Facial Nerve Paralysis and COVID‐19: A Systematic Review

Authors: Amirpouyan Namavarian, MD, 1 Anas Eid, BMSc, 2 Hedyeh Ziai, MD, 1 Emily YiQin Cheng, BSc, 3 and Danny Enepekides, MD, MSc, FRCSC Laryngoscope. 2022 Aug 8 : 10.1002/lary.30333. doi: 10.1002/lary.30333

Abstract

Objective

Several cases of facial nerve paralysis (FNP) post‐COVID‐19 infection have been reported with varying presentations and management. This study aims to identify FNP clinical characteristics and recovery outcomes among patients acutely infected with COVID‐19. We hypothesize that FNP is a potentially unique sequalae associated with COVID‐19 infections.

Methods

A systematic review of PubMed‐Medline, OVID Embase, and Web of Science databases from inception to November 2021 was conducted following the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses guidelines.

Results

This search identified 630 studies with 53 meeting inclusion criteria. This resulted in 72 patients, of which 30 (42%) were diagnosed with Guillain‐Barré Syndrome (GBS). Non‐GBS patients were on average younger (36 vs. 53 years) and more likely to present with unilateral FNP (88%) compared to GBS patients who presented predominantly with bilateral FNP (74%). Among non‐GBS patients, majority (70%) of FNP presented a median of 8 [IQR 10] days after the onset of initial COVID‐19 symptom(s). Treatment for non‐GBS patients consisted of steroids (60%), antivirals (29%), antibiotics (21%), and no treatment (21%). Complete FNP recovery in non‐GBS patients was achieved in 67% patients within a median of 11 [IQR 24] days.

Conclusion

FNP is a possible presentation post COVID‐19 infections, associated with both GBS and non‐GBS patients. Although no causation can be assumed, the clinical course of isolated FNP associated with COVID‐19 raises the possibility of a unique presentation differing from Bell’s palsy, seen with higher proportion of patients developing bilateral FNP and a shorter duration to complete recovery. Laryngoscope, 2022

Keywords: Bell’s palsy, COVID‐19, facial nerve, paralysis

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Abstract

Several cases of facial nerve paralysis (FNP) post‐COVID‐19 infection have been reported. This study aims to identify FNP clinical characteristics and recovery outcomes among patients acutely infected with COVID‐19. A systematic review of databases was performed resulting in 53 included studies and a total of 72 patients, of which 30 (42%) were diagnosed with Guillain‐Barré Syndrome (GBS). Among non‐GBS patients, 70% of FNP presented a median of 8 days after the onset of initial COVID‐19 symptom(s). Complete FNP recovery in non‐GBS patients was achieved in 67% patients within a median of 11 days. Although no causation can be assumed, the clinical course of isolated FNP associated with COVID‐19 raises the possibility of a unique presentation differing from Bell’s palsy, seen with higher proportion of patients developing bilateral FNP and a shorter duration to complete recovery.

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INTRODUCTION

Facial nerve paralysis/palsy (FNP) is a debilitating condition with significant morbidity associated with functional and psychological implications. 1 Although the etiology of FNP is broad, viral‐associated Bell’s palsy is thought to be the most prevalent contributor. 2 Herpes simplex virus (HSV) and Varicella zoster virus (VZV) are known contributors in the development of Bell’s Palsy in the pediatric and adult population. 3 Since the onset of the COVID‐19 pandemic, FNP incidence has increased and there has been a suggested association with COVID‐19 infections. 5 8

Many neurological symptoms have been reported in patients infected with COVID‐19 including anosmia, ageusia, myalgia, paraplegias, and facial palsy among others. 9 10 FNP has been described by numerous studies as an outcome of COVID‐19, either as an isolated symptom in patients who have otherwise been asymptomatic or in combination with other COVID‐19 symptoms. 6 11 Guillain‐Barré Syndrome (GBS), an autoimmune polyneuropathy, is linked to viral infections including Epstein–Barr virus (EBV), VZV, human immunodeficiency virus, and influenza among others. 12 GBS has also been described by numerous case reports as a sequelae of COVID‐19 infections, with many reported cases of FNP. 13 The mechanism of GBS is believed to involve an aberrant immune response resulting in nerve trauma secondary to inappropriate complement activation and inflammatory mediators. 14

The current literature highlights facial paralysis in COVID‐19 infected patients including both adult and pediatric cohorts. Although many case reports have described the presence of acute facial paralysis in COVID‐19 patients, to date, there is no comprehensive systematic review on these patients. The objective of this study is to identify FNP clinical characteristics and recovery outcomes among patients acutely infected with COVID‐19 (confirmed by a positive reverse transcription polymerase chain reaction [RT‐PCR]). We hypothesize that FNP is a potentially unique sequalae associated with COVID‐19 infections. In this systematic review, we summarize the current literature on the presentations of facial nerve paralysis in COVID‐19 patients and describe the management of these patients with the aim of providing guidance for future practitioners on these patients’ clinical diagnosis and management.

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METHODS

Search Strategy

This systematic review was completed using the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA) guidelines (Fig. 1). The search strategy was conducted using Ovid Embase, PubMed‐Medline, CINAHL and Web of Science databases from inception to November 2021. The database search was done by two reviewers (a.e./a.n.). Keywords and medical subject headings (MeSH) included facial, facial nerve, peripheral facial nerve, paralysis, paresis, palsy, droop, impair*, Bell’s palsy, weakness, disease, movement, COVID‐19, coronavirus, covid, and SARS‐CoV‐2. The exact search details used for all databases are found in Table S1.

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Fig. 1

PRISMA flow diagram. aTwo studies were included after a screen of the citations from the papers during the eligibility phase. RT‐PCR = reverse transcription polymerase chain reaction. [Color figure can be viewed in the online issue, which is available at www.laryngoscope.com.]

Inclusion and Exclusion Criteria

Inclusion criteria consisted of studies reporting FNP in adult and/or pediatric patients actively infected with COVID‐19. This was defined as a positive COVID‐19 RT‐PCR result. There was no comparator and the outcomes recorded included study design, patient demographic, and FNP clinical characteristics and recovery outcome. Published original studies including case reports, randomized controlled trials, prospective, or retrospective observational studies, cross‐sectional and case–control trials since journal inception were included. Patients with non‐active COVID‐19 infections (i.e., negative RT‐PCR results) despite positive serology (positive immunoglobulin G) were excluded. Furthermore, papers published in a non‐English language or non‐peer reviewed publications (abstracts, conference posters, reviews, letters to editors, and editorials) were also excluded.

Data Extraction and Analysis

The search titles and abstracts were independently screened by two reviewers (a.e./a.n.) based on the inclusion and exclusion criteria. Complete manuscripts were retrieved and independently reviewed by the same two reviewers. If there were any disagreements in article selection between the two reviewers, these were resolved by consensus. If a disagreement persisted, a third reviewer was consulted (h.z.). All titles, abstracts, and full texts screening were completed using Covidence (version 1501). Cross‐checking of the included articles and relevant reviews, as well as a manual web search was conducted for unidentified articles. Extracted data included study design, study population demographics, and clinical characteristics. Information regarding FNP onset, laterality, House‐Brackmann (HB) score, associated symptoms, investigations, treatments, and outcomes was extracted. Patients in studies that did not report HB score were assigned a score by the reviewers based on the described clinical presentation and HB scale by the reviewers when possible. 15 Similarly, if there was any disagreement between the two reviewers, a third reviewer was consulted.

Risk of Bias Assessment

The Joanna Briggs Institute critical appraisal checklist for case reports and case series assessment tools were used to appraise the quality of the studies. This was independently assessed by two authors (a.e. and e.c.). Discrepancies were resolved by consensus or by involving a third author (a.n.). The quality of the studies was quantified according to the assessment tools and a final quality rating of “Good,” “Fair,” or “Poor” was given (Table S2A and B). For case reports, “Good” was defined as at least 6 out of 8 criteria met, “Fair” as 4 or 5 criteria met, and “Poor” as 3 or less criteria met. For case series, “Good” was defined as at least 7 out of 10 criteria met, “Fair” as 5 or 6 criteria met, and “Poor” as 4 or less criteria met.

Statistical Analysis

Descriptive statistics were computed for all variables. Categorical variables were reported as unweighted frequencies and percentages. Continuous variables were reported as medians and interquartile range (IQR). Subgroup analysis was performed based on GBS status. IBM SPSS Statistics for Windows, Version 27.0 was used for all statistical analyses.

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RESULTS

Study Selection

Our search identified 1064 studies. After duplicates were removed, a total of 630 studies were reviewed for initial screening. Fifty‐two studies met our inclusion, and two studies were found during our screen of citations listed in our included papers. A total of 54 studies were included (Fig. 1), resulting in 73 patients. 5 10 11 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 The characteristics of each study can be found in Table S3.

Clinical Features: Non‐GBS Versus GBS Patients

The clinical presentations are summarized in Table I. Forty‐two percent of patients presented with FNP in the context of GBS. Patients without GBS were younger than those with GBS (36 vs. 54 years, respectively). Additionally, more non‐GBS patients presented with unilateral FNP compared to those with GBS (88% vs. 26%, respectively). Furthermore, non‐GBS patients had a shorter delay to FNP onset (median [IQR]; 8 [10] days) from the onset of initial COVID‐19 symptoms compared to GBS patients (16 [11] days).

TABLE I

Overall Study Demographics and FNP Clinical Presentations.

Non‐GBS (n = 42)GBS (n = 30)
Patients (%)5842
Age (years), median [IQR]36 [22]54 [23]
Male, n (%)19 (49)21 (70)
Onset of FNP relative to COVID‐19 symptoms, n (%)
Only FNP4 (11)0
Before or concurrent7 (19)2 (6.8)
After26 (70)27 (93.1)
Days from initial symptoms to onset of FNP, median [IQR]8 [10]16 [11]
Unilateral FNP, n (%)37 (88)7 (25.9)
Degree of FNP, median [IQR]3 [2]4.5 [3]
Complete recovery of FNP achieved, n (%)20 (67)4 (13.3)
Days to complete recovery of FNP, median11 [24]30

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FNP = facial nerve paralysis; GBS = Guillain‐Barré Syndrome; IQR = interquartile range.

Thirty‐two studies reported the severity of the FNP using the House‐Brackmann scale, the median grade was 3 [IQR 2] and 4.5 [3] for non‐GBS and GBS patients, respectively.

Of the COVID‐19 symptoms, the most reported were fever (36% and 60% in non‐GBS and GBS patients, respectively) and cough (32% and 63% in non‐GBS and GBS patients, respectively). When considering neurological symptoms in patients with COVID‐19 other than FNP, impairments in taste function (e.g., ageusia, hypogeusia or dysgeusia) were most reported (10% in non‐GBS vs. 37% in GBS) followed by impairments in olfaction (8% and 23% in non‐GBS and GBS patients, respectively). The detailed distribution of symptoms associated with COVID‐19 is found in Table II.

TABLE II

Patient Symptoms.

SymptomNon‐GBS (n = 42), n (%)GBS (n = 30), n (%)
Non‐neurologic
Fever10 (36)18 (60)
Cough9 (32)19 (63.3)
Myalgia8 (29)5 (16.7)
Dyspnea5 (18)7 (23.3)
Fatigue3 (11)5 (16.7)
Neurologic
Anosmia or hyposmia3 (8)7 (23.3)
Ageusia, hypogeusia, dysgeusia4 (10)11 (36.7)
Dysarthria04 (13.3)
Dysphagia04 (13.3)
Odynophagia1 (3)1 (3.3)
Diplopia1 (3)3 (10)

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GBS = Guillain‐Barré Syndrome.

When considering the distribution of non‐neurological COVID‐19 symptoms based on patient GBS status, more GBS patients presented with a cough compared to non‐GBS patients (63% vs. 32%, respectively) (Table II). More GBS presented with taste dysfunction (37% vs. 10%), dysarthria (13% vs. 0%), and dysphagia (13% vs. 0%) compared with non‐GBS patients.

Imaging

The distribution of utilized imaging investigations is shown in Table S3. Magnetic resonance imaging was performed in 36 patients, all of which reported no structural pathology contributing to their FNP (i.e., retro cochlear or middle ear pathology).

Treatment

A summary of the management is shown in Table III. The non‐GBS patients were most frequently treated with steroids (n = 25, 60%), followed by antivirals (n = 12, 29%), antibiotics (n = 9, 21%), symptom management/no treatment (n = 9, 21%), intravenous immunoglobulins (IVIG) (n = 4, 10%), hydroxychloroquine (n = 4, 10%), and physiotherapy (n = 2, 5%). On the other hand, patients with GBS were most treated with IVIG (n = 24, 80%), followed by hydroxychloroquine (n = 12, 43%), plasmapheresis (n = 8, 27%), steroids (n = 7, 23%), antivirals (n = 6, 21%), antibiotics (n = 6, 21%), and physiotherapy (n = 1, 3%).

TABLE III

Patient Management.

TreatmentNon‐GBS (%)GBS (%)
Steroids25 (60)7 (23.3)
Antivirals12 (29)6 (21.4)
Antibiotics9 (21)6 (21.4)
Hydroxychloroquine4 (10)12 (42.9)
IVIG4 (10)24 (80)
Plasmapheresis08 (26.7)
Physiotherapy2 (5)1 (3.3)
No treatment9 (21)0

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GBS = Guillain‐Barré Syndrome; IVIG = intravenous immunoglobulins.

Recovery Outcomes: Non‐GBS Versus GBS

More patients presenting without GBS had complete recovery of their FNP symptoms compared to those with GBS (67% vs. 13% respectively; Table I). Among those with complete recovery in the non‐GBS group, the majority (80%) did not have any additional neurological symptoms, whereas a minority (20%) had further cranial nerve involvement. Fifty‐three percent (n = 8) of those 15 patients treated with steroids in the non‐GBS group completely recovered within 60 days. In contrast, only 15% (n = 2/13) of the GBS patients treated with IVIG achieved complete FNP recovery within 44 days. There was insufficient data on steroid therapy among GBS patients to compare outcomes to non‐GBS patients.

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DISCUSSION

This systematic review summarizes FNP in the context of COVID‐19 infections highlighting patients with systemic autoimmune pathology of GBS and isolated FNP (non‐GBS). Most patients had moderate FNP as graded on the HB scale. Of the reported non‐neurological COVID‐19 symptoms, the most common were fever and cough. Patients with and without GBS during COVID‐19 infections presented and progressed with FNP differently, with GBS patients typically presenting with a delayed onset, more severe FNP, and worse facial nerve outcomes. Additionally, the clinical course of isolated FNP associated with COVID‐19 appears to differ from typical Bell’s palsy. Non‐GBS FNP patients had a shorter duration to complete recovery and a higher proportion of bilateral FNP compared to Bell’s palsy patients. This suggests that we may be observing an etiology different than Bell’s palsy patients with differing presentation and prognosis.

Patients diagnosed with GBS were on average older than non‐GBS patients and the duration from the onset of COVID‐19 symptoms to the manifestation of FNP differed considerably between the GBS and non‐GBS diagnosed subgroups. The most common treatments for non‐GBS patients consisted of steroids, antivirals, and antibiotics. Complete recovery of FNP in non‐GBS patients was achieved in over two thirds of patients within an average of under 3 weeks. In contrast, only 17% of GBS patients achieved complete recovery of FNP within an average of over a month.

Clinical Presentation

The initial COVID‐19 symptoms including cough, fever, and dyspnea can be challenging to interpret as they are similar to common upper respiratory tract infections. With the advent of COVID‐19, clinical suspicion of these symptoms has become increasingly recognized and should also be considered when taking a history from a patient presenting with acute FNP. In the context of known viral etiologies related to FNP, COVID‐19 infected patients presented differently. For example, when evaluating the non‐GBS patient category, most patients with FNP after COVID‐19 infection (70%) presented on average 9 days (1–20 days) after the onset of initial COVID‐19 symptom(s). In comparison, FNP secondary to Ramsay Hunt syndrome typically presents either before or concurrently with the typical manifestations including VZV blisters. 64 65

In terms of laterality, bilateral FNP is an extremely rare clinical manifestation of Bell’s palsy, accounting for only up to 2% of these patients. 66 67 68 69 In comparison, a larger proportion (12%) of the isolated FNP patients in this review presented with bilateral FNP. This may be explained by the potentially greater inflammatory impact of the COVID‐19 virus on the facial nerve that has been previously hypothesized. 6 In our study, approximately 75% of the GBS patients presented with bilateral FNP which was higher than non‐GBS patients. Unlike Bell’s palsy, GBS has systemic involvement, more severe symptoms, and highly variable clinical course and outcome. 70

Lastly, a small minority (11%) of the non‐GBS patients presented with FNP as either their presenting or sole symptom of COVID‐19 during an active infection. These findings highlight the importance of considering COVID‐19 infection in the differential diagnosis when evaluating patients with isolated FNP symptoms who may otherwise be asymptomatic. An RT‐PCR for COVID‐19 may be considered in an infectious work‐up of patients presenting with isolated FNP.

Treatments and Outcomes

The most common treatment for non‐GBS patients consisted of steroids, antivirals, and/or antibiotics. Twenty percent of patients had no treatment. According to the American Academy of Neurology (AAN) and the American Academy of Otolaryngology‐Head and Neck Surgery Foundation (AAO‐HNSF), the treatment of Bell’s palsy primarily focuses on the use of corticosteroids and advises against the routine use of antiviral therapy. 71 72 73 However, previous studies have shown that treatment of FNP from Bell’s palsy and RHS with acyclovir and prednisone leads to better outcomes. 74 75 Half of those treated with steroids and half of patients treated with antiviral therapy had complete recovery within 60 days. Among our non‐GBS patients, there were no differences in outcomes between prednisone monotherapy and the combination therapy with antivirals.

Our findings suggest that patients with GBS who develop FNP were more likely to develop severe presentations and were more prone to worse clinical outcomes. Patients presenting with FNP in the context of GBS were most treated with IVIG, followed by hydroxychloroquine, plasmapheresis, and/or steroids. The first line treatments for GBS are plasma exchange or IVIG therapy which should be initiated within 7 and 14 days of symptom onset, respectively, to hasten recovery. 76 In contrast, corticosteroids are not recommended for the treatment of GBS, as several clinical trials have shown no benefit in recovery outcomes compared to placebo. 77 This could explain why steroids were much less commonly used in our GBS patients compared to plasmapheresis and IVIG. Importantly, patients presenting with GBS and FNP were over three times less likely to have complete recovery of FNP compared to non‐GBS patients. This can be explained by the systemic involvement of GBS with more severe symptoms, and highly variable clinical course and outcome. 70

When comparing patients with Bell’s palsy, FNP associated with COVID‐19 infection appeared to have a shorter time to complete recovery. Complete recovery of FNP in non‐GBS patients was achieved in over two thirds of patients within almost 20 days with and without treatments. Previous studies on the natural history of Bell’s palsy have suggested that approximately 85% of patients begin to experience some recovery of their FNP within the first 3 weeks. 71 However, complete recovery of Bell’s palsy with steroid treatment is typically seen in 3–9 months and our study was limited in terms of follow up duration. 78 In our non‐GBS cohort, complete recovery was achieved in the majority (62%) within the first 2 months.

Although our study did not identify any significant predictors of FNP outcomes related to treatment for COVID‐19 patients, this is likely due to the limited sample size, and is an area for future research.

Etiology

Infectious etiology of FNP has a broad differential. Presumed culprits include HSV, VZV, EBV, and Borrelia burgdorferi. With the advent of COVID‐19, our results suggest that the etiology of FNP in non‐GBS COVID‐19 patients is potentially novel.

COVID‐19 has been hypothesized to cause neurologic damage by two distinct mechanisms: (1) dissemination to the central nervous system by hematogenous spread or trans‐neuronally via cranial nerves causing direct neuronal damage due to viral neurotropism and (2) neuronal damage secondary to an abnormal immune‐mediated response. 6 79 The first is thought to be responsible for cranial nerve manifestations (e.g., hypogeusia, hyposmia, headache, and vertigo), whereas the latter mechanism is believed to result in severe complications and contribute to the development of dysimmune neuropathies like GBS. 13 80

Our findings indicate that among the non‐GBS patients, a suggestion can be made of an association between COVID‐19 and a clinical manifestation of FNP, although no causation can be assumed. Although the acute onset and age distribution of the non‐GBS patients present similarly to Bell’s palsy, the differences in clinical presentations and outcomes should be considered. The non‐GBS subgroup had a relatively shorter duration to complete recovery and a higher proportion of bilateral FNP compared to Bell’s palsy patients. 69 78

This study is not without limitations. Firstly, a full infectious work‐up to rule out other potential infectious causes of FNP was done in only 41% patients, although it was non‐contributory except for one patient who also had an active concurrent EBV infection. Secondly, there was variability in the length of follow‐up with the majority being 60 days or less and thus long‐term outcomes data are limited. Since the full recovery of Bell’s palsy typically occurs within a year, this limitation may be underestimating the recovery in our patients. Furthermore, we did not discuss treatment specific outcomes as we were unable to control for multiple patient specific variables and concurrent treatments. Another important limitation is that case reports and case series are more likely to report severe manifestations of COVID‐19. Therefore, the patients included in our study may not represent the complete spectrum of FNP associated COVID‐19, and instead could underestimate the true prevalence of mild, undifferentiated, or undiagnosed cases. Additionally, the onset of FNP was determined relative to patient awareness of related COVID‐19 symptom(s) which may have been non‐specific and may not have been accurately reported. Finally, since the completion of our literature search in November 2021, subsequent omicron and delta variants may not have been adequately represented in our results. Despite these limitations, this study is the first systematic review on patients with COVID‐19 and FNP and may help advance knowledge and guide management of these patients.

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CONCLUSION

Although COVID‐19 symptoms are predominantly respiratory, emerging evidence has highlighted various neurologic manifestations associated with COVID‐19 infections. Our study highlights and delineates the presentations of FNP in the context of COVID‐19 for systemic conditions such as GBS as well as an isolated FNP. Systemic and isolated cases of FNP during COVID‐19 infections present and progress differently. Additionally, the clinical course of isolated FNP associated with COVID‐19 appears to differ from typical Bell’s palsy presentation and prognosis. This suggests that patients with COVID‐19 may have an atypical presentation of Bell’s palsy with a more severe initial presentation and a relatively better prognosis with higher propensity for complete recovery. This review suggests COVID‐19 infection may be associated with the development of a unique clinical manifestation of FNP. There is some literature associating FNP with COVID‐19, although a causal association cannot be definitively assumed. Our study may help future practitioners in identifying FNP as a possible sequela of COVID‐19 infection that may aid in the management of these patients.

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Supporting information

Table S1. Database Search Algorithm.

Table S2A. Case Reports Risk of Bias Assessment.

Table S2B. Case Series Risk of Bias Assessment.

Table S3. Study Demographics

Click here for additional data file.(93K, docx)

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Peripheral facial nerve palsy associated with COVID-19

Journal of NeuroVirology volume 26, pages941–944 (2020)Cite this article

Authors: Marco A. LimaMarcus Tulius T. SilvaCristiane N. SoaresRenanCoutinhoHenrique S. OliveiraLivia AfonsoOtávio EspíndolaAna Claudia Leite & Abelardo Araujo 

Abstract

COVID-19 pandemic revealed several neurological syndromes related to this infection. We describe the clinical, laboratory, and radiological features of eight patients with COVID-19 who developed peripheral facial palsy during infection. In three patients, facial palsy was the first symptom. Nerve damage resulted in mild dysfunction in five patients and moderate in three. SARS-Cov-2 was not detected in CSF by PCR in any of the samples. Seven out of eight patients were treated with steroids and all patients have complete or partial recovery of the symptoms. Peripheral facial palsy should be added to the spectrum of neurological manifestations associated with COVID-19.

Introduction

The ongoing COVID-19 pandemic has affected millions of people worldwide and revealed several neurological syndromes related to this infection. Anosmia/ageusia, encephalitis, encephalopathy, cerebrovascular complications, myelitis, and Guillain-Barré syndrome, among other neurological complications, occur in a significant proportion of patients (Ellul et al. 2020; Paterson et al. 2020).

Acute facial nerve palsy commonly occurs in clinical practice and is associated with considerable distress due to possible functional and esthetic sequelae (Jowett 2018). There are many potential mechanisms implicated in its occurrence, including viral infections. Herein, we review the clinical and laboratory features of eight patients with COVID-19 who developed peripheral facial palsy during the clinical course of the infection or as its first symptom.

Methods

Case series of eight patients seen from May to July 2020 with a diagnosis of COVID-19 based on positive SARS-CoV-2 RNA RT-qPCR in nasal and oropharyngeal swabs (Biomanguinhos kit (E+P1), FIOCRUZ, Brazil).

Data about the onset of facial palsy, associated clinical conditions, brain imaging, cerebrospinal fluid parameters, treatment, and outcome were recorded. Facial palsy was graded according to the House-Brackmann scale (House and Brackmann 1985). This study was approved by the Local Ethical Committee at INI/FIOCRUZ.

Results

Among the eight patients, seven were women. All had COVID-19 diagnosis based on positive SARS-CoV-2 RNA RT-qPCR in nasal and oropharyngeal swabs. The mean age was 36 years (range 25–50 years). In three patients, facial palsy was the first symptom of COVID-19, while in the remaining five, it appeared from 2 to 10 days after onset of other clinical manifestations. All patients had mild respiratory and systemic COVID-19 symptoms, and none required hospitalization. According to the House-Brackmann grading system, nerve damage resulted in mild (grade 2) dysfunction in five patients and moderate (grade 3) in three (Table 1). The neurological examination disclosed no abnormalities in all but one patient, who had an associated ipsilateral abducent nerve palsy. Deep tendon reflexes were preserved, and no sensory abnormalities were present. Six patients underwent lumbar puncture with normal opening pressure in all cases. CSF analysis showed no inflammatory changes except for a mild protein elevation in one patient (50 mg/dl) (Table 1). SARS-Cov-2 was not detected in CSF by PCR in any of the samples. Imaging (CT scan or MRI) was normal in seven patients. In one patient, MRI showed contrast enhancement in the distal intracanalicular portion in the tympanic and mastoid segments of the left facial nerve (Fig. 1).Table 1 Clinical and laboratory manifestations of COVID-19 patients with facial palsy

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figure 1
Fig. 1

Six out of seven patients were treated with oral steroids (prednisone 40–60 mg/day for 5–7 days) and one received intravenous methylprednisolone. One patient with mild manifestations received only supportive care (eye lubricant) with complete recovery 2 days later. Two patients received oral acyclovir concomitant to steroids due to possible Herpes simplex virus infection. Complete recovery occurred in five patients, while the other three still had some degree of facial weakness at the last follow-up 30 days after onset of neurological symptoms.

Discussion

Infections such as HSV-1, VZV, and Lyme disease are common causes of facial paralysis (Owusu et al. 2018). The rapid expansion of COVID-19 pandemics led to the development of a growing number of neurological syndromes. Our study shows that peripheral facial palsy can occur during the clinical course of COVID-19 or anticipate other typical manifestations such as fever and respiratory symptoms.

Interestingly, all but one of our patients were women. Idiopathic facial palsy does not have a gender preference (Katusic et al. 1986). Indeed, our sample is too small to assume any conclusion, and the two other cases of isolated facial palsy in association with COVID-19 described by Goh and Casas were men (Casas et al. 2020; Goh et al. 2020).

Most patients in this study had isolated facial palsy with mild or moderate dysfunction and no other neurological findings. Except for the two described above by Goh and Casas (Casas et al. 2020; Goh et al. 2020), in all other studies, facial paralysis in COVID-19 patients occurred unilaterally or bilaterally in association with other manifestations of Guillain-Barré syndrome (Manganotti et al. 2020; Ottaviani et al. 2020; Juliao Caamaño and Alonso Beato 2020; Paybast et al. 2020; Sancho-Saldaña et al. 2020; Bigaut et al. 2020).

CSF basic parameters (cellularity, protein, and glucose levels) are usually normal in patients with idiopathic facial paralysis as observed in our series (Bremell and Hagberg 2011). SARS-CoV2 was not detected in any five cases who underwent lumbar puncture, which is consistent with a recent study that failed to show viral RNA in the CSF of COVID-19 patients with different neurological syndromes (Espíndola et al. 2020).

Possible mechanisms related to nerve damage in idiopathic facial nerve paralysis include ischemia of vasa nervorum and demyelination induced by an inflammatory process (Zhang et al. 2020). Microthrombi and other vascular changes have been consistently reported in several postmortem studies (Silberzahn et al. 1988; Nunes Duarte-Neto et al. 2020) and may be implicated in the development of facial nerve ischemia in COVID-19 patients. Direct viral damage or an autoimmune reaction toward the nerve producing inflammation would be alternative or contributing mechanisms to dysfunction.

Supportive care and oral steroids are the mainstays of treatment (Sullivan et al. 2007). Our patients had complete recovery or significant improvement in few weeks after treatment as the patient reported by Casas et al. (2020), suggesting a good outcome when peripheral facial palsy occurs in association with COVID-19.

In conclusion, peripheral facial palsy should be added to the spectrum of neurological manifestations associated with COVID-19. Most patients had an uncomplicated course with good outcome, and SARS-CoV-2 RNA could not be detected in CSF of any patient.

References

Ocular Adverse Events After COVID-19 Vaccination

Authors: Xin Le Ng, MBBS, a Bjorn Kaijun Betzler, MBBS, b Ilaria Testi, MD, c Su Ling Ho, FRCS, a Melissa Tien, FRCOphth, a Wei Kiong Ngo, FRCOphth, a Manfred Zierhut, PhD, d Soon Phaik Chee, FRCSEd, e , f , g Vishali Gupta, PhD, h Carlos E Pavesio, FRCOphth, b Marc D. de Smet, PhD, i , j and Rupesh Agrawal, FRCS a , b , e , f , g , k Ocul Immunol Inflamm. 2021 : 1–9.

Published online 2021 Sep 24. doi: 10.1080/09273948.2021.1976221 PMCID: PMC8477588 PMID: 34559576

ABSTRACT

Purpose

The COVID-19 pandemic has galvanized the development of new vaccines at an unprecedented pace. Since the widespread implementation of vaccination campaigns, reports of ocular adverse effects after COVID-19 vaccinations have emerged. This review summarizes ocular adverse effects possibly associated with COVID-19 vaccination, and discusses their clinical characteristics and management.

Methods

Narrative Literature Review.

Results

Ocular adverse effects of COVID-19 vaccinations include facial nerve palsy, abducens nerve palsy, acute macular neuroretinopathy, central serous retinopathy, thrombosis, uveitis, multiple evanescent white dot syndrome, Vogt-Koyanagi-Harada disease reactivation, and new-onset Graves’ Disease. Studies in current literature are primarily retrospective case series or isolated case reports – these are inherently weak in establishing association or causality. Nevertheless, the described presentations resemble the reported ocular manifestations of the COVID-19 disease itself. Hence, we hypothesize that the human body’s immune response to COVID-19 vaccinations may be involved in the pathogenesis of the ocular adverse effects post-COVID-19 vaccination.

Conclusion

Ophthalmologists and generalists should be aware of the possible, albeit rare, ocular adverse effects after COVID-19 vaccination.

KEYWORDS: COVID-19, vaccination, ocular inflammation, adverse effects, uveitis

Historically, vaccines have been known to be associated with ocular phenomena. For example, vaccinations against influenza, yellow fever, hepatitis B, and Neisseria meningitidis have been associated with uveitis, acute idiopathic maculopathy, acute macular neuroretinopathy (AMN), Vogt-Koyanagi-Harada disease (VKH), and multiple evanescent white dot syndrome (MEWDS).1–7 The surge in the literature on COVID-19 and rapid development of vaccination regimens has produced reports on the ocular manifestations of COVID-19, as well as ocular adverse effects of COVID-19 vaccinations. Some of the reported ocular manifestations of COVID-19 infection include conjunctivitis, episcleritis, uveitis, vascular changes in the retina and cotton wool spots, optic neuritis, ocular motility deficits from cranial nerve palsies, and transient accommodation deficits.8–13

There are currently four types of COVID-19 vaccines. These include mRNA vaccines (BNT162b2, Pfizer-BioNTech14; mRNA-1273, Moderna15), protein subunit vaccines (NVX-CoV2373, Novavax16), vector vaccines (Ad26.COV2, Janssen Johnson & Johnson17; ChAdOx1 nCoV-19/ AZD1222, Oxford-AstraZeneca18), and whole virus vaccines (PiCoVacc, Sinovac19; BBIBP-CorV, Sinopharm20). While their respective trial reports on vaccine safety have shown that ocular adverse effects are rare, the possible manifestations are still a cause for concern, given the scale of the current vaccination campaign against COVID-19.

This review provides a comprehensive overview of COVID-19 vaccine-induced ocular adverse effects. A review of the incidence of such conditions is timely and would be beneficial to ophthalmologists and general physicians alike, in identifying patients who may be at a higher risk of ocular adverse events so that protocols for close monitoring of patients at risk can be designed and implemented.

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Methodology

For this narrative review, relevant publications were identified through a computerized database search of MEDLINE, EMBASE and Google Scholar. The search comprised the following keywords: ‘COVID,’ ‘COVID-19,ʹ ‘SARS-COV-2,ʹ ‘coronavirus,’ ‘vaccination,’ ‘ocular complications,’ ‘ocular manifestation,’ ‘thrombosis,’ ‘retinopathy,’ ‘maculopathy,’ ‘uveitis,’ ‘ocular inflammation.’ Search results were screened for relevance. References cited within the identified articles were used to further augment the search. This review encompassed an international search, but only articles published in English were used. We restricted our search to articles published within the past decade, up till August 21, 2021.

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Results

A total of 23 articles reported ocular findings associated with COVID-19 vaccinations (Table 1). Ocular complications were reported in 74 unique individuals – including facial nerve palsy/ Bell’s palsy, abducens nerve palsy, AMN, superior ophthalmic vein (SOV) thrombosis, corneal graft rejection, uveitis, central serous chorioretinopathy, VKH reactivation, and onset of Graves’ disease. The reported entities appear to overlap with the ocular manifestations of COVID-19 itself, suggesting a common pathway between virus and vaccine-mediated immune response in humans.

Table 1.

Summary of studies describing ocular adverse effects secondary to COVID-19 vaccination

StudySummaryVaccineDose InvolvedTime to onset of symptomsOcular Symptom and Number of Cases (n)
Bayas et al.21
Bilateral superior ophthalmic vein thrombosis, ischaemic stroke, and immune thrombocytopenia after ChAdOx1 nCoV-19 vaccination.
A case report of bilateral superior ophthalmic vein thrombosis post-vaccinationAZD1222110 daysConjunctival congestion, retroorbital pain, diplopia
n = 1
Bøhler et al.22
Acute macular neuroretinopathy following COVID-19 vaccination.
A case report of acute macular neuroretinopathy (AMN) post-vaccinationAZD122212 daysParacentral scotoma
n = 1
Book et al.23
Bilateral Acute Macular Neuroretinopathy After Vaccination Against SARS-CoV-2
A case report of Bilateral Acute Macular Neuroretinopathy post-vaccinationAZD122213 daysBilateral paracentral scotoma
n = 1
Collela et al.24
Bell’s palsy following COVID-19 vaccination
A case report of Bell’s Palsy post-vaccinationBNT162b215 daysLeft sided facial droop
n = 1
Crnej et al.25
Acute corneal endothelial graft rejection following COVID-19 vaccination
A case report of DMEK rejection post-vaccinationBNT162b217 daysSudden painless decrease of vision
n = 1
Elsheikh et al.26
Acute Uveitis following COVID-19 Vaccination
A case report of juvenile idiopathic arthritis-associated anterior uveitis post-vaccinationBBIBP-CorV25 daysBilateral blurred vision, photophobia
n = 1
Fowler et al.27
Acute-onset central serous retinopathy after immunization with COVID-19 mRNA vaccine.
A case report of acute-onset central serous retinopathy (CSR) post-vaccinationBNT162b213 daysBlurring of vision, metamorphopsia
n = 1
Goyal et al.28
Bilateral Multifocal Choroiditis following COVID-19 Vaccination
A case report of bilateral multifocal choroiditis post-vaccinationAZD122229 daysRight eye floater that progressed gradually from the periphery toward the center
n = 1
Mambretti et al.29
Acute Macular Neuroretinopathy following Coronavirus Disease 2019 Vaccination.
A case report of acute macular neuroretinopathy (AMN) post-vaccinationAZD122212 daysParacentral scotoma
n = 2
Michel et al.30
Acute Macular Neuroretinopathy After COVID-19 Vaccine.
A case report of acute macular neuroretinopathy (AMN) post-vaccinationAZD122212 daysCentral scotoma
n = 1
Mudie et al.31
Panuveitis following Vaccination for COVID-19.
A case report of panuveitis post-vaccinationBNT162b223 daysReduction in visual acuity, ocular pain, red eye, photophobia
n = 1
Ozonoff et al.32
Bell’s palsy and SARS-CoV-2 vaccine.
A case series of numerical imbalance in incidences of Bell’s palsy between vaccine and placebo arms during trialsBNT162b2, mRNA-1273NANAn = 7
Papasavvas et al.33
Reactivation of Vogt-Koyanagi-Harada disease under control for more than 6 years, following anti-SARS-CoV-2 vaccination.
A case report of reactivation of Vogt-Koyanagi-Harada disease post-vaccinationBNT162b226 weeksPhotophobia, ocular pain
n = 1
Phylactou et al.34
Characteristics of endothelial corneal transplant rejection following immunisation with SARS-CoV-2 messenger RNA vaccine.
A case report of Descemet membrane endothelial keratoplasty (DMEK) patients with graft rejection post-vaccinationBNT162b21, 27 days to 3 weeksBlurred vision, red eye, photophobia
n = 2
Rabinovitch et al.35
Uveitis following the BNT162b2 mRNA vaccination against SARS-CoV-2 infection
Multicentre, retrospective study describing vaccine-related uveitis and multiple evanescent white dot syndrome post-vaccinationBNT162b21, 21–30 daysBlurred vision, red eye, photophobia
n = 23
Ravichandran et al.36
Corneal graft rejection after COVID-19 vaccination.
A case report of PKP patient with graft rejection post-vaccinationAZD122213 weeksBlurred vision, red eye
n = 1
Renisi et al.37
Anterior uveitis onset after BNT162b2 vaccination
A case report of anterior uveitis post-vaccinationBNT162b2214 daysBlurred vision, red eye, photophobia
n = 1
Repajic et al.38
Bell’s Palsy after second dose of Pfizer COVID-19 vaccination in a patient with history of recurrent Bell’s palsy
A case report of Bell’s palsy post-vaccination. This patient had a history of 3 episodes of Bell’s palsyBNT162b2236 hFacial droop
n = 1
Reyes-Capo et al.39
Acute Abducens Nerve Palsy Following COVID-19 Vaccination.
A case report of isolated abducens nerve palsy post-vaccinationBNT162b212 daysPainless, horizontal, binocular diplopia
n = 1
Santovito et al.40
Acute reduction of visual acuity and visual field after Pfizer-BioNTech COVID-19 vaccine 2nd dose: a case report.
A case report of possible uveitis post-vaccinationBNT162b223 daysReduction in visual acuity, visual distortion
n = 1
Shemer et al.41
Association of COVID-19 Vaccination and Facial Nerve Palsy: A Case-Control Study
A case-control study of association between facial nerve palsy between vaccinated and unvaccinated groupsBNT162b21, 29–14 daysn = 21
Vera-Lastra et al.42
Two Cases of Graves’ Disease Following SARS-CoV-2 Vaccination: An Autoimmune/Inflammatory Syndrome Induced by Adjuvants.
A case report of Graves’ disease activation post-vaccinationBNT162b212–3 daysn = 2
Wasser et al.43
Keratoplasty Rejection After the BNT162b2 messenger RNA Vaccine.
A case report of penetrating keratoplasty (PKP) patients with graft rejection post-vaccinationBNT162b2113–14 daysBlurred vision, ocular discomfort, red eye
n = 2

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Facial Nerve Palsy

The Pfizer-BioNTech (BNT162b2)14 and Moderna (mRNA-1273)15 vaccine trials suggest an imbalance in the incidence of Bell’s palsy following vaccination compared with the placebo arm of each trial. Among 36,901 vaccine arm participants in combined data, there were seven Bell’s palsy cases (1:5272) compared with one Bell’s palsy case among placebo arm participants (1:36,938). The United States Food and Drug Administration (FDA) initially reported that the observed frequency of reported Bell’s palsy in the vaccine group was consistent with the expected background rate in the general population, providing no clear basis to conclude a causal relationship.44,45 Ozonoff et al.32 commented that such reporting was misconceived. Given the generally agreed incidence of Bell’s palsy at 15–30 cases per 100,000 person-years,46,47 the median 2-month observation period of the clinical trials translated to an observed incidence of 3.5–7 times higher in the vaccine arms than the general population. Cirillo et al.46 provided an alternative interpretation – given that safety data were collected for 2 months after the second, not the first dose, the observed incidence might be 1.5–3 times higher than the general population. Collela et al.24 and Repajic et al.38 provided detailed expositions of the signs and symptoms that led to a diagnosis of Bell’s palsy in COVID-19 BNT162b2 vaccine recipients. An Israeli case-control study41 found that 21 of 37 individuals (56.8%) with facial nerve palsy were recently vaccinated with the first or second dose of the BNT162b2 vaccine, compared with 44 of 74 (59.5%) in the control group. After adjustment for pre-existing immune- or inflammatory-related disorders, diabetes, and a previous episode of peripheral nerve palsy, odds ratio (OR) for exposure to the vaccine among cases was insignificant at 0.84 (95%CI 0.37–1.90, p-value = 0.67). Based on the OR from different studies, it is highly unlikely that Bell’s palsy is associated with COVID-19 vaccination and if at all, the pathophysiological process for facial nerve palsy post COVID-19 vaccination needs to be hypothesized and proven. While facial nerve palsy is a reported adverse event in other vaccinations,32 such as influenza and meningococcal conjugate vaccinations, mRNA-based vaccines might follow a different immune mechanism.

Abducens Nerve Palsy

A healthy 59-year-old female presented with isolated abducens nerve palsy following a febrile episode two days after receiving the BNT162b2 vaccine.39 No details on the persistence of the palsy were provided. Slit lamp, fundus examination, and non-contrast magnetic resonance imaging (MRI) of the brain and orbits were unremarkable.

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AMN

AMN is a rare condition characterized by macular reddish-brown, wedge-shaped lesions, the apices of which are often directed toward the fovea.48 This is often accompanied by paracentral scotomas and mild loss of vision at onset.48 Four studies22,23,29,30 reported cases of AMN. All patients were female and received the ChAdOx1 nCoV-19 vaccine. All were on oral contraceptive pills (OCP) and manifested symptoms two days after the first dose. Three reported fever, and one reported flu-like symptoms prior to the appearance of the scotoma. In two patients, the visual symptoms lasted <24 h. On optical coherence tomography (OCT), hyperreflectivity of the outer nuclear and plexiform layers was seen along with disruption of the ellipsoid zone. Subtle capillary dropout was also noted on OCT angiography.

AMN is a rare retinal disease, the pathophysiology of which is still unknown, although a microvascular abnormality in the deep capillary plexus of the retina is hypothesized.48,49 Of the AMN cases reviewed, all subjects were confounded by OCP usage. OCP usage has been associated with structural changes to the macula, retinal nerve fiber layer, and choroidal thickness50 and identified as a risk factor for AMN. However, the relative rarity of AMN and the temporal association between the vaccine administration and the onset of the disease should be taken into consideration. This is likely due to the presence of estrogen and progesterone receptors in ocular tissues of premenopausal women, including the choroid and retina.51 It has been postulated that concurrent OCP usage may increase the susceptibility of ocular tissues to AMN.48 Whether the potential thrombogenic role of COVID-19 vaccination played an additional role in the AMN pathogenesis of these patients has yet to be established.

Central Serous Chorioretinopathy

A 33-year-old male presented with blurring of vision and metamorphopsia 69 h after receiving the first dose of BNT162b2 and was diagnosed with central serous chorioretinopathy.27 He had a previous ocular history of mild hyperopic refractive error. Dilated fundus examination revealed foveal reflex loss and a swollen macula without haemorrhage. OCT was performed, which showed macular serous detachment of the neurosensory retina, with OCT angiography showing general attenuation of choriocapillaris flow signal in the area of serous retinal detachment. Fundus fluorescein angiography showed point leakage. The patient was prescribed spironolactone, and all symptoms eventually resolved on follow up.

Ophthalmic Vein Thrombosis

Regarding post-vaccination thrombosis, rare cases of post vaccination immune thrombotic thrombocytopenia and cerebral venous sinus thrombosis (CVST) after administration of the adenovirus vector vaccines ChAdOx1 nCoV-19 and Ad26.COV2 have been well described.52–57 Anatomically, CVST post-COVID-19 vaccination has been reported to occur in virtually all the dural venous sinuses,52 and a majority of patients are females.52 This section focuses on superior ophthalmic vein thrombosis, as reported in two isolated cases.21,58 Both patients received the ChAdOx1 nCoV-19 vaccine. Panovska-Stavridis et al.58 describe a 29-year-old female who presented with severe headache, orbital swelling with proptosis, limited ocular motility, vertical diplopia, and reduced visual acuity 10 days after the first dose. Initial findings showed thrombocytopenia of 18 × 109/L and high D-dimer levels of 35712 μg/L. Antibody screening showed high levels of antibodies against Heparin/Platelet Factor 4 complex. Contrast-enhanced MRI demonstrated central filling defects and a widened and enhanced left SOV, revealing thrombosis. The patient was treated with intravenous immunoglobulin (IVIG) for two days followed with tapered oral prednisolone. All symptoms resolved within 5 days. Bayas et al.21 described a 55-year-old female with bilateral SOV thrombosis on post-dose day 10, also definitively diagnosed on MRI showing filling defects and T2 enhancement of both SOV. Laboratory investigations supported a diagnosis of secondary immune thrombocytopenia. Despite therapeutic heparinization, the patient developed an ischemic stroke in the left parietal lobe, middle cerebral artery region on post-dose day 18. Healthcare professionals should be on the alert for possible cases of thromboembolism – CVST, pulmonary, deep vein thrombosis, or in the ophthalmic context – SOV thrombosis – after ChAdOx1 nCoV-19 or Ad26.COV2 administration.

Corneal Graft Rejection

Four articles described corneal graft rejection soon after receiving a COVID-19 vaccination.25,34,36,43 Phylactou et al.34 reported two cases of allograft rejection following Descemet’s membrane endothelial keratoplasty (DMEK); both were female. A 66-year-old woman received the BNT162b2 vaccine 14 days after grafting and developed endothelial graft rejection 7 days later (day 21 post-transplant). She had a history of well-controlled human immunodeficiency virus infection with undetectable viral load. The other case, an 83-year-old woman, underwent DMEK 6 years before BNT162b2 administration. She developed symptoms 3 weeks after the second dose. For both DMEK cases, slit lamp examination and anterior segment optical coherence tomography (OCT) revealed moderate conjunctival injection, diffuse corneal oedema, and fine keratic precipitates limited to the donor endothelium with anterior chamber cells. Crnej et al.25 reported the case of a 71-year old male that presented with acute endothelial rejection 7 days after receiving the first dose of BNT162b2, 5 months after DMEK surgery. Topical dexamethasone 1 mg/mL every two hours was initiated. BCVA improved to 20/25 with a clear cornea one week later. The patient opted to receive his second dose after being counselled for the possible association between the first dose of vaccination and the acute transplant rejection. The graft remained clear, and visual acuity remained stable 3 weeks after the second dose. Rejections were also reported following three penetrating keratoplasty (PKP) cases36,43; all three were male; 1 case had a previous re-graft. Two of the PKP rejections manifested 13 to 14 days after receiving the first dose43 of the vaccine, while the third occurred after 21 days, also from the first dose.36

Regarding corneal graft rejection, any systemic immune dysregulation may compromise corneal ocular immune privilege and increase the patient’s susceptibility for rejection.59There is a report about acute corneal endothelial graft rejection with coinciding COVID-19 infection.60 Inflammation in COVID-19 patients is characterized by increased tumor necrosis factor–α (TNF–α) and interleukin-6 (IL-6) production.61 Cells of the innate immune system can invade the cornea and result in the up regulation of cytokines (including TNF–α, chemokines) and other pro-inflammatory molecules, which can result in rejection of the corneal transplants. With activation of the immune system post-vaccination, these mechanisms may contribute to vaccine-related corneal graft rejection. Reports on graft rejection after other viral vaccinations are scarce.62–64

New Onset Uveitis

We identified five case reports26,28,31,37,40 and one multicenter, retrospective case series35 describing uveitis after COVID-19 vaccination. In one case report,26 an 18-year-old female with a history of antinuclear antibody (ANA) positive oligoarticular juvenile idiopathic arthritis (JIA) presented with bilateral anterior uveitis 5 days after the second dose of BBIBP-CorV. HLA-B27 testing returned negative.

She was started on topical prednisolone acetate 1% every 2 h and cyclopentolate hydrochloride three times daily, with complete resolution and bilateral 6/6 visual acuity by 6 weeks. Goyal et al.28 described bilateral choroiditis in a 34-year-old male 9 days after the second dose of AZD1222. The patient presented with a right eye floater that rapidly progressed to severe visual loss within 12 hours. OCT revealed massive subretinal fluid involving the macula in the right eye. The left eye had milder subretinal fluid not involving the macula. B-scan showed bilateral choroidal thickening. He was started on oral prednisolone 1 mg/kg/day. Visual acuity was reinstated to 6/6 bilaterally in eleven days. In the remaining four articles, all subjects received the BNT162b2 vaccine. Santovito et al.40 described a male patient with a SARS-COV-2 infection several months earlier who developed transient visual field loss 3 days after a first dose of BNT162b2. The visual acuity deficit lasted less than a day and was associated with a plethora of systemic nonspecific symptoms, such as unilateral headache, nausea, asthenia, and mild confusion. No further investigations were performed. Mudie et al.31 described a female subject who developed panuveitis three days after the second dose. Her vision improved on a tapering dose of 50 mg/day of oral prednisone and two hourly difluprednate lasting three weeks. At the end of three weeks, there was recurrence of choroidal thickening and systemic corticosteroid therapy was recommenced. OCT showed vitreous debris, retinal and choroidal thickening. Fluorescein angiography (FA) revealed mild peripheral vascular leakage. Rabinovitch et al.35 described 21 cases of uveitis in Israel following COVID-19 vaccination. 8 and 13 cases occurred after the first and second BNT162b2 doses respectively. There were 19 patients with anterior uveitis whereas two patients were diagnosed to have multiple evanescent white dot syndrome (MEWDS) (after receiving the initial diagnosis of anterior uveitis). MEWDS is a rare self-limiting condition of the retinal pigment epithelium (RPE) or outer retina,65 following the second vaccination. MEWDS cases were not treated. Mean time between vaccination to uveitis onset was 7.5 ± 7.3 days (1–30 days). At final follow-up, complete resolution was achieved in all but two eyes, which showed significant improvement. One case of severe anterior uveitis developed vitritis and macular edema following second vaccination, which needed and completely resolved following intravitreal dexamethasone.35

VKH Reactivation

One article by Papasavvas et al. was identified.33 The reported subject was a woman with a pre-existing diagnosis of VKH well controlled for the past six years. The initial onset of VKH was severe, necessitating infliximab infusions which were continued as regular maintenance therapy. She manifested a severe reactivation of VKH 6 weeks after receiving the second dose of the BNT162b2 vaccine. She had received infliximab infusions 3.5 weeks before the first vaccine dose and 7.5 weeks before the second vaccine dose.33 Slit-lamp examination showed anterior chamber inflammation with mutton-fat keratic precipitates, and OCT was performed, revealing retinal folds, subretinal fluid and increased choroidal thickness. Oral corticosteroids were initiated, alongside infliximab therapy, with the disease reactivation brought under control. However, as the VKH reactivation was reported six weeks after receiving the second dose of vaccination, it is difficult to establish a temporal association between COVID-19 vaccination and VKH reactivation based on this single case report.

Graves’ Disease

Onset of Graves’ disease (GD) in two subjects was reported a few days after the first dose of BNT162b2.42 One patient had suffered a prior COVID-19 infection and a history pulmonary arterial hypertension. Both were newly diagnosed with GD on the manifestation of symptoms. Both received a dose of the BNT162b2 vaccine and reported symptoms 2–3 days after. No description of ocular symptoms or ophthalmic investigations were included in the study. The study found the subjects’ presentation to fit the diagnostic criteria for autoimmune/inflammatory syndrome induced by adjuvants (ASIA),66 also known as Shoenfeld’s Syndrome. As Graves’ disease is known to involve orbits and/or ocular surface, we have included this two cases in this comprehensive review even though the reported cases did not had any ocular manifestations at time of presentation.

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Discussion

At present, given the nascent nature of COVID-19 vaccines and evolving data on their adverse effects, it is imperative to emphasize that no causality can be established from this review. Furthermore, of the published cases with clear ocular pathology demonstrated on examination and investigation, most recovered well with swift initiation of treatment. It is important to remember the remarkably low incidence of adverse events related to the vaccine considering the massive rollout campaign across the world. To date, there is no evidence to suggest that individuals should avoid getting vaccinated for ophthalmic-related reasons.

Most of the reviewed literature includes case reports and series, and there are limits to the detail provided regarding ophthalmic assessment, treatment initiated, visual outcome and of underreporting of cases. Furthermore, there is heterogeneity in terms of investigations performed, affecting analysis of the cases. Given that vaccine induced ocular phenomena have been established with a multitude of other vaccines, that COVID-19 vaccinations are not exempt is unsurprising. There remains a larger question of elucidating the mechanisms involved in a maladaptive immune response and identifying the susceptible individuals for closer follow up.

Vaccinations in the autoimmune population decreases the burden of infection. To boost vaccine efficacy, adjuvants are often added to potentiate their effect on the innate and adaptive immune systems. While generally safe and effective, in a fraction of subjects (perhaps genetically or otherwise predisposed), the administration of adjuvants can lead to an autoimmune or inflammatory syndrome.52 The adjuvants included in COVID-19 mRNA vaccines stimulate innate immunity through endosolic or cytoplasmic nucleic acid receptors.67 Several autoimmune diseases, particularly connective tissues diseases are associated with an altered nucleic acid metabolism and processing which may trigger an immune response following immunization.68,69

The consequences of maladaptive immune response in those with autoimmune disease resulting in reactivation of disease should be considered. It is also essential to establish the response of autoimmune disease patients to vaccines and if the response is suboptimal in this population. This would have far-reaching consequences on future development of vaccines and risk-stratification of at-risk groups. Leibowitz et al.70 reviewed evidence that suggests uveitis and autoimmune diseases have a systemic overlap, and the development of uveitis may represent an undiagnosed autoimmune condition. There may thus be a role for further workup for more widespread inflammatory disease in individuals who develop ocular inflammatory events following COVID vaccination.

Comparative models for reactivation of autoimmune diseases post-vaccination have not demonstrated an increased risk in reactivation following vaccination for other diseases.71 Regarding the COVID-19 vaccine, Achiron et al.85 found no increase in relapse activity in multiple sclerosis (MS) patients in an observational study. In fact, the recommendations provided were to vaccinate MS patients to alleviate the disease burden of COVID-19.

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Conclusions

The current literature shows substantial overlap between the ocular adverse effects of COVID-19 infection and COVID-19 vaccination. Reports on such adverse effects are rare, and further longitudinal, multicenter studies are required to prove such associations, if any. It may be useful to identify the high risk characteristics for the patients developing ocular adverse events in response to COVID-19 infection or vaccination. As COVID-19 gradually becomes an endemic disease, a dedicated international registry for compiling of rare ocular adverse effects post COVID-19 vaccination could facilitate our understanding of the subject. Such cases can be retrospectively reviewed or prospectively followed-up.

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Bell’s Palsy as a Late Neurologic Manifestation of COVID-19 Infection

Authors: Ibiyemi O. OkeOlubunmi O. OladunjoyeAdeolu O. OladunjoyeAnish PaudelRyan Zimmerman

Abstract

Bell’s palsy is acute peripheral facial nerve palsy; its cause is often unknown but it can be triggered by acute viral infection. Coronavirus disease 2019 (COVID-19) infection commonly presents with respiratory symptoms, but neurologic complications have been reported. A few studies have reported the occurrence of facial nerve palsy during the COVID-19 pandemic. We present a case of Bell’s palsy in a 36-year-old man with COVID-19 infection and a past medical history of nephrolithiasis. He presented to the emergency room with a day history of sudden right facial weakness and difficulty closing his right eye four weeks following a diagnosis of COVID-19 infection. Physical examination revealed right lower motor neuron facial nerve palsy (House-Brackmann grade IV). Serologic screen for Lyme disease, human immunodeficiency virus (HIV), and herpes simplex virus (HSV) 1 and 2 were negative for acute infection; however, neuroimaging with MRI confirmed Bell’s palsy. He made remarkable improvement following treatment with a course of valacyclovir and methylprednisolone. This case adds to the growing body of literature on neurological complications that should be considered when managing patients with COVID-19 infection.

Introduction

Bell’s palsy is an acute peripheral lower motor neuron (LMN) facial nerve palsy leading to weakness on one side of the face without any other neurologic abnormalities on examination. The cause is often unknown; however, herpes simplex virus isoform 1 (HSV 1) and/or herpes zoster virus (HZV) reactivation is thought to be the most likely cause [1]. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the novel virus that causes coronavirus disease 2019 (COVID-19). It was first identified in Wuhan, a city in Hubei province of China, in December 2019.

There are a few theories on the neuropathogenesis of COVID-19, which include the binding of coronavirus to angiotensin-converting enzyme 2 (ACE2) receptors, which are widely distributed on glial cells and neurons [2,3]. Dubé et al. postulated in their study with animal models that there is axonal transport of human coronavirus (HCoV) OC43 protein into the nervous system [4]. These two mechanisms may lead to nerve damage through direct injury, autoimmunity, and ischemia of the vasa nervorum or inflammatory demyelination [5,6].

Facial nerve palsy may be the first presentation of COVID-19 and it may occur within a few days of its diagnosis [7-13]. We present a patient with a unilateral LMN facial nerve palsy four weeks after a diagnosis of COVID-19 infection.

For More Information: https://www.cureus.com/articles/54173-bells-palsy-as-a-late-neurologic-manifestation-of-covid-19-infection