key: cord-0756008-ziemri09
authors: Assiri, Sara A; Althaqafi, Raad M M; Alswat, Khaled; Alghamdi, Ahmed Abdullah; Alomairi, Naif E; Nemenqani, Dalal M; Ibrahim, Zein S; Elkady, Ahmed
title: Post COVID-19 Vaccination-Associated Neurological Complications
date: 2022-02-02
journal: Neuropsychiatr Dis Treat
DOI: 10.2147/ndt.s343438
sha: 3a68a01e2799a37b410cb3758d47e189610fed06
doc_id: 756008
cord_uid: ziemri09

PURPOSE: Neurological sequelae after COVID-19 vaccination are rare. We investigated the possible pathogenesis behind the development of neurological complications within a short period after Saudi residents received a COVID-19 vaccine. PATIENTS AND METHODS: We evaluated 18 patients who recently received a COVID-19 vaccine (Comirnaty and Vaxzevria vaccines) and presented with neurological complications to the Saudi German Hospitals in Jeddah, Saudi Arabia. Neurologists assessed the patients’ clinical presentation, radiological investigations, and laboratory findings. RESULTS: Three patients who received the first dose of the Vaxzevria vaccine experienced severe cerebral venous thrombosis, two of them were complicated by intracranial hemorrhage. Their laboratory investigations showed very high d-dimers and severe thrombocytopenia, which have been linked to higher mortality and poor outcome. Ischemic stroke occurred in eight cases (44.4%) with a predominance in older male patients. Three patients presented with seizures, two had optic neuritis. Guillain–Barré syndrome (GBS) and Miller Fisher syndrome (MFS) occurred in two male patients following vaccination with Comirnaty. CONCLUSION: Neurological complications after COVID-19 vaccinations are very rare, and only a few cases have been reported worldwide. The shared pathophysiological basis between COVID-19 viral infection and COVID-19 vaccines stands behind the very rare neurological complications resulting from the hypercoagulable state triggered by the general inflammatory condition. We suspect some differences in the pathogenesis of ischemic stroke caused by COVID-19 infection and COVID-19 vaccines, which render COVID-19 vaccine-associated ischemic stroke more responsive to treatment. To date, no definitive association between the vaccine and GBS has been proven by any strong evidence, but it has recently been added as a very rare side effect of the Janssen COVID-19 vaccine. No possible links of Miller Fisher syndrome to COVID-19 vaccines have been reported before the one reported in this study.

Health and economies have been affected globally by the devastating pandemic resulting from coronavirus disease 2019 (COVID- 19) . As of December 23rd, 2021, more than 279,572,610 cases had been reported with 5,398,772 documented deaths. 1 Health organizations worldwide have reached a decision that widespread vaccination in all countries is inevitable to survive this deadly pandemic.

A number of vaccines have been approved based on randomized, blinded, controlled trials that started in December 2020. These approved vaccines include two mRNA-based vaccines that encode the spike protein antigen of SARS-CoV-2 encapsulated in lipid nanoparticles: Comirnaty (BNT162b2, Pfizer-BioNTech) and Spikevax mRNA-1273 (Moderna). The other two vaccines are a recombinant chimpanzee adenoviral vector encoding the spike glycoprotein of SARS CoV-2 called Vaxzevria (ChAdOx1 nCov-19, AstraZeneca) and a recombinant adenovirus type 26 vector encoding SARS-CoV-2 spike protein (Ad26.COV2.S, Johnson & Johnson/Janssen). 2 Putting aside the uneven vaccine distribution between countries, certain countries have had a high percentage of vaccinated citizens. More than 90.68% of the population in the United Arab Emirates have received a second dose of All patients had a confirmed negative polymerase chain reaction (PCR) result for COVID-19 before admission. Blood samples were taken from all patients, and all available laboratory tests were recorded and included the following: hemoglobin (13-15 g/dl), platelets (140-440,109/L), fibrinogen <150 mg/dL, blood glucose, HbA1c% (4.8-6), creatinine (0.5-1.1 mg/ dL), troponin-I (10-26 pg/mL), and prothrombin time (PT) , from which INR ratios were calculated. In addition, thyroid-stimulating hormone (TSH) (0.4-4.0 mU/L), alanine transaminase (ALT) (<55 U/L), high-density lipoprotein (>60 mg/dL), low-density lipoprotein (<100 mg/dL), total cholesterol (<200 mg/dL), and triglycerides (<150 mg/dL) were included. All patients were subjected to echocardiography with ejection fraction taken as a marker for the efficiency of cardiac functions. Measurements of blood pressure and heart rate were used to evaluate hypertension.

All patients were seen by a consultant neurologist who evaluated them according to Modified Rankin Scale (MRS) and Glasgow Coma Scale/Score (GCS). Patients were subjected to brain computerized tomography (CT) or magnetic resonance imaging (MRI) and vessel imaging, such as magnetic resonance angiography (MRA), magnetic resonance venography (MRV), CT venography (CTV), and cerebral angiography when clinically indicated. Data were analyzed using IBM SPSS Statistics for Windows, Version 23.0. Means, standard deviations (SDs), medians, interquartile ranges (IQRs), and percentages were calculated. The Mann-Whitney U-test was used to compare the two independent groups for nonparametric parameters. We used an independent t-test for parametric variables.

We applied the FAPIC predictive scoring model for mortality 15 to our first three patients. If any of the following was applicable, a point was scored: age less than or 60 years, platelet count of less than 2510 9 /mL, fibrinogen less than 150 mg/dL, intracranial hemorrhage (ICH), and CVT. The predicted mortality increased with each point: 2.08% with FAPIC score 0, 6.66% with FAPIC score 1, 19.31% with FAPIC score 2, 44.54% with FAPIC score 3, 72.94% with FAPIC score 4, and 90.05% with FAPIC score 5.

The total cohort's mean age was 48.8 years (IQR 36-59 years), and there was no gender predominance. The mean age of female patients was 46.2 years (IQR 26-69 years), and the mean age of male patients was 51.4 years (IQR 39.5-60.5 years). The number of days between receiving the vaccine and presenting with various neurological complications ranged between 4 and 25 days with an average of 10 days (Figure 1 ), while the average days of hospital admission was 8 days. Of the 18 patients studied, ischemic stroke was encountered in eight patients (constituting 44.4% of all presented cases), and severe CVT occurred in 16.6% of cases.

The 10 patients who received the first dose of the Oxford-AstraZeneca Vaxzevria COVID-19 vaccine had a mean age of 43.6 years (IQR 28-58 years). Table 1 shows all clinical, laboratory and radiological data of patients who presented with neurological sequelae after receiving this vaccine. Cerebral Venous Thrombosis (CVT) Three patients had severe CVT (Table 1, cases 1, 2, and 3) after the first dose of the Vaxzevria vaccine by 10, 12, and 4 days, respectively, with a median of 10 days. All patients were females under 40 years of age. Two of the three CVT patients who died had an intracerebral hemorrhage with herniation after rebleeding (Table 1, cases 1 and 2) . Their initial complaint was headache, followed by clinical deterioration of GCS to scores of 8 and 6 points for the first and second cases, respectively. Laboratory results revealed thrombocytopenia as low as 11,109/L in the first case, 17,109/L in the second case, and 21,109/L in the third one. Overall, they had the highest D-dimers readings among our total cohort of 18 patients.

Prothrombin time was also elevated in all three cases. The first two patients had a low hemoglobin level, and the second case had a low fibrinogen level of 128 mg/dl. Lipid profile results revealed high triglyceride levels, low HDL, and normal total cholesterol levels in all three patients, and the first two cases had elevated LDL. We calculated the FAPIC score for all three patients, and the first case scored 4 points, so her expected probability of death was 72.94% (fibrinogen was not available for the first case, so it was not included). The second case scored 5 points, and her expected probability of death was 90.05%, while the third case scored 3 points and had an expected probability of death of 44.54%. Figure 2 shows the radiological brain imaging of cases 1, 2, and 3 presenting with CVT.

Bilateral optic neuritis occurred in a 24-year-old female, and right unilateral optic neuritis occurred in a 42-year-old male patient after the first dose of Vaxzevria Oxford-AstraZeneca vaccine by 14 and 19 days, respectively (Table 1, cases 9 and 10). Both were medically free and presented with decreased visual acuity and eye pain. The 42-year-old male patient was a smoker and had elevated triglyceride and LDL levels, as well as mildly elevated blood pressure. Both recovered completely after less than 10 days of hospital admission.

Four male patients had an ischemic cerebrovascular accident (Table 1 , cases 4, 5, 6, and 7). All of them had comorbidities and were older than 40 years old. The oldest patient was 66 years old (Table 1 , Case 4) and presented with a seizure, low blood pressure, aphasia, and dysphagia, in addition to motor, sensory, and visual affection at 10 days after receiving the first dose of the AstraZeneca vaccine. He had multiple comorbidities, including diabetes that was poorly controlled with HbA1C of 10.6, as well as a previous stroke. He spent the longest duration in the intensive care unit (ICU), and his MRI showed a right middle cerebral infarction.

A 46-year-old Filipino male (Table 1 , case 5) presented with a seizure, ataxia, dysarthria, and motor and sensory affection at 7 days after receiving the first dose of the AstraZeneca vaccine. He had a known case of poorly controlled diabetes with HbA1C of 13.7 and highly elevated triglyceride, total cholesterol, and LDL readings. Figure 3C and G show the MRI and MRA done for this case.

The third ischemic stroke patient was 56 years old (Table 1 , case 6). His MRI showed a right lacunar thalamic stroke, and he presented at 2 days after receiving the vaccine with ataxia and vertigo. He was diagnosed as a case of vestibular neuritis. The fourth case was an Indian hypertensive patient and a 62-year-old male (Table 1, case 7). His MRI showed pontine infarction, as shown in Figure 3D . Figure 3H shows his MRA. He presented 4 days after receiving the vaccine with dysarthria and motor, sensory, and visual affection.

A 58-year-old female patient with a known case of controlled hypothyroidism and hypertension ( Table 1, case 8) presented with an isolated first-time seizure after receiving the first dose of Vaxzevria the vaccine within 25 days. Her GCS on presentation was 10, and she was admitted to the ICU. Her MRI and CT brain were unremarkable, and her TSH and blood pressure were within normal limits. She spent a total of 4 days of admission. Additionally, two of the patients who had an ischemic stroke also presented with first-time seizure. 

The eight patients who received the Comirnaty vaccine had a mean age of 55.3 years (IQR 36.5-69.5) years. Table 2 demonstrates all clinical, laboratory, and radiological data of these patients.

A 36-year-old male patient was diagnosed with GBS ( 

An 80-year-old female patient presented with motor, sensory, and visual affection in addition to seizures, vertigo, dysphagia, and dysarthria after receiving the second dose of the Pfizer-BioNTech vaccine by 16 days. She was admitted to the ICU for 8 days. She had a known case of hypertension, diabetes, and epilepsy, and she had been seizure free for years on Depakine.

Four patients had an ischemic cerebrovascular incident ( Figure 3B and F show the MRI and MRA done for this case.

A 59-year-old Palestinian male presented after receiving the second dose of the Pfizer-BioNTech vaccine by 23 days with motor and sensory affection in addition to dysphagia and dysarthria. He had dyslipidemia, and on admission, his triglyceride level was 187 mg/dl, and his total cholesterol was 285 mg/dl, while his LDL was 169 mg/dl. Figure 3A and F show the MRI and cerebral angiography done for this case, revealing right middle cerebral artery infarction.

The oldest among this group of ischemic stroke patients was an 80-year-old Ethiopian woman who received the second dose of Pfizer-BioNTech vaccine, and then seven days later, she presented with motor, sensory, and visual affection in addition to aphasia, dysphagia, and dysarthria. She was admitted to the ICU for 18 days, where her MRI and MRA showed left middle cerebellar artery occlusion. The youngest patient was a 36-year-old asthmatic female who received the first dose of the Pfizer-BioNTech vaccine and presented 6 days later with motor and sensory affection, in addition to aphasia and dysphagia. Her brain imaging revealed a left middle cerebellar artery occlusion. One 56-year-old hypertensive female patient had a transient ischemic attack after the first dose of Pfizer-BioNTech vaccine by 8 days. She had an episode of aphasia and dysarthria. Table 3 shows a comparison of the coagulation profiles between the two groups receiving the AstraZeneca and Pfizer vaccines.

This study investigated neurological complications for their possible association with COVID-19 vaccination among Saudi residents. In accordance with a recent report, 6 the timing of the neurological symptoms' presentation among our patients ranged from 4 to 25 days with an average of 10 days after vaccination. CVT CVT was severe in three female patients under 40 years old, and all of them received the first dose of the Oxford-AstraZeneca Vaxzevria vaccine. This is in accordance with EMA and WHO reports. 8, 16 Thrombosis with thrombocytopenia syndrome (TTS) has been reported as a very rare complication following vaccination with Vaxzevria with 70% predilection to middle-aged females; it is caused by IgG antibodies that recognize platelet factor 4 (PF4) leading to platelet activation. 17 The predominance of CVT among middle-aged females who were vaccinated with the Vaxzevria vaccine was also observed in a case series by Greinacher et al. 2 CVT occurrence in young females, as presented in the current study, and its resemblance to the available literature should raise attention and prompt further investigation of the Vaxzevria vaccine's risk in this particular population.

Similarly, CVT following vaccination with the Johnson & Johnson vaccine, another adenoviral vector-based vaccine, has been reported and compared with CVT following the Vaxzevria vaccine.

They have shown no difference in mortality between the two groups, but patients who received the Vaxzevria vaccine presented earlier after a median of 10 days, 18 which matches the results in the present study. Two out of the three CVT patients in the current study died, and their radiological investigations showed intracranial hemorrhage, while labs showed severe thrombocytopenia. Like previously reported cases, 19 mortality was associated with intracranial hemorrhage and very low platelet counts. The FAPIC score is a recent novel scoring system suggested by Hwang et al to predict the probability of death among patients presenting with thrombotic thrombocytopenia after receiving an adenoviral vaccine. The scores depend on the age, platelet count, fibrinogen level, and intracranial hemorrhage, in addition to CVT. 15 It is important to note that the two deceased patients had the highest D-dimers readings overall among our 18 studied cases. Thus, in the current study, D-dimer elevation indicates the severity of the coagulopathy and its related complications, including CVT and its association with poor outcomes in COVID-19-vaccinated individuals, especially those receiving the Vaxzevria vaccine, in a similar way to COVID-19 patients. 20 Severe CVT occurred in 16.6% of our 18 cases, which approaches the reported incidence of 21% of CVT among COVID-19 patients. 21 Interestingly, COVID-19 infection-associated CVT has been reported in patients who have various co-morbidities. 22 However, our three cases who had CVT were medically free and did not receive any previous medications. This may indicate an insignificant role of the suggested risk factors in those individuals and could refocus clinicians' attention to depend mainly on the clinical symptoms at the time of the patient's admission.

In the current study, the equal distribution of the ischemic stroke occurrence between those receiving the Oxford-AstraZeneca and Pfizer-BioNTech COVID-19 vaccines may indicate a general reaction of the body that is prompted by the vaccines. Although the mechanism of the presented neurological complications after COVID-19 vaccination has not been precisely explained, it could be attributed to the COVID-19 vaccine-triggered inflammatory condition like in the course of COVID-19 viral infection, which induces disseminated intravascular coagulation (DIC) 23 concurrent with vascular endothelial dysfunction, 24 leading to large-vessel stroke. 25 This hypothesis may be the main cause, especially in mRNA-based vaccines, which depend on giving the mRNA code of spike protein to human cells. In turn, this directs the 

cell machinery to synthesize the spike protein, and after being released from the cells, it stimulates the immune system to recognize and memorize it and attack it in the future. 26 Based on this hypothesis, the vaccine-triggered inflammatory condition may be considered the main pathway for the COVID-19 vaccines' neurological complications, in addition to cytokine-mediated neuroinflammation. 27 Of course, this is separate from the local effect of viral-induced neurodegeneration in cases of COVID-19 infection, including the viralinduced effect on the blood brain barrier (BBB) and its associated neurons and neuroglia cell inflammation. 28 The likelihood of ischemic stroke is increased with COVID-19 infection, increasing mortality among patients. 29 Out of the 18 cases studied, ischemic stroke was encountered in eight cases, who were mostly elderly males, with four in each vaccine group.

The occurrence of stroke in COVID-19 vaccinated individuals in the current study seems to have the same tendency as those occurring in COVID-19 viral infections, with a predominance in older age. 30 This is inconsistent with a previous retrospective study from Wuhan, China. 31 Moreover, in this study, MRI and vessel imaging studies revealed that the majority of patients who experienced stroke showed large vessel infarction, similar to younger COVID-19 infected patients who have been reported with similar presentation. 32 Further investigation is still needed to determine whether this observation distinguishes stroke presenting in young patients who have a natural COVID-19 infection from older vaccinated individuals.

Notably, in the current study, most of patients who experienced stroke had risk factors and common comorbidities such as dyslipidemia, hypertension, and diabetes, which is in agreement with previously reported stroke-predisposing factors in COVID-19 patients. 33 In contrast to previous studies showing high mortality associated with stroke in COVID-19 patients, 34 all patients who experienced stroke in the current study survived and were discharged home after, with only 3 of them requiring extended care. This may raise the question of whether COVID-19 vaccine-associated stroke is more responsive to treatment than natural COVID-19 infection-associated stroke. The complicated pathogenesis of COVID-19 infection-associated thrombus might render it more resistant and difficult to treat when compared to thrombus resulting from COVID-19 vaccines. This could be due to the viral induced-vascular endothelial changes, 35 in addition to COVID-19-associated inflammation in the neurons and neuroglia cells. 28 

Out of the 10 cases injected with the first dose of the Oxford-AstraZeneca COVID-19 vaccine, three cases presented with seizures as a neurological complication. COVID-19 infection has been reported to cause seizures as one of the neurological complications of this viral infection. 36 However, it was hypothesized to occur due to viral invasion of the central nervous system (CNS) inducing the microglia to initiate an inflammatory cascade, 37 with the release of the astrocytes and microglia inflammatory cytokines including TNF-α, IL-6, IL-1B, NO, PGE2, and free radicals. 36, 38 It was also hypothesized to be caused by severe hypoxia from respiratory failure, 36 which causes a cytokine storm release leading to organ failure. 39 Seizures were also reported after vaccination in a 68-year-old man in India. 40 In another study, an 83-year-old woman and a 76-year-old man with no previous neurological diseases presented with seizures and encephalopathy after receiving Spikevax Moderna COVID-19 vaccination. 41 These COVID-19 vaccine-associated seizures could be attributed to the vaccine-induced cell machinery synthesizing and releasing spike protein, which stimulates an exaggerated inflammatory condition and causes hyperthermia. It is worth mentioning that hyperthermia has been recognized to induce glial cell activation and increase BBB permeability. 42 Increased BBB permeability permits peripheral blood cells and albumin passage to the CNS, causing disruption of its osmotic balance 43, 44 and allowing the passage of peripheral cytokines into it, causing seizures. 37 The occurrence of seizures in the current study was mostly among the group vaccinated with Oxford-AstraZeneca Vaxzevria, which might indicate that it causes a strong inflammatory reaction.

In the current study, bilateral optic neuritis occurred in a 24-year-old female, and right unilateral optic neuritis occurred in a 42-year-old male after the first dose of the Oxford-AstraZeneca vaccine by 14 and 19 days, respectively. COVID-19 vaccine-associated optic neuritis could be attributed to myelin sheath destruction and axonal degeneration, 45 150 caused by inflammatory mediators produced by peripheral blood cells that have migrated through the hyperthermiadisrupted BBB. 42 The occurrence of optic neuritis among the Oxford-AstraZeneca Vaxzevria group may add additional evidence to the severity of the body's reaction to this vaccine in individuals with currently undetermined risk factors. Intriguingly, COVID-19 infection resulting in optic neuritis has been reported in older age in a 63-year-old man, 45 and a 64-year-old woman. 46 However, the results of the current study indicate that the optic neuritis associated with Oxford-AstraZeneca Vaxzevria occurred in young and middle-aged patients. It is still unknown whether the body's reaction or the pathogenesis of the optic neuritis differs between COVID-19-infected and COVID-19-vaccinated individuals, resulting in some variation in the age distribution.

Two male patients among our cohort who received the Pfizer Comirnaty vaccine were diagnosed with GBS and MFS. In February 2021, the first reported case of GBS following the first dose of the Pfizer Comirnaty vaccine was an 82-year-old female patient. 47 A 65-year-old male patient was diagnosed with GBS after receiving the first dose of the Pfizer Comirnaty vaccine, 48 and a 67-year-old man was diagnosed with GBS 15 days after receiving the first dose of the AstraZeneca Vaxzevria vaccine. 49 GBS following COVID-19 infection was also highlighted and reported in more than 40 cases. 50 However, to date, there are no specific GBS features distinguishing those cases presumably caused by COVID-19, and additionally, molecular mimicry linking COVID-19 to GBS has not been proven by any strong evidence. 51 There is no definitive association linking SARS-COV-2 to the sporadic incidence of GBS, and since COVID-19 vaccines are synthesized based on the same spike protein of SARS-COV-2, there is lack of causative link between the vaccine and GBS. 52 More recently, the EMA has reported that GBS will be added as a very rare side effect of the Janssen COVID-19 vaccine. 53 MFS is a variant of GBS characterized by ataxia, ophthalmoplegia, and areflexia. MFS has been reported in 7 cases after COVID-19 infection, and most patients were men. 54 However, the occurrence of MFS after vaccination is extremely rare and has been published as case reports following seasonal influenza vaccination. 55 To our knowledge, our patient who was diagnosed with MFS nine days following the Pfizer vaccination is the first reported case to be possibly linked to COVID-19 vaccine ( Table 2, case 18 ).

The current study does not establish a causal link between the reported 18 patients' complications and COVID-19 vaccines. Descriptive case series such as our study help to monitor the safety of vaccines, but they do not clarify whether the link between such complications and vaccines is causal or coincidental. One of the many limitations that we faced was the difficulty in reaching the total number of all vaccinated individuals within the area served by the hospital where we performed our study, and hence, we were unable to express the incidence of neurological complication among the total number of vaccinated individuals. Moreover, anti-PF4 antibody testing was unavailable during the study period. Additionally, we could not obtain the previous history of COVID-19 infection in our 18 patients, although all patients had confirmed negative PCR results for COVID-19 infection before admission. During the study period, there were no patients vaccinated with Johnson & Johnson or Moderna vaccines presenting with neurological complications to our hospital, which is why this study did not include patients vaccinated with vaccines other than the Oxford-AstraZeneca Vaxzevria or Pfizer-BioNTech Comirnaty vaccines.

Neurological complications associated with mRNA vaccination seem to be induced by a shared pathophysiological basis with COVID-19 viral infection, including spike protein attachment to human cells triggering a general inflammatory state. This inflammatory state can lead to hypercoagulopathy manifesting as an ischemic stroke or CVT complicated by intracranial hemorrhage. Strokes encountered in this study showed better response to treatment than those reported in association with COVID-19 viral infection. The body's reaction to COVID-19 vaccines is stronger with the Oxford-AstraZeneca Vaxzevria vaccine than with the Pfizer-BioNTech vaccine Comirnaty, which results in severe neurological complications and mortality in individuals with currently undetermined risk factors. Careful and continuous DovePress documentation and monitoring of the adverse reactions encountered following vaccinations may help to identify risk factors that render some individuals susceptible to specific complications.

Approval from the Saudi German Hospital ethical committee was obtained on May 21, 2021. Patients' consent to review their medical records was not required and it was waived by the Saudi German Hospital Ethical Committee due to the retrospective nature of the study. Privacy and anonymization of the participants are maintained with confidentiality and the study was conducted in accordance with the Declaration of Helsinki.

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This journal is indexed on PubMed Central, the 'PsycINFO' database and CAS, and is the official journal of The International Neuropsychiatric Association (INA). The manuscript management system is completely online and includes a very quick and fair peer-review system, which is all easy to use

We greatly acknowledge the Taif University Researchers Supporting Program (TURSP-2020/233) of Taif University, Taif, Saudi Arabia, for facilitating this work.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

All authors confirm that there are no competing interests to disclose.