COVID-19 vaccination. BMJ Case Rep. 2021;14(7):e244125. doi: 10.1136/bcr-2021-244125. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

126. Bonifacio GB, Patel D, Cook S, et al. 2021 Bilateral facial weakness with paraesthesia variant of Guillain-Barré syndrome following Vaxzevria COVID-19 vaccine [published online ahead of print, 2021 Jul 14]. J Neurol Neurosurg Psychiatry jnnp-2021–327027. doi:10.1136/jnnp-2021-327027 [PubMed]

127. Waheed W, Carey ME, Tandan SR, Tandan R. Post COVID-19 vaccine small fiber neuropathy. Muscle Nerve. 2021;64(1):E1–E2. doi: 10.1002/mus.27251. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

128. Mahajan S, Zhang F, Mahajan A, Zimnowodzki S. Parsonage Turner syndrome after COVID-19 vaccination. Muscle Nerve. 2021;64(1):E3–E4. doi: 10.1002/mus.27255. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

129. Diaz-Segarra N, Edmond A, Gilbert C, Mckay O, Kloepping C, Yonclas P. 2021 Painless idiopathic neuralgic amyotrophy after COVID-19 vaccination: a case report [published online ahead of print, 2021 Apr 22]. PM R.;10.1002/pmrj.12619 [PMC free article] [PubMed]

130. Antonio Crespo Burillo J, Martínez CL, Arguedas CG, Pueyo FJM. Neuralgia amiotrófica secundaria a vacuna contra COVID-19 Vaxzevria (AstraZeneca) [Amyotrophic neuralgia secondary to Vaxzevria (AstraZeneca) COVID-19 vaccine] Neurologia. 2021;36(7):571–572. doi: 10.1016/j.nrl.2021.05.007. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

131. McMahon DE, Amerson E, Rosenbach M, et al. Cutaneous reactions reported after Moderna and Pfizer COVID-19 vaccination: a registry-based study of 414 cases. J Am Acad Dermatol. 2021;85(1):46–55. doi: 10.1016/j.jaad.2021.03.092. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

132. Arora P, Sardana K, Mathachan SR, Malhotra P. 2021 Herpes zoster after inactivated COVID-19 vaccine: a cutaneous adverse effect of the vaccine [published online ahead of print, 2021 Jun 2]. J Cosmet Dermatol. 10.1111/jocd.14268. [PMC free article] [PubMed]

133. Lladó I, Fernández-Bernáldez A, Rodríguez-Jiménez P 2021. “Varicella zoster virus reactivation and mRNA vaccines as a trigger”. Reply to: Herpes-Zoster reactivation after mRNA-1273 (Moderna) SARS-CoV-2 Vaccination [published online ahead of print, 2021 Jul 22]. JAAD Case Rep. 10.1016/j.jdcr.2021.07.011. [PMC free article] [PubMed]

134. Tessas I, Kluger N. Ipsilateral herpes zoster after the first dose of BNT162b2 mRNA COVID-19 vaccine. J Eur Acad Dermatol Venereol. 2021;35(10):e620–e622. doi: 10.1111/jdv.17422. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

135. Rodríguez-Jiménez P, Chicharro P, Cabrera LM, et al. Varicella-zoster virus reactivation after SARS-CoV-2 BNT162b2 mRNA vaccination: Report of 5 cases. JAAD Case Rep. 2021;12:58–59. doi: 10.1016/j.jdcr.2021.04.014. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

136. Eid E, Abdullah L, Kurban M, Abbas O. Herpes zoster emergence following mRNA COVID-19 vaccine. J Med Virol. 2021 doi: 10.1002/jmv.27036. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

137. Bostan E, Yalici-Armagan B. Herpes zoster following inactivated COVID-19 vaccine: a coexistence or coincidence? J Cosmet Dermatol. 2021;20(6):1566–1567. doi: 10.1111/jocd.14035. [PubMed] [CrossRef] [Google Scholar]

138. Furer V, Zisman D, Kibari A, Rimar D, Paran Y, Elkayam O. 2021 Herpes zoster following BNT162b2 mRNA Covid-19 vaccination in patients with autoimmune inflammatory rheumatic diseases: a case series [published online ahead of print, 2021 Apr 12]. Rheumatology (Oxford) keab345. doi:10.1093/rheumatology/keab345 [PMC free article] [PubMed]

139. Aksu SB, Öztürk GZ. A rare case of shingles after COVID-19 vaccine: is it a possible adverse effect? Clin Exp Vaccine Res. 2021;10(2):198–201. doi: 10.7774/cevr.2021.10.2.198. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

140. Chiu HH, Wei KC, Chen A, Wang WH. 2021 Herpes zoster following COVID-19 vaccine: report of 3 cases [published online ahead of print, 2021 Jul 22]. QJM.;hcab208. 10.1093/qjmed/ hcab208 [PMC free article] [PubMed]

141. Alpalhão M, Filipe P. Herpes Zoster following SARS-CoV-2 vaccination – a series of 4 cases. J Eur Acad Dermatol Venereol. 2021;35(11):e750–e752. doi: 10.1111/jdv.17555. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

142. Channa L, Torre K, Rothe M. Letter to the editor: Herpes-Zoster reactivation after mRNA-1273 (Moderna) SARS-CoV-2 Vaccination. JAAD Case Rep. 2021;15:60–61. doi: 10.1016/j.jdcr.2021.05.042. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

143. Tan A, Stepien KM, Narayana STK. Carnitine palmitoyltransferase II deficiency and post-COVID vaccination rhabdomyolysis. QJM. 2021;19:hcab077. doi: 10.1093/qjmed/hcab077. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

144. Mack M, Nichols L, Guerrero DM. Rhabdomyolysis secondary to COVID-19 vaccination. Cureus. 2021;13(5):e15004. doi: 10.7759/cureus.15004. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

145. Nassar M, Chung H, Dhayaparan Y, et al. COVID-19 vaccine induced rhabdomyolysis: Case report with literature review. Diabetes Metab Syndr. 2021;15(4):102170. doi: 10.1016/j.dsx.2021.06.007. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

146. Theodorou DJ, Theodorou SJ, Axiotis A, Gianniki M, Tsifetaki N. COVID-19 vaccine-related myositis. QJM. 2021;1146(424):425. doi: 10.1093/qjmed/hcab043. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

147. Godoy IRB, Rodrigues TC, Skaf A. Myositis ossificans following COVID-19 vaccination. QJM. 2021;9:hcab161. doi: 10.1093/qjmed/hcab161. [PMC free article] [PubMed] [CrossRef] [Google Scholar]

Bone Marrow Suppression Secondary to the COVID-19 Booster Vaccine: A Case Report

TAuthors: oral Shastri 1Navkiran Randhawa 2Ragia Aly 3Masood Ghouse 3 PMID: 35210894PMCID: PMC8863340DOI: 10.2147/JBM.S350290 J Blood Med.  2022; 13: 69–74.Published online 2022 Feb 18. doi: 10.2147/JBM.S350290

Abstract

As of September 2021, SARS-CoV-2 booster shots became widely available in the US to ensure continued protection against the virus. A temporal relationship has been previously reported between the first or second dose of the COVID-19 vaccine and the development of thrombocytopenia. However, adverse events related to the third COVID-19 vaccine are still being reported and studied. We report a 74-year-old male who developed bone marrow suppression and pancytopenia recorded seven days after receiving the Pfizer SARS-CoV-2 vaccine. During his hospital stay, the patient’s hemoglobin, white blood cell, and platelet levels continued to trend downwards. However, all three levels showed improvement one week after discharge without robust intervention. Global vaccination is of utmost importance, as is understanding and documenting post-vaccination reactions including bone marrow suppression. Prompt evaluation and patient education are imperative to improve patient outcomes and combat hesitancy against vaccine administration.

Introduction

Since its emergence in December of 2019, the rapid spread of severe acute respiratory syndrome coronavirus (SARS-CoV-2) has quickly affected millions of lives across every continent.1 This highly transmittable and pathogenic viral infection has led to massive mitigation efforts and allocation of resources to prevent the spread of transmission and high mortality related to complications.2 The establishment of higher levels of community (herd) immunity and protection against SARS-CoV-2 via the widespread deployment of effective vaccines has become a global effort.3 In December of 2020, the FDA issued an Emergency use Authorization for the Pfizer-BioNTech and Moderna COVID-19 Vaccine as a two-dose series.4 In September 2021, booster vaccines became widely administered in the US due to waning immunity of the COVID-19 vaccines against variants of SARS-CoV-2 along with ensuring continued protection against the virus.5

Serious adverse events such as anaphylaxis, Guillain-Barre Syndrome, myocarditis, pericarditis, thrombocytopenia, and death have been previously reported following the first and/or second dose of vaccine.6 To our knowledge, no cases have been reported regarding bone marrow suppression related to the third COVID-19 vaccine. Adverse events reported between August 12-September 19, 2021 from the COVID-19 booster vaccine supported similar reactions to those after dose two.7 According to the Centers for Disease Control and Prevention (CDC), these initial findings indicate no unexpected patterns of adverse reactions after an additional dose of COVID-19 vaccination.7 However, adverse events related to the COVID-19 booster are still being reported and studied.6 This report presents a case of bone marrow suppression occurring after the third COVID-19 vaccine without a similar reaction after the first or second dose.Go to:

Case Report

A 74-year-old male with a history of polychondritis and hypothyroidism presented to the hospital after falling out of his chair and inability to ambulate. The patient was found to be mildly confused upon arrival to the emergency room, limiting our ability to obtain a full verbal history. Chart review revealed the patient had received his third Pfizer Covid vaccine shot seven days before admission followed by fatigue, decreased appetite, fever, and chills. The patient had received the second Pfizer Covid-19 shot nine months before the booster. No reactions to the previous two shots were noted.

Upon initial evaluation, vital signs were within normal limits and a physical exam revealed significant tenderness in the upper arm and no gross bleeding (Figure 1). Computed tomography (CT) imaging (Figure 2) was significant for enhancement of the left axillary lymph node. The patient’s initial complete blood count (CBC) was remarkable for a hemoglobin count of 9.9 g/dl and platelet count of 84 x 109/L; both values lower than his prior hemoglobin count of 13.7 g/dl and platelet count of 180 x 109/L from December of 2020. His mean corpuscular volume (MCV) was elevated at 101.3 femtolitres from his prior MCV value of 95.8 femtolitres in December of 2020. His white blood cell (WBC) count was recorded at 7.6 x 109/L.

An external file that holds a picture, illustration, etc.
Object name is JBM-13-69-g0001.jpg

Figure 1

The patient’s upper arm showed erythema with no gross bleeding near the injection site

An external file that holds a picture, illustration, etc.
Object name is JBM-13-69-g0002.jpg

Figure 2

The patient’s CT imaging of the thoracic region showed enhancement of the left axillary lymph node.

The hemoglobin, WBC, and platelet count further down trended from his baseline (Figures 3​5).5). Anemia labs including ferritin levels (554 ng/mL), vitamin B12 (253 pg/mL), total bilirubin (0.5 mg/dL), and reticulocyte count (0.8%) were nonsignificant during the patient’s hospital stay. The patient’s left shoulder presented with extensive bruising, erythema, papular rash, warmth, and tenderness on palpation during the hospitalization. An improvement in WBC and platelet levels was noted on day 4 of hospitalization.

An external file that holds a picture, illustration, etc.
Object name is JBM-13-69-g0003.jpg

Figure 3

The patient’s hemoglobin count throughout his hospital course and 6 days after discharge.

An external file that holds a picture, illustration, etc.
Object name is JBM-13-69-g0004.jpg

Figure 4

The patient’s WBC count throughout his hospital course and 6 days after discharge.

An external file that holds a picture, illustration, etc.
Object name is JBM-13-69-g0005.jpg

Figure 5

The patient’s platelet count throughout his hospital course and 6 days after discharge.

Before discharge, the patient was fully alert and oriented and reported improvement in his symptoms. Examination of his lateral left arm showed decreased erythema and bruising with slight petechiae. The patient was discharged due to stabilization of labs and encouraged to take oral vitamin B12 supplements. During his outpatient follow-up six days after hospitalization, his hemoglobin increased to 10.5 g/dl, WBC count increased to 4.9 x 109/L, and platelets increased to 101 x 109/L.

Discussion

This paper presents a patient with pancytopenia recorded seven days after receiving the Pfizer booster vaccine. Interestingly, this patient did not report any reactions after the first or second dose of the Pfizer vaccine against SARS-CoV-2. Pancytopenia refers to a decrease in all peripheral bloodlines and is present when all three cell lines are below the normal reference range.8 The patient’s physical exam showed no signs of active bleeding along with his labs indicating no evidence of hemolysis. The patient’s hemoglobin, platelet, and white blood cell count presented below baseline followed by a decrease and slight improvement during his hospital stay. Six days after hospitalization, all three cell lines showed improvement. The temporal association with the booster vaccine and negative infectious disease workup raised suspicion for vaccine-induced bone marrow suppression. In addition, the patient’s reticulocyte count and lactate dehydrogenase value were consistent with hypoproliferation within the bone marrow.

Currently, there is a gap in knowledge of adverse events specific to the third vaccine against SARS-CoV-2 due to the recent initiation of administration and ongoing reporting of events.6 To our knowledge, bone marrow suppression after any dose of vaccine against SARS-CoV-2 has not been previously reported. However, a prior case of pancytopenia after the third vaccination with a recombinant hepatitis B vaccine has previously been reported.9 The patient’s bone marrow biopsy within this case displayed a paucity of late myeloid elements and CD8+ T cells.9 It was believed the patient’s CD8+T cells were causing excessive production of IFN-γ; a stimulant of negative regulators of hematopoiesis such as tumor necrosis factor and lymphotoxin.10 IFN-γ has also previously been reported to create immunological effects comprising an upregulation of histocompatibility gene transcription and alteration in class I and II antigen expression at the cell surface.11 It was predicted these changes resulted in an autoimmune reaction causing suppression of maturation of hematopoietic progenitor cells and pancytopenia.9 Via a similar mechanism, we believe that our patient’s pancytopenia was immune-mediated, potentially triggered by the vaccination.

Vaccines against SARS-CoV-2 (first or second dose) and the induction of Idiopathic Thrombocytopenic Purpura (ITP) have also been recently acknowledged in multiple cases.12 Our patient presented with low platelet levels and associated petechiae and purpura at the site of the vaccination. However, the patient’s presentation of low hemoglobin and white blood cells along with normal reticulocyte levels was more indicative of pancytopenia secondary to bone marrow suppression. In patients presenting with pancytopenia, the history and the physical exam should help assess the severity of the pancytopenia and comorbid illnesses that may complicate the disorder.13 In addition, suspicious medications and exposure to toxic agents should be ruled out.13 Initial screening laboratory evaluation should include the patient’s complete blood count, peripheral blood smear examination, reticulocyte count, complete metabolic panel, prothrombin time/partial thromboplastin time, and blood type and screen. Common interventions to alleviate bone marrow suppression and pancytopenia include treating the underlying cause and utilizing supplements to boost red blood cell production if indicated.

Vaccines against SARS-CoV-2 undergo continuous safety monitoring; adverse events are very rare.14 However, vaccine hesitancy remains a barrier towards full population inoculation against SARS-CoV-2 and is influenced by misinformation regarding vaccine safety.15 One study using an anonymous online questionnaire found a person’s trust in the effectiveness of the vaccine was a major facilitative factor affecting willingness to vaccinate.16 The same study also found that 66.7% of unvaccinated participants thought the vaccine’s safety was not enough, making it the main reason for reluctance or hesitance to be vaccinated.16 Therefore, education of adverse events and available interventions post-vaccination is imperative to prevent the spread of misinformation and combat hesitancy towards vaccination.15

As of September 19, 2021, about 2.2 million people in the United States received a third vaccine against SARS-CoV-2.17 Among those who received the vaccine, 22,000 people reported the effects of the vaccine with no unexpected patterns of adverse reactions.17 Our patient demonstrates abnormal pancytopenia first recorded seven days after receiving the booster vaccine, possibly indicating a rare adverse event from the vaccination given the temporal relationship. While additional studies and observations are indicated to verify bone marrow suppression as an adverse reaction, this case report provides an opportunity for patient education and treatment planning before symptoms arise.

Conclusion

Our case report highlights pancytopenia secondary to bone marrow suppression following Pfizer vaccination against SARS-CoV-2. It is important to consider the possibility of bone marrow suppression following the third vaccine against SARS-CoV-2. Although additional studies are indicated to determine the risk factors and pathogenesis of vaccine-induced bone marrow suppression, prompt evaluation and initiation of interventions can improve patient outcomes.

References

1. Fernandes A, Chaudhari S, Jamil N, Gopalakrishnan G. COVID-19 vaccine. Endocr Pract. 2021;27(2):170–172. doi:10.1016/j.eprac.2021.01.013 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

2. Johansson MA, Quandelacy TM, Kada S, et al. SARS-CoV-2 transmission from people without COVID-19 symptoms. JAMA Network Open. 2021;4(1):e2035057–e2035057. doi:10.1001/jamanetworkopen.2020.35057 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

3. Graham BS. Rapid COVID-19 vaccine development. Science. 2020;368(6494):945–946. doi:10.1126/science.abb8923 [PubMed] [CrossRef] [Google Scholar]

4. Gee J, Marquez P, Su J, et al. First month of COVID-19 vaccine safety monitoring—United States, December 14, 2020–January 13. Morb Mortal Wkly Rep. 2021;70(8):283. doi:10.15585/mmwr.mm7008e3 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

5. Mahase E. Covid-19 booster vaccines: what we know and who’s doing what. BMJ. 2021. doi: 10.1136/bmj.n2082 [PubMed] [CrossRef] [Google Scholar]

6. Centers for Disease Control and Prevention. Selected adverse events reported after COVID-19 vaccination. Centers for Disease Control and Prevention. Available from: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/adverse-events.html. Accessed November 8, 2021. [Google Scholar]

7. Hause AM. Safety monitoring of an additional dose. Centers for Disease Control and Prevention; 2021. Available from: https://www.cdc.gov/mmwr/volumes/70/wr/mm7039e4.htm. Accessed February 11, 2022. [Google Scholar]

8. Valent P. Low blood counts: immune mediated, idiopathic, or myelodysplasia. Hematology. 2012;2012(1):485–491. doi:10.1182/asheducation.V2012.1.485.3798522 [PubMed] [CrossRef] [Google Scholar]

9. Viallard JF, Boiron JM, Parrens M, et al. Severe pancytopenia triggered by recombinant hepatitis B vaccine. Br J Haematol. 2000;110(1):230–233. doi:10.1046/j.1365-2141.2000.02171.x [PubMed] [CrossRef] [Google Scholar]

10. Collart MA, Belin D, Vassalli JD, De Kossodo S, Vassalli P. Gamma interferon enhances macrophage transcription of the tumor necrosis factor/cachectin, interleukin 1, and urokinase genes, which are controlled by short-lived repressors. J Exp Med. 1986;164(6):2113–2118. doi:10.1084/jem.164.6.2113 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

11. Wallach D, Fellous M, Revel M. Preferential effect of gamma interferon on the synthesis of HLA antigens and their mRNAs in human cells. Nature. 1982;299(5886):833–836. doi:10.1038/299833a0 [PubMed] [CrossRef] [Google Scholar]

12. Shah SRA, Dolkar S, Mathew J, et al. COVID-19 vaccination associated severe immune thrombocytopenia. Exp Hematol Oncol. 2021;10:42. doi:10.1186/s40164-021-00235-0 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

13. Elizabeth P, Weinzierl MD, Daniel A, Arber MD. The differential diagnosis and bone marrow evaluation of new-onset pancytopenia. Am J Clin Pathol. 2013;139(1):9–29. doi:10.1309/AJCP50AEEYGREWUZ [PubMed] [CrossRef] [Google Scholar]

14. Centers for Disease Control and Prevention. COVID-19 vaccination; 2020. Available from: https://www.cdc.gov/coronavirus/2019-ncov/vaccines/safety/safety-of-vaccines.html. Accessed February 11, 2022.

15. Dror AA, Eisenbach N, Taiber S, et al. Vaccine hesitancy: the next challenge in the fight against COVID-19. Eur J Epidemiol. 2020;35:775–779. doi:10.1007/s10654-020-00671-y [PMC free article] [PubMed] [CrossRef] [Google Scholar]

16. Gan L, Chen Y, Hu P, et al. Willingness to receive SARS-CoV-2 vaccination and associated factors among Chinese adults: a cross sectional survey. Int J Environ Res Public Health. 2021;18(4):1993. doi:10.3390/ijerph18041993 [PMC free article] [PubMed] [CrossRef] [Google Scholar]

17. STAT. Early data suggest side effects after Covid booster similar to second dose; 2021. Available from: https://www.statnews.com/2021/09/28/side-effect-rates-from-a-third-covid-19-vaccine-dose-similar-to-those-after-second-shot-early-data-indicate/.

Spike protein in mRNA COVID vaccines: One of the most bioactive substances known to mankind

Source: https://www.planet-today.com/2022/03/spike-protein-in-mrna-covid-vaccines.html

The spike protein present in Wuhan coronavirus (COVID-19) vaccines is one of the most bioactive and potentially damaging substances known to mankind. It penetrates the blood-brain barrier, cell nucleus and even affects DNA replication. The spike protein appears to reprogram the immune system in a strange way. The BNT162b2 mRNA vaccine against the COVID-19 virus has been shown to reprogram both adaptive and innate immune responses. When it penetrates the cell nuclei, the free-floating spike protein inhibits DNA repair. There had been immune system problems in the vaccinated, and it is becoming apparent that they do not actually develop broad natural immunity. Instead, they produce more S antibodies against the spike protein that they were originally vaccinated with. A recent surveillance report from the U.K. Health Security Agency showed that N antibody levels appear to be lower in individuals who acquire infection following two doses of the vaccine. This means that the vaccines interfere with the immune system’s ability to produce antibodies against the virus following infection. In the case of the N antibody, this is shown to be against the nucleocapsid protein, which serves as the shell of the virus and is an important part of the immune system response of the unvaccinated population. (Related: After you are vaccine damaged, if you complain about symptoms you will be REQUIRED to take psychiatric medications until your “disorder” is cured.) If any mutations to the spike protein of the COVID virus occur in the future, the vaccinated will be more vulnerable and may possibly be unprotected due to their inability to produce the N antibody. Meanwhile, the unvaccinated would have much better immunity to any mutations due to their ability to produce both S and N antibodies after infection. America’s Front Line Doctors also warned that vaccines are turning people’s bodies into walking spike protein factories, which causes the body to create antibodies to them. “First, these vaccines ‘mis-train’ the immune system to recognize only a small part of the virus [the spike protein]. Variants that differ, even slightly, in this protein are able to escape the narrow spectrum of antibodies created by the vaccines,” AFLDS explained. “Second, the vaccines create ‘vaccine addicts,’ meaning persons become dependent upon regular booster shots because they have been ‘vaccinated’ only against a tiny portion of a mutating virus.” The group also cited Australian Health Minister Dr. Kerry Chant, who said that COVID will become endemic and people will have to get used to taking endless vaccines. Finally, there is the simple fact that the vaccines do not, in any way, prevent infection in the nose and upper airways, which is where fully vaccinated people tend to show the highest viral loads. Immune problems and other vaccine infections Vaccinated individuals have also encountered immune problems and reinfections. These conditions, dubbed VAIDS (or Vaccine Acquired Immune Deficiency Syndrome), have been very concerning as they could be damaging to individuals. While not an official scientific term, it is important to bring attention to VAIDS, especially for those who are concerned about the immune health of their vaccinated loved ones. In late January, an anti-mandate rally in Italy reiterated the claim that COVID-19 vaccines were toxic and that they could cause a variety of medical catastrophes down the line. Professor Luc Montagnier, a Nobel Prize winner for medicine for his discovery of the human immunodeficiency virus (HIV) said himself that those who received the third dose of COVID vaccines should go to the laboratory and take AIDS tests, then sue their governments. If Montagnier and other dissident experts are correct about “the great die-off,” then around one to two billion deaths are to be expected in the near future. If the estimation seems alarming, then people should be more aware of the rising number of adverse effects, including cancers and cardiac problems, that developed worldwide. Even Pfizer itself has a long list of possible adverse events from its vaccines, with nine pages of illnesses barely scratching the surface.

SARS-CoV-2 mRNA Vaccination-Associated Myocarditis in Children Ages 12-17: A Stratified National Database Analysis

Authors: RALPH TURCHIANO    • 

Abstract

Establishing the rate of post-vaccination cardiac myocarditis in the 12-15 and 16-17-year-old population in the context of their COVID-19 hospitalization risk is critical for developing a vaccination recommendation framework that balances harms with benefits for this patient demographic. Design, Setting and Participants: Using the Vaccine Adverse Event Reporting System (VAERS), this retrospective epidemiological assessment reviewed reports filed between January 1, 2021, and June 18, 2021, among adolescents ages 12-17 who received mRNA vaccination against COVID-19. Symptom search criteria included the words myocarditis, pericarditis, and myopericarditis to identify children with evidence of cardiac injury. The word troponin was a required element in the laboratory findings. Inclusion criteria were aligned with the CDC working case definition for probable myocarditis. Stratified cardiac adverse event (CAE) rates were reported for age, sex and vaccination dose number. A harm-benefit analysis was conducted using existing literature on COVID-19-related hospitalization risks in this demographic. Main outcome measures: 1) Stratified rates of mRNA vaccine-related myocarditis in adolescents age 12-15 and 16-17; and 2) harm-benefit analysis of vaccine-related CAEs in relation to COVID-19 hospitalization risk. Results: A total of 257 CAEs were identified. Rates per million following dose 2 among males were 162.2 (ages 12-15) and 94.0 (ages 16-17); among females, rates were 13.0 and 13.4 per million, respectively. For boys 12-15 without medical comorbidities receiving their second mRNA vaccination dose, the rate of CAE is 3.7-6.1 times higher than their 120-day COVID-19 hospitalization risk as of August 21, 2021 (7-day hospitalizations 1.5/100k population) and 2.6-4.3-fold higher at times of high weekly hospitalization risk (2.1/100k), such as during January 2021. For boys 16-17 without medical comorbidities, the rate of CAE is currently 2.1-3.5 times higher than their 120-day COVID-19 hospitalization risk, and 1.5-2.5 times higher at times of high weekly COVID-19 hospitalization. Conclusions: Post-vaccination CAE rate was highest in young boys aged 12-15 following dose two. For boys 12-17 without medical comorbidities, the likelihood of post vaccination dose two CAE is 162.2 and 94.0/million respectively. This incidence exceeds their expected 120-day COVID-19 hospitalization rate at both moderate (August 21, 2021 rates) and high COVID-19 hospitalization incidence. Further research into the severity and long-term sequelae of post-vaccination CAE is warranted. Quantification of the benefits of the second vaccination dose and vaccination in addition to natural immunity in this demographic may be indicated to minimize harm.

Millennials Experienced the “Worst-Ever Excess Mortality in History” – An 84% Increase In Deaths After Vaccine Mandates

The most recent data from the CDC shows that U.S. millennials, aged 25-44, experienced a record-setting 84% increase in excess mortality during the final four months of 2021, according to the analysis of financial expert and Blackrock whistleblower, Edward Dowd,

Dowd, with the assistance of an insurance industry expert, compiled data from the CDC showing that, in just the second half of 2021, the total number of excess deaths for millennials was higher than the number of Americans who died in the entirety of the Vietnam War. Between August and December, there were over 61,000 deaths in this age group, compared to 58,000 over the course of 10 years in Vietnam.

In all, excess death among those who are traditionally the healthiest Americans is up by 84%.

SARS-CoV-2 vaccine-associated-tinnitus: A review

Authors: Syed HassanAhmedaSummaiyyaWaseemaTaha GulShaikhaNashwa AbdulQadiraSarush AhmedSiddiquiaIrfanUllahbAbdulWarisbZohaibYousafc

Annals of Medicine and Surgery Volume 75, March 2022, 103293

Abstract

The global vaccination drive against severe acute respiratory syndrome coronavirus-2 is being pursued at a historic pace. Unexpected adverse effects have been reported following vaccination, including thrombotic thrombocytopeniamyocarditis, amongst others. More recently, some cases of tinnitus are reported post-vaccination. According to the Vaccine Adverse Events Reporting System (VAERS), 12,247 cases of coronavirus post-vaccination tinnitus have been reported till September 14, 2021. To the best of our knowledge, this is the first review evaluating any otologic manifestation following vaccine administration and aims to evaluate the potential pathophysiologyclinical approach, and treatment. Although the incidence is infrequent, there is a need to understand the precise mechanisms and treatment for vaccine-associated-tinnitus.

1. Introduction

The SARS-CoV-2 virus has infected approximately 225 million people globally, resulting in 4.6 million deaths [1]. It commonly manifests as fever, dry cough, shortness of breath, fatigue, and myalgias. However, it can also lead to severe complications like pneumonia, leukopenia, kidney failure, myocardial involvement, and central nervous system (CNS) disorders [2].

Vaccinations are arguably the most effective preventive tool against SARS-CoV-2. In August 2020, Russia became the first country to register Sputnik V, a coronavirus vaccine based on human adenovirus vectors rAd26 and rAd5 developed by the Gamaleya national center of epidemiology and microbiology. However, this vaccine was approved without phase III trials, raising concerns over its safety [3].

The currently available vaccines underwent clinical trials and were approved after demonstrating an acceptable safety profile and efficacy [4]. To date, 5.5 billion vaccine doses have been administered [1]. The adverse effects of vaccines are mostly mild and transient, commonly including pain at the injection site, pyrexia, headache, myalgias, fatigue, chills [5] and dermatologic manifestations like Pityriasis Rosea [6]. However, severe complications like anaphylaxis [7], vaccine-induced immune thrombotic thrombocytopenia [8], myocarditis [9] have also been reported. The adverse effects of vaccine are markedly outweighed by their beneficial effects, in decreasing hospital admissions and deaths due to the SARS-CoV-2 [10,11].

Investigations of the otologic manifestations of the SARS-CoV-2 suggest the incidence of tinnitus, hearing loss, sensorineural hearing loss (SNHL), otalgia, amongst others. However, only association with tinnitus and hearing loss were statistically significant [12]. More recently, cases of tinnitus presented following both vector-based and mRNA SARS-CoV-2 vaccines [13,14]. According to the Vaccine Adverse Event Reporting System (VAERS), 12,247 cases of tinnitus post-coronavirus vaccination have been reported [15].

Tinnitus is an otologic symptom characterized by a conscious perception of sound without an external auditory stimulus. The prevalence varies from one population subset to another [16]. The study by Jong Kim et al., which employed data from the Korean National Health and Nutrition Examination survey, reported tinnitus prevalence to be 20.7% among adults, i.e., 20- to 98-year-old [17]. The National Health and Nutritional Examination survey data indicated a prevalence of 16.5% among the overall population and 6.6% among Asian Americans [18]. Along with varying prevalence, it has also been associated with a wide range of risk factors including male gender, hearing impairment, ear infections, stress, unemployment, military services, dyslipidemiaosteoarthritisrheumatoid arthritis, asthma, depression, thyroid disease, noise exposure, history of head injury and numerous others [17,19].

Herein, we review the association between SARS-CoV-2 vaccines and tinnitus. This review aims to evaluate the potential pathophysiologyclinical approach to diagnosis and management of post-vaccination tinnitus.

2. Literature search, data extraction, and results

Two independent authors (SHA, TGS) conducted a thorough literature search over PubMed, Cochrane Library, and Google Scholar from inception till September 12, 2021, without any language restriction. To achieve comprehensive results, search string comprised of keywords, “SARS-CoV-2 Vaccine”, “Coronavirus Vaccine,” “Corona Vaccine,” “COVID-19 Vaccine”, “Tinnitus,” “Ear Ringing,” “Otologic Manifestations,” and separated by BOOLEAN operators “OR” and “AND.” All relevant case reports, case series, cohort studies, editorials, and correspondences were reviewed. Grey literature and bibliographies of the relevant articles were also screened. Results of the literature search are summarized in Fig. 1. The work has been reported in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 criteria [20].

Fig. 1

Ultimately, two studies [13,14] (case report and case series) were retrieved for inclusion in the review. The studies comprised data from four patients (three males and one female) with a mean age of 41.8 ± 12.6 years. The following figure (Fig. 2) demonstrates the geographical locations where these cases were reported. Out of the four reported cases, three presented in Italy, while one was reported from Taiwan. Along with these findings, future research may enable us to predict the gender, age groups, and geographical locations that may leave certain individuals more susceptible to COVID-19 vaccine-associated tinnitus than others.

Fig. 2

Following studies selection, two independent authors (SW, NAQ) retrieved all the relevant data comprising of author’s name, patient’s age, and sex, past medical history, vaccine administered, time from dose administration till the onset of symptoms, presenting complaint, laboratory findings, treatment interventions, and outcome into a table. All significant findings are summarized in Table 1. Any discrepancies were resolved by discussion with a third reviewer (SS).

Table 1. A tabulation of the outcomes of literature review.

AuthorAge
Sex
Past Medical HistoryVaccine AdministeredTime from Vaccination to Onset of symptomsPresenting ComplaintInvestigationsTreatmentOutcome
Tao-Tseng et al. [14]37 y/o MaleGlaucoma is treated with latanoprost and brimonidine eye dropsChAdOx1 nCoV-19 AstraZeneca (1st dose)5 hIntermittent, high pitch, right ear tinnitus, high fever with chills and myalgias. It progressed to continuous high pitch and intermittent low pitch tinnitus.THI = 28 (5 h post vaccination)
THI = 46 (after visiting emergency)
Audiometry test on 1st May revealed normal PTA and short SiSi
THI (post-treatment) = 0
Single-dose of 10 mg IV dexamethasone and 3 × 5 mg oral prednisone daily for 3 days.Recovered on day 4
Parrino et al. [13]37 y/o FemaleGlaucoma, undifferentiated connective tissue disease, and transient tinnitus due to acute otitis media 20 years previouslyBNT162b2 mRNA-vaccine Pfizer (1st dose)7 hRight ear tinnitus, short-term dizziness, pain at the injection site.Otoscopy investigation was normal.
PTA revealed normal bilateral hearing with slight asymmetry on the right ear
THI = 90/100
Psychoacoustic Measures of Tinnitus = 20 dB pure tone at 10,000 Hz
THI (post-treatment) = 78/100
30 mg Deflazacort daily given orally for first 5 days followed by 15mg/daily dose for next 5 days.Recovering
Parrino et al. [13]63 y/o MaleBilateral symmetrical mild high frequencies SNHL, chronic gastritis, extrinsic asthma, and reactive depression for which he had undergone psychotherapyBNT162b2 mRNA-vaccine Pfizer (1st dose)20 hLeft tinnitus associated with hyperacusis and dysacusis and local pain at the injection siteOtoscopy examination was normal.
PTA revealed slight threshold worsening on the left ear
Psychoacoustic Measures of Tinnitus = white noise of 25 dB intensity
THI = 76/100
THI (after 7 days) = 36/100
Corticosteroid therapy was proposed, but the patient refused.Recovering
Parrino et al. [13]30 y/o MaleHashimoto thyroiditisBNT162b2 mRNA-vaccine Pfizer (2nd dose)6 daysLeft tinnitus, hyperacusis, dysacusis. Reported fever, nausea, and local pain after dose administration that was treated with 1 × 1000 mg acetaminophenOtoscopy was normal
PTA showed normal bilateral hearing.
THI = 78/100
THI (post-treatment) = 6/100
10 days course of oral prednisone at 50 mg/day for first 4 days followed by 25 mg/day for the next 3 days and 12.5 mg/day for the last 3 days.Recovered

THI: Tinnitus Handicap Inventory, PTA: Pure Tone Average, SiSi: Short increment Sensitivity index, SNLH: sensorineural hearing loss.

3. COVID-19 vaccines and their characteristics

Most of the current COVID-19 vaccines use the genetic code of spike protein to stimulate a protective immune reaction against coronavirus. The viral vector vaccines (AstraZeneca, sputnik, Janssen) incorporate spike protein gene into adenovirus DNA, which induces spike protein formation and hence antibodies, conferring protection against the virus. Conversely, mRNA vaccines (Pfizer, Moderna) deliver messenger RNA for spike protein into the host cells, stimulating a protective response [21]. Another category of COVID-19 vaccines (Sinopharm, Sinovac) employs a weakened or attenuated virus, capable of replication but not potent enough to cause the disease itself [22].

Moreover, research done after SARS-CoV-1 indicated the protective and long-lasting effect of T-cell immunity. The transfer of T-cells led to a swift viral clearance and disease elimination [23,24] Unlike antibody response, T cell memory can last longer as seen in SARS-CoV-1 when the immunity was even detected 4 years after the infection. Especially, Regulatory T cells play a vital role in resolving the infection, confirmed from the fact that they were found to be risen in COVID-19 patients [25]. Along with them, circulating follicular T helper cells have been seen in individuals with COVID-19. They play a major role in representing antibody response to infection. Hence, despite no vaccine currently offering the T-cell response to COVID-19, there is a room to further investigations.

Listed in Table 2 are some of the most common vaccines currently used to counter the pandemic and their characteristics including mechanism of action, dosage, time between dosages, efficacy, general and serious adverse effects. What is of immense concern is the fact that despite a vast previous knowledge on T-cell immunity, none of the marketed vaccine is using it as a mechanism of their action. Hence, leaving room for further investigations.

Table 2. Table 2: Characteristics of COVID-19 vaccines.

VaccineManufacturer & CountryMechanism of ActionDoses – Time Between DosesEfficacyAdverse EffectsSerious Adverse Effects
BNT162b2BioNTech, Fosun Pharma, Pfizer – America and GermanyRNA vaccine [26,27]Two doses – 3 weeks [26]100% against severe disease as per CDC, 93% against severe disease as per FDA [26]Redness, Swelling, Headache, Muscle pain, Chills, Fever, Nausea, Tiredness [28]Lymphadenopathy, paroxysmal ventricular arrhythmia, syncope, and right leg paresthesia [29], heart inflammation in young adults [26]
mRNA-1273Moderna- U.S. and SwitzerlandRNA vaccine [26]Two doses – 4 weeks [26]>90% [26]Pain, swelling, redness, fever, fatigue, headache, vomiting, arthralgia, myalgia, urticaria [28]Bell’s Palsy, facial swelling [27]
ChAdOx1 nCoV-19/AZD1222AstraZeneca (University of Oxford) – U.K.Viral vector vaccine [27]Two doses −4 to 12 weeks [26]76% (phase III trials) [26]Redness, myalgias, arthralgias, and headache [27]Pulmonary embolism, Thromboembolism [27]
Ad26.COV2.SJohnson & Johnson -U.S.Viral vector vaccine [26]A single dose [26]72% [26]Pain, redness, and swelling at the injection site [27]Rare and Severe blood clots [27]
Ad5-nCoVCansino – ChinaViral vector vaccine [30]A single dose [30]65.7% [30]Fever, redness, and pain [30]Not reported [30]
CoronavacSinovac – ChinaInactivated Virus [31]Two doses – 2 to 4 weeks [32]51% [32]Pain on injection [31]Acute hypersensitivity with the manifestation of urticaria [31]
BBIBP-CorVSinopharm – ChinaInactivated Virus [33]Two doses – 2 to 3 weeks apart, followed by a booster dose in Age group >18 years [33].79% [33]Pain at the vaccination site, fatigue, lethargy, headache, and tenderness [34]
Gam-COVID-Vac/Sputnik VGamaleya Research Institute of Epidemiology and Microbiology – RussiaViral Vector Vaccine [35]2 doses, 3 weeks apart [35]91.6% [35]Mild pain at the injection site, fever, headache, fatigue, and muscle aches [36]

WHO: World Health Organization; CDC: Center for Disease Control and Prevention; FDA: U.S. Food and Drug Administration.

Moreover, all the listed vaccines include the ones currently, accepted in many countries throughout the world. With frequent introduction of numerous vaccines in the market to combat the pandemic, there is a definite need to evaluate their characteristics in comparison and the better ones shall be publicly made available.

4. Pathophysiology

Tinnitus is defined as intermittent or continuous, unilateral or bilateral, pulsatile or non-pulsatile, acute or chronic, and subjective or objective [37,38]. There are several classifications categorizing tinnitus into numerous types, with each type associated with multiple potential etiologies. It can result from a lesion in the auditory pathway. Potential etiologies may include otitis externacerumen impactionotosclerosis, otitis media, cholesteatomavestibular schwannomaMeniere’s diseasecolitisneuritis, and ototoxic drugs [37,38]. The character of tinnitus can vary based on etiology. Furthermore, certain non-otologic conditions like vascular anomalies, myoclonus, and nasopharyngeal carcinoma can also contribute. Despite several cases of tinnitus being reported post-SARS-CoV-2 vaccination, the precise pathophysiology is still not clear.

4.1. Molecular mimicry

Based on the mechanisms behind other COVID-19 vaccine-induced disorders (38, 39) and the phenomenon of molecular mimicry [41], a cross-reactivity between anti-spike SARS-CoV-2 antibodies and otologic antigens is a possibility. The heptapeptide resemblance between coronavirus spike glycoprotein and numerous human proteins further supports molecular mimicry as a potential mechanism behind such vaccine-induced disorders [41]. Several autoimmune conditions, including vaccine-induced thrombotic thrombocytopenia (VITT) [8] and Guillain-Barré syndrome (GBS) [40], have been reported following coronavirus vaccination. Anti-spike antibodies may potentially react with antigens anywhere along the auditory pathway and initiate an inflammatory reaction involving the tympanic membrane, ossicular chain, cochlea, cochlear vessels, organ of Corti, etc. Therefore, understanding the phenomenon of cross-reactivity and molecular mimicry may be helpful in postulating potential treatment behind not only tinnitus but also the rare events of vaccination associated hearing loss and other otologic manifestations [42]. Moreover, serologic investigations may play a role in understanding the underlying mechanism. Specific findings, such as raised anti-platelet factor 4, have been reported in cases of VITT post-COVID-19 vaccination [39].

4.2. Autoimmune reactions

Antibodies can form complexes with one or more antigens leading to a type III hypersensitivity reaction. Deposition of circulating immune complexes and vestibule-cochlear antibodies can play a role in autoimmune inner ear disease [43,44]. Incidence of pre-existing autoimmune conditions like Hashimoto thyroiditis and gastritis in patients, as shown in Table 1, further leaves patients prone to immune dysfunction and thus abnormal immune responses [13]. However, future research should investigate the incidence of post-vaccination tinnitus in individuals with autoimmune diseases with a suitable control as all the currently reported patients were known cases of such conditions. Moreover, several potential genes, including Glial cell Derived Neurotrophic Factor (GDNF), Brain Derived Neurotrophic Factor (BDNF), potassium recycling pathway genes, 5-Hydroxytryptamine Receptor 7 (HTR7), Potassium Voltage Gated Channel Subfamily E Regulatory Subunit 3 (KCNE3), and a few others, have been studied to understand the underlying mechanism. However, the evidence is still insufficient to draw any conclusion [45]. Therefore, genetic predisposition and immunologic pathways may play a role in post-vaccination-tinnitus.

4.3. Past medical history

Literature suggests a relationship between glaucoma and tinnitus, with glaucoma patients having 19% increased odds for tinnitus than in patients without it [46]. The mechanism linking these disorders is ambiguous, but vascular dysregulation may play a significant role in causing both disorders. Nitric oxide (NO) production inhibition is a potential mechanism [46]. NO is a regulator of intraocular pressure (IOP), thus linking defects in the nitric oxide guanylate cyclase (NO-GC) pathway with glaucoma [47]. Furthermore, diminished jugular vein NO levels have been reported in tinnitus patients, leading to the reduced blood supply to the ears [46]. As shown in Table 1, two of the reported cases had pre-existing glaucoma. Therefore, any potential association between vaccines and NO dysregulation should be investigated. Certain COVID-19 vaccines have been associated with vaccine-induced thrombotic thrombocytopenia [8]. Developing thrombus can reduce the blood supply to the ear and increase the probability of developing tinnitus. The existing literature lacks articles investigating associations between vaccines and NO levels. Therefore, the association of vaccines with NO deficiency in genetically susceptible patients should be investigated. Lastly, the association between vaccines and other vascular dysregulations must also be evaluated, as such abnormalities can disrupt laminar blood flow and cause pulsatile tinnitus [48].

4.4. Ototoxicity

Numerous drugs and chemical substances have been reported as ototoxic, causing damage to the auditory pathway and cochlear hair cells. Exposure to such agents, including aminoglycosidesvancomycin, platinum-based anticancer drugsloop diureticsquinine, toluene, styrene, lead, trichloroethylene, and others, may lead to tinnitus, hearing loss, and other otologic manifestations [37,49]. The mechanisms behind ototoxicity are not fully understood but may involve chemical and electrophysiological alterations in the inner ear structures and the eighth cranial nerve. Certain agents, including loop diuretics, incite such symptoms by inhibiting endolymph production from stria vascularis, whereas drugs like aminoglycosides and cisplatin are directly toxic to the hair cells the organ of Corti. Meanwhile, Non-Steroidal Anti-Inflammatory Drugs (NSAID) induce ototoxicity by reducing cochlear blood flow and alterations in the sensory cell functions [50]. Hence, the possibility of one or more vaccine components exerting ototoxic effects cannot be written off and requires attention.

Furthermore, the current literature also proposes certain risk factors associated with drug-induced ototoxicity. For example, age, hypoalbuminemia, and uremia significantly increase the risk of developing NSAIDs induced ototoxicity. Similarly, erythromycin-related ototoxicity is more commonly associated with hepatic and renal failure, increasing age and female gender [50]. Therefore, genetic predispositions and associated conditions may also play a significant role in determining the development of vaccine-induced tinnitus. As shown in Table 1, most of the cases reported till now were transient, which may be accountable to past administration of offending agents as seen in cases of erythromycin, aminoglycosides, vancomycin, and NSAIDs associated ototoxicity, which resolved upon early discontinuation of the inciting agent [50].

4.5. Psychological conditions

Anxiety-related adverse events (AEFI) following vaccination, defined by WHO, “a range of symptoms and signs that may arise around immunization that are related to anxiety and not to the vaccine product, a defect in the quality of the vaccine or an error of the immunization program” [51], have been witnessed in around 25% COVID-19 vaccination cases in India, as reported by Government of India, Ministry of health and family welfare, immunization division [52]. These responses may include vasovagal mediated reactions, hyperventilation mediated reactions, and stress-related psychiatric reactions or disorders [53]. Loharikar et al. [54], in their systematic review, reported common symptoms of it to be dizziness, headache, and fainting with rapid onset after vaccination. There are several speculations on the causative agents behind AEFIs after immunization. Since most of the vaccines are delivered through needles, it may be possible that trypanophobia, affecting at least 10% of the population around the globe [55], may trigger stress, hence leading to a stress-mediated response. Moreover, hearing or witnessing someone else’s sickness can lead to reporting similar symptoms, known as psychogenic illness, as reported by Blaine Ditto et al. [56]. Hence, a possible connection can exist between people’s presumption and social media misinformation, leading to anxiety and possible adverse reaction.

Vaccine hesitancy, defined as a “delay in acceptance or refusal of vaccination despite the availability of vaccination services” [57], is a complex behavior, and the most common cause of it usually includes perceived risks vs. benefits, religious beliefs, and lack of knowledge [58]. People with vaccine hesitancy may have pre-assumed beliefs. Hence, after getting vaccinated, there is a chance of facing AEFIs, with symptoms constellating stress. Numerous studies have demonstrated anxiety and stress as risk factors for tinnitus [17,19]. In one of the reported cases [13], the patient had a history of reactive depression. Therefore, the incidence of anxiety and stress disorders also need to be explored, with a particular emphasis on vaccine-related anxiety, as a potential cause of tinnitus developing post-vaccination.

4.6. Overview

While several suggested hypotheses exist, the precise mechanism behind vaccine-induced tinnitus remains undetermined, leaving room for future studies. Furthermore, as shown in Table 1, two reported cases had a medical history of otologic conditions involving recovered tinnitus and SNHL. Therefore, the possibility of vaccines aggravating underlying otologic disorders and exacerbating any morphologic damage also needs to be explored. Lastly, the character of tinnitus, including subjective or objective, intermittent or continuous, and pulsatile or non-pulsatile, can also give beneficial insight into understanding the involved sights and underlying mechanisms.

5. Clinical approach and management

To start the treatment regimen, it is crucial to determine a well-established diagnosis for Tinnitus. For this purpose, a well-focused and detailed history and examination are necessary [38]. In case of vaccine-induced tinnitus, vaccine administered, days since dose administered to the onset of symptoms, and any other adverse effects experienced must be further added. Additionally, a particular emphasis must be placed on pre-existing health conditions, specifically autoimmune diseases like Hashimoto thyroiditis, otologic conditions like SNHL, glaucoma, and psychological well-being. All the reported patients presented with a history of one or more of the aforementioned disorders, as shown in Table 1. However, any such association has not yet been established and requires further investigation to be concluded as potential risk factors for vaccine-induced tinnitus. Routine cranial nerve examinationotoscopyWeber’s test, and Rinne test, that are used for tinnitus diagnosis in general [38], may also be used for confirmation of the disorder post-vaccination. Due to the significant association between tinnitus and hearing impairment [59], audiology should be performed as well.

Tinnitus handicap inventory (THI), a reliable and valid questionnaire to evaluate tinnitus-related disability [60], is recommended by the tinnitus research initiative (TRI) [61]. To date, it has been translated into numerous languages and is being used across the globe. In THI, the scores of 0, 2, and 4 are assigned to no, sometimes, and yes, respectively, to answer a subset of questions. The scores can vary from 0 to 100, with higher scores indicating a more significant disability. Based on scores, the patients can be classified into five categories: Scores ranging between (1) 0 to 16 indicate no handicap, (2) 18 to 36 indicate mild handicap, (3) 38 to 56 indicate moderate, (4) 58 to 76 indicate severe handicap and (5) 78 to 100 indicate catastrophic handicap [62]. This scale can be employed to evaluate both the severity of the condition and therapeutic response, as reported in the included studies [13,14].

While the treatment options for non-vaccine-induced tinnitus show a significant degree of variance, corticosteroids were the lead treatment choice for SARS-CoV-2 vaccine-induced tinnitus, as reported in both the included studies [13,14]. Based on the results, Tseng et al. [14] recommend immediate use of steroids for sudden onset tinnitus post-coronavirus vaccination. The reason may lie in their underlying immunosuppressive mechanism. After entering the cell, Corticosteroid forms a steroid-receptor complex in the cytoplasm, which then modifies transcription by incorporating itself into DNA. Hence playing their role in synthesizing or inhibiting certain proteins. A well-known protein synthesized by them is lipocortin, which inhibits Phospholipase A2, ultimately inhibiting arachidonic acid (AA) which leads to hampered Leukotrienes and Prostaglandins production. It also impedes mRNA that plays role in interleukin-1 formation [63] as well as sequestrate CD4+ T-lymphocytes in the reticuloendothelial system, all building up and leading to immunosuppression [64].

Although two out of four patients showed improvement following drug administration, the efficacy of steroid therapy is yet to be investigated in larger populations.

There is also a dire need to perform trials for other pharmacological interventions that can be administered in post-vaccine tinnitus. Numerous non-pharmacological (counseling, tinnitus retraining therapy, sound therapy, auditory perceptual training) as well pharmacological interventions (sodium channel blockers, anti-depressants, anti-convulsant, benzodiazepines, and several others) for treatment of tinnitus have been evaluated [16,65], however, there is insufficient data for tinnitus following vaccination, despite that vaccine-induced tinnitus have also been reported after hepatitis B, rabies, measles and (influenza A virus subtype) H1N1 vaccines, associated to Sensorineural hearing loss (SNHL) [66].

Thereby, deeming high-quality trials evaluating the efficacy of conventional treatment necessary. Lastly, the transient nature also requires special attention, as one of the patients recovered without any medication [13].

6. Adverse effects monitoring

Although the COVID-19 vaccines were approved after rigorous testing and trials, the center for disease control and prevention (CDC) has taken numerous initiatives to ensure a highly intensive safety monitoring program to determine potential adverse effects that may not be reported during clinal trials. Several vaccine safety monitoring systems are being employed, including the VAERS, v-safe, clinical immunization safety assessment (CISA) program, vaccine safety datalink (VSD), and a few others. This wide range of systems allows patients, attendants, and healthcare workers to report any side effects they have been experiencing following SARS-CoV-2 vaccination. CDC and vaccine safety experts evaluate all the reports regularly and assess vaccines safety on their basis [67]. Investigations into reported side effects are conducted to ensure vaccines safety, as was observed following cases of thrombotic thrombocytopenia, which led to a temporary ban on two vaccines and were only lifted once the vaccines demonstrated an acceptable safety profile. With already established benefits and such critical safety monitoring, the COVID-19 global vaccination program must be supported and appreciated for prioritizing public safety. However, such reporting systems may be more useful if there was a way to determine if the reported adverse events were vaccine-induced, exacerbated following vaccination, or due to some underlying pathology.

7. Conclusion

This review scrutinizes the currently available literature and highlights potential pathophysiology and clinical approaches to diagnose and manage vaccine-induced tinnitus. Although the incidence of COVID-19 vaccine-associated tinnitus is rare, there is an overwhelming need to discern the precise pathophysiology and clinical management as a better understanding of adverse events may help in encountering vaccine hesitancy and hence fostering the COVID-19 global vaccination program. Despite the incidence of adverse events, the benefits of the SARS-CoV-2 vaccine in reducing hospitalization and deaths continue to outweigh the rare ramifications.

8. Limitations

This study carries some limitations. Firstly, given the limited number of cases reported, there is an imperative need to overcome the paucity of data and evaluate the impact of different COVID-19 vaccines, type of tinnitus, response to conventional treatment options, and reversible nature of the condition. Secondly, all the patients evaluated reported substantial past medical history and carried a high risk of immune dysregulation; therefore, the role of genetic predisposition and underlying conditions requires special surveillance, which can help redefine vaccine administration criteria to avoid any further cases.

Department of Internal Medicine, Hamad Medical Corporation, Doha, Qatarzohaib.yousaf@gmail.com

References

[1]WHO coronavirus (COVID-19) dashboard | WHO coronavirus (COVID-19) dashboard with vaccination datahttps://covid19.who.int/, Accessed 19th Sep 2021Google Scholar[

2]H. Esakandari, M. Nabi-Afjadi, J. Fakkari-Afjadi, N. Farahmandian, S.M. Miresmaeili, E. BahreiniA comprehensive review of COVID-19 characteristicsBiol. Proced. Online, 22 (1) (2020), 10.1186/S12575-020-00128-2 View PDFGoogle Scholar[

3]B.M. PrüβCurrent state of the first COVID-19 vaccinesVaccines, 9 (1) (2021), pp. 1-12, 10.3390/VACCINES9010030 View PDFView Record in ScopusGoogle Scholar[

4]Z.P. Yan, M. Yang, C.L. LaiCOVID-19 vaccines: a review of the safety and efficacy of current clinical trialsPharmaceuticals, 14 (5) (2021), 10.3390/PH14050406 View PDFGoogle Scholar[

5]A.F. Hernández, D. Calina, K. Poulas, A.O. Docea, A.M. TsatsakisSafety of COVID-19 vaccines administered in the EU: should we be concerned?Toxicol. Rep., 8 (2021), pp. 871-879, 10.1016/J.TOXREP.2021.04.003ArticleDownload PDFView Record in ScopusGoogle Scholar[

6]S.A. Temiz, A. Abdelmaksoud, R. Dursun, K. Durmaz, R. Sadoughifar, A. HasanPityriasis rosea following SARS-CoV-2 vaccination: a case seriesJ. Cosmet. Dermatol., 20 (10) (2021), pp. 3080-3084, 10.1111/JOCD.14372 View PDFView Record in ScopusGoogle Scholar[

7. Greenhawt, E.M. Abrams, M. Shaker, et al.The risk of allergic reaction to SARS-CoV-2 vaccines and recommended evaluation and management: a systematic review, meta-analysis, GRADE Assessment, and international consensus approachJ. Allergy Clin. Immunol. Pract. (2021), 10.1016/J.JAIP.2021.06.006Published online View PDFGoogle Scholar[

8 S.H. Ahmed, T.G. Shaikh, S. Waseem, N.A. Qadir, Z. Yousaf, I. UllahVaccine-induced thrombotic thrombocytopenia following coronavirus vaccine: a narrative reviewAnn. Med. Surg. (2021), p. 102988, 10.1016/J.AMSU.2021.102988Published online October 30 View PDFGoogle Scholar[

9]B. Singh, P. Kaur, L. Cedeno, et al.COVID-19 mRNA vaccine and myocarditisEur. J. Case Rep. Intern. Med. (2021), 10.12890/2021_002681Published online June 14 View PDFGoogle Scholar[10]S.M. Moghadas, T.N. Vilches, K. Zhang, et al.The impact of vaccination on COVID-19 outbreaks in the United StatesmedRxiv (2020), 

10.1101/2020.11.27.20240051Published online November 30 View PDFGoogle Scholar[

11]H.L. Moline, M. Whitaker, L. Deng, et al.Effectiveness of COVID-19 vaccines in preventing hospitalization among adults aged ≥65 Years — COVID-NET, 13 states, February–April 2021MMWR (Morb. Mortal. Wkly. Rep.), 70 (32) (2021), p. 1088, 10.15585/MMWR.MM7032E3 View PDFView Record in ScopusGoogle Scholar[

12]Z. Jafari, B.E. Kolb, M.H. MohajeraniHearing loss, tinnitus, and dizziness in COVID-19: a systematic review and meta-analysisCan. J. Neurol. Sci. (2021), p. 1, 10.1017/CJN.2021.63Le Journal Canadien Des Sciences Neurologiques. Published online View PDFGoogle Scholar[

13]D. Parrino, A. Frosolini, C. Gallo, R.D. de Siati, G. Spinato, C. de FilippisTinnitus following COVID-19 vaccination: report of three casesInt. J. Audiol. (2021), pp. 1-4, 10.1080/14992027.2021.19319690(0) View PDFGoogle Scholar[

14]P.T. Tseng, T.Y. Chen, Y.S. Sun, Y.W. Chen, J.J. ChenThe reversible tinnitus and cochleopathy followed first-dose AstraZeneca COVID-19 vaccinationQJM: Int. J. Med. (2021), pp. 1-9, 10.1093/qjmed/hcab210Published online View PDFView Record in ScopusGoogle Scholar[

15]The vaccine adverse event reporting system (VAERS) results formhttps://wonder.cdc.gov/controller/datarequest/D8;jsessionid=12CA0722184B2B3F6A88AE4A4AE0, Accessed 19th Sep 2021Google Scholar[

16]B. Langguth, P.M. Kreuzer, T. Kleinjung, D. de RidderTinnitus: causes and clinical managementLancet Neurol., 12 (9) (2013), pp. 920-930, 10.1016/S1474-4422(13)70160-1ArticleDownload PDFView Record in ScopusGoogle Scholar[

17]H.J. Kim, H.J. Lee, S.Y. An, et al.Analysis of the prevalence and associated risk factors of tinnitus in adultsPLoS One, 10 (5) (2015), 10.1371/JOURNAL.PONE.0127578 View PDFGoogle Scholar[

18]J.S. Choi, A.J. Yu, C.C.J. Voelker, J.K. Doherty, J.S. Oghalai, L.M. FisherPrevalence of tinnitus and associated factors among Asian Americans: results from a national sampleLaryngoscope, 130 (12) (2020), pp. E933-E940, 10.1002/lary.28535 View PDFView Record in ScopusGoogle Scholar

[19]D.M. Nondahl, K.J. Cruickshanks, G.H. Huang, et al.Tinnitus and its risk factors in the Beaver dam offspring studyInt. J. Audiol., 50 (5) (2011), p. 313, 10.3109/14992027.2010.551220 View PDFView Record in ScopusGoogle Scholar[

20]M.J. Page, J.E. McKenzie, P.M. Bossuyt, et al.The PRISMA 2020 statement: an updated guideline for reporting systematic reviewsInt. J. Surg., 88 (2021), p. 105906, 10.1016/J.IJSU.2021.105906ArticleDownload PDFView Record in ScopusGoogle Scholar[

21]A.J.M. Ligtenberg, H.S. BrandLigtenberg AJM, Brand HS. Wat zijn de verschillen tussen diverse vaccins tegen COVID-19? [What are the differences between the various covid-19 vaccines?](epub ahead of print 2021)Ned Tijdschr Tandheelkd., 128 (2021), 10.5177/ntvt.2021.epub.21038Published 2021 Jul 6. doi:10.5177/ntvt.2021.epub.21038 View PDFGoogle Scholar[

22]I. Delrue, D. Verzele, A. Madder, H.J. NauwynckInactivated virus vaccines from chemistry to prophylaxis: merits, risks and challengesExpet Rev. Vaccine, 11 (6) (2014), pp. 695-719, 10.1586/ERV.12.38dx.doi.org/101586/erv1238 View PDFGoogle Scholar[

23]J. Z, J. Z, S. PT cell responses are required for protection from clinical disease and for virus clearance in severe acute respiratory syndrome coronavirus-infected miceJ. Virol., 84 (18) (2010), pp. 9318-9325, 10.1128/JVI.01049-10 View PDFGoogle Scholar[

24]R. KamepalliHow immune T-cell augmentation can help prevent COVID-19: a possible nutritional solution using ketogenic lifestyleUniv. Louisville J. Respir. Infect., 4 (1) (2020), p. 7, 10.18297/jri/vol4/iss1/7 View PDFView Record in ScopusGoogle Scholar[

25]M. T, Y. L, R. Z, et al.Immunopathological characteristics of coronavirus disease 2019 cases in Guangzhou, ChinaImmunology, 160 (3) (2020), pp. 261-268, 10.1111/IMM.13223 View PDFGoogle Scholar[

26]Comparing the COVID-19 vaccines: how are they different? > news > yale medicinehttps://www.yalemedicine.org/news/covid-19-vaccine-comparison, Accessed 23rd Sep 2021Google Scholar[

27]M.T. Mascellino, F Di Timoteo, M. De Angelis, A. OlivaOverview of the main anti-SARS-CoV-2 vaccines: mechanism of action, efficacy and safetyInfect. Drug Resist., 14 (2021), pp. 3459-3476, 10.2147/IDR.S315727 View PDFView Record in ScopusGoogle Scholar[

28]COVID-19 Vaccines: Comparison of Biological, Pharmacological Characteristics and Adverse Effects of Pfizer/BioNTech and Moderna Vaccines.Google Scholar[

29]P. FP, T. SJ, K. N, et al.Safety and efficacy of the BNT162b2 mRNA covid-19 vaccineN. Engl. J. Med., 383 (27) (2020), pp. 2603-2615, 10.1056/NEJMOA2034577 View PDFGoogle Scholar[

30]CanSino vaccine in Pakistan: side effects, efficacy, approval, price, etc – *updated 23 September 2021* – wego bloghttps://blog.wego.com/cansino-vaccine-pakistan/, Accessed 23rd Sep 2021Google Scholar[

31]Y. Z, G. Z, H. P, et al.Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trialLancet Infect. Dis., 21 (2) (2021), pp. 181-192, 10.1016/S1473-3099(20)30843-4 View PDFGoogle Scholar[

32]The Sinovac-CoronaVac COVID-19 vaccine: what you need to knowhttps://www.who.int/news-room/feature-stories/detail/the-sinovac-covid-19-vaccine-what-you-need-to-know?gclid=CjwKCAjwy7CKBhBMEiwA0Eb7aihNZUJbAujxMi25FEPTAggpbDVF0lqcZqT9i4kCEngjY4LqxhezbBoCYDwQAvD_BwE, Accessed 23rd Sep 2021Google Scholar[

33]The Sinopharm COVID-19 vaccine: what you need to knowhttps://www.who.int/news-room/feature-stories/detail/the-sinopharm-covid-19-vaccine-what-you-need-to-know, Accessed 23rd Sep 2021Google Scholar

[34]B.Q. Saeed, R. AlShahrabi, S.S. Alhaj, Z.M. Alkokhardi, A.O. AdreesSide effects and perceptions following Sinopharm COVID-19 vaccinationInt. J. Infect. Dis., 111 (2021), pp. 219-226, 10.1016/J.IJID.2021.08.013ArticleDownload PDFView Record in ScopusGoogle Scholar[

35]I. Jones, P. Roy, V. SputnikCOVID-19 vaccine candidate appears safe and effectiveLancet, 397 (2021), p. 642, 10.1016/S0140-6736(21)00191-410275ArticleDownload PDFView Record in ScopusGoogle Scholar[

36]Pagotto V, Ferloni A, Soriano MM, et al. ACTIVE MONITORING OF EARLY SAFETY OF SPUTNIK V VACCINE IN BUENOS AIRES, ARGENTINA.Google Scholar[

37]C.B. Coelho, R. Santos, K.F. Campara, R. TylerClassification of tinnitus: multiple causes with the same nameOtolaryngol. Clin., 53 (4) (2020), pp. 515-529, 10.1016/j.otc.2020.03.015ArticleDownload PDFView Record in ScopusGoogle Scholar[

38]A.A. Esmaili, J. RentonA review of tinnitusAust. J. Gen. Pract., 47 (4) (2018), pp. 205-208, 10.31128/AJGP-12-17-4420 View PDFView Record in ScopusGoogle Scholar[

39]P. Rzymski, B. Perek, R. FlisiakThrombotic thrombocytopenia after covid-19 vaccination: in search of the underlying mechanismVaccines, 9 (6) (2021), pp. 1-12, 10.3390/vaccines9060559 View PDFView Record in ScopusGoogle Scholar[

40]T. Hasan, M. Khan, F. Khan, G. HamzaCase of Guillain-Barré syndrome following COVID-19 vaccineBMJ Case Rep., 14 (6) (2021), 10.1136/BCR-2021-243629 View PDFGoogle Scholar[

41]D. Kanduc, Y. ShoenfeldMolecular mimicry between SARS-CoV-2 spike glycoprotein and mammalian proteomes: implications for the vaccineImmunol. Res., 68 (5) (2020), pp. 310-313, 10.1007/S12026-020-09152-62020 View PDFView Record in ScopusGoogle Scholar[

42]E.J. Formeister, W. Chien, Y. Agrawal, J.P. Carey, C.M. Stewart, D.Q. SunPreliminary analysis of association between COVID-19 vaccination and sudden hearing loss using US centers for disease control and prevention vaccine adverse events reporting system dataJAMA Otolaryngol Head Neck Surg., 147 (7) (2021), pp. 674-676, 10.1001/JAMAOTO.2021.0869 View PDFView Record in ScopusGoogle Scholar[

43]O. Shamriz, Y. Tal, M. GrossAutoimmune inner ear disease: immune biomarkers, audiovestibular aspects, and therapeutic modalities of cogan’s syndromeJ. Immunol. Res. (2018), 10.1155/2018/14986402018 View PDFGoogle Scholar[

44]A. Ciorba, V. Corazzi, C. Bianchini, et al.Autoimmune inner ear disease (AIED): a diagnostic challengeInt. J. Immunopathol. Pharmacol., 32 (2018), 10.1177/2058738418808680 View PDFGoogle Scholar[

45]S.A. JA LEHeritability and genetics contribution to tinnitusOtolaryngol. Clin., 53 (4) (2020), pp. 501-513, 10.1016/J.OTC.2020.03.003 View PDFGoogle Scholar[

46]A.R. Loiselle, A. Neustaeter, E. de Kleine, P. van Dijk, N.M. JansoniusAssociations between tinnitus and glaucoma suggest a common mechanism: a clinical and population-based studyHear. Res., 386 (2020), p. 107862, 10.1016/J.HEARES.2019.107862ArticleDownload PDFView Record in ScopusGoogle Scholar[

47]L.K. Wareham, E.S. Buys, R.M. SappingtonThe nitric oxide-guanylate cyclase pathway and glaucomaNitric Oxide : Biol. Chem., 77 (2018), p. 75, 10.1016/J.NIOX.2018.04.010ArticleDownload PDFView Record in ScopusGoogle Scholar[

48]E. Hofmann, R. Behr, T. Neumann-Haefelin, K. SchwagerPulsatile tinnitus: imaging and differential diagnosisDtsch. Ärztebl. Int., 110 (26) (2013), p. 451, 10.3238/ARZTEBL.2013.0451 View PDFView Record in ScopusGoogle Scholar[

49]E. NiesOtotoxic substances at the workplace: a brief updateArh. Hig. Rad. Toksikol., 63 (2) (2012), pp. 147-152, 10.2478/10004-1254-63-2012-2199 View PDFView Record in ScopusGoogle Scholar[

50]H. S, L. P, J. BD, M. F, M. GDrug-induced tinnitus and other hearing disordersDrug Saf., 14 (3) (1996), pp. 198-212, 10.2165/00002018-199614030-00006 View PDFGoogle Scholar[

51]Module 3 – immunization anxiety-related reactions – WHO vaccine safety basicshttps://vaccine-safety-training.org/immunization-anxiety-related-reactions.html, Accessed 27th Sep 2021Google Scholar[

52]Z-16025/05/2012 Imm P/F Government of India Ministry of Health & Family Welfare Immunization Division Date : 12 Th July , 2021 Nirman Bhawan , New Delhi Causality Assessment Results of 88 Reported Serious Adverse Events Following Immunization (2021)(AEFI. Published online)Google Scholar[

53]G. MS, M. NE, M. CM, et al.Immunization stress-related response – redefining immunization anxiety-related reaction as an adverse event following immunizationVaccine, 38 (14) (2020), pp. 3015-3020, 10.1016/J.VACCINE.2020.02.046 View PDFGoogle Scholar

[54]L. A, S. TA, M. NE, et al.Anxiety-related adverse events following immunization (AEFI): a systematic review of published clusters of illnessVaccine, 36 (2) (2018), pp. 299-305, 10.1016/J.VACCINE.2017.11.017 View PDFGoogle Scholar[

55]C.J. Sokolowski, J.A. Giovannitti, S.G. BoynesNeedle phobia: etiology, adverse consequences, and patient managementDent. Clin., 54 (4) (2010), pp. 731-744, 10.1016/J.CDEN.2010.06.012ArticleDownload PDFView Record in ScopusGoogle Scholar[

56]N.B. B D, S.B. C HSocial contagion of vasovagal reactions in the blood collection clinic: a possible example of mass psychogenic illnessHealth Psychol. : Off. J. Div. Health Psychol. Am. Psychol. Assoc., 33 (7) (2014), pp. 639-645, 10.1037/HEA0000053 View PDFGoogle Scholar

[57]M. NEVaccine hesitancy: definition, scope and determinantsVaccine, 33 (34) (2015), pp. 4161-4164, 10.1016/J.VACCINE.2015.04.036 View PDFGoogle Scholar[

58]E. K, H.J. LThe benefit of the doubt or doubts over benefits? A systematic literature review of perceived risks of vaccines in European populationsVaccine, 35 (37) (2017), pp. 4840-4850, 10.1016/J.VACCINE.2017.07.061 View PDFGoogle Scholar[

59]B.C. Oosterloo, P.H. Croll, Rjb Jong, M.K. Ikram, A. GoedegeburePrevalence of tinnitus in an aging population and its relation to age and hearing lossOtolaryngology-Head Neck Surg. (Tokyo), 164 (4) (2021), p. 859, 10.1177/0194599820957296 View PDFView Record in ScopusGoogle Scholar[

60]C.W. Newman, G.P. Jacobson, J.B. SpitzerDevelopment of the tinnitus handicap inventoryArch. Otolaryngol. Head Neck Surg., 122 (2) (1996), pp. 143-148, 10.1001/ARCHOTOL.1996.01890140029007  View PDFView Record in ScopusGoogle Scholar[

61]B. Langguth, R. Goodey, A. Azevedo, et al.Consensus for tinnitus patient assessment and treatment outcome measurement: tinnitus Research Initiative meeting, RegensburgProg. Brain Res., 166 (July 2006), pp. 525-536, 10.1016/S0079-6123(07)66050-62007 View PDFGoogle Scholar[

62]A. McCombe, D. Baguley, R. Coles, L. McKenna, C. McKinney, P. Windle-TaylorGuidelines for the grading of tinnitus severity: the results of a working group commissioned by the British Association of Otolaryngologists, Head and Neck Surgeons, 1999Clin. Otolaryngol. Allied Sci., 26 (5) (2001), pp. 388-393, 10.1046/J.1365-2273.2001.00490.X View PDFView Record in ScopusGoogle Scholar[

63]Topical corticosteroids: mechanisms of action – PubMedhttps://pubmed.ncbi.nlm.nih.gov/2533778/, Accessed 30th Dec 2021Google Scholar[

64]N.R. Barshes, S.E. Goodpastor, J.A. GossPharmacologic immunosuppressionFront. Biosci. : J. Vis. Literacy, 9 (2004), pp. 411-420, 10.2741/1249 View PDFView Record in ScopusGoogle Scholar[

65]D.J. Hoare, V.L. Kowalkowski, S. Kang, D.A. HallSystematic review and meta-analyses of randomized controlled trials examining tinnitus managementLaryngoscope, 121 (7) (2011), pp. 1555-1564, 10.1002/LARY.21825 View PDFView Record in ScopusGoogle Scholar[

66]S. Okhovat, R. Fox, J. Magill, A. NarulaSudden onset unilateral sensorineural hearing loss after rabies vaccinationBMJ Case Rep., 2015 (2015), 10.1136/BCR-2015-211977 View PDFGoogle Scholar[

67]CDC Monitors Health Reports Submitted after COVID-19 Vaccination to Ensure Continued Safety COVID-19 Vaccines Are Part of the Most Intensive Vaccine Safety Monitoring Effort in U . S . History (2019), p. 323652Published onlineGoogle Scholar