Abstract

Peripheral facial paralysis (PFP) has been shown to be a neurological manifestation of COVID-19. The current study presents two cases of PFP after COVID-19, along with a rapid review of known cases in the literature. Both case reports were conducted following CARE guidelines. We also performed a systematic review of PFP cases temporally related to COVID-19 using PubMed, Embase, and Cochrane Library databases on August 30, 2021, using a rapid review methodology. The two patients experienced PFP 102 and 110 days after COVID-19 symptom onset. SARS-CoV-2 RNA was detected in nasal samples through reverse-transcription real-time polymerase chain reaction (RT-qPCR) testing. Anosmia was the only other neurological manifestation. PFP was treated with steroids in both cases, with complete subsequent recovery. In the rapid review, we identified 764 articles and included 43 studies. From those, 128 patients with PFP were analyzed, of whom 42.1% (54/128) were male, 39.06% (50/128) female, and in 23 cases the gender was not reported. The age range was 18 to 59 (54.68%). The median time between COVID-19 and PFP was three days (ranging from the first symptom of COVID-19 to 40 days after the acute phase of infection). Late PFP associated with COVID-19 presents mild symptoms and improves with time, with no identified predictors. Late PFP should be added to the spectrum of neurological manifestations associated with the long-term effects of SARS-CoV-2 infection as a post COVID-19 condition.

Keywords:
SARS-CoV-2 infection; Peripheral facial paralysis; Post-COVID; Neurological manifestation

1. Background

The COVID-19 pandemic has affected millions of people and threatened global public health [11. P.A.H. Organization (2021) Cumulative confirmed and probable COVID-19 cases reportedly by Countries and Territories in the Region of the Americas. https://ais.paho.org/phip/viz/COVID19Table.asp, p 9.
https://ais.paho.org/phip/viz/COVID19Tab... , 22. Pascoal DB, Carvalho ACS, Mata LELFS, Lopes TP, Lopes LP, Cruz CM. Síndrome Respiratória Aguda: Uma resposta imunológica exacerbada ao COVID19. BJHR. 2020;3(2):2978-94.]. After months of the virus spreading, cases of post-COVID-19 syndrome began to emerge, characterized by signs and symptoms that develop during or after infection, continue for more than 12 weeks, and cannot be explained by any alternative diagnosis. Post-COVID-19 conditions are a wide range of new, returning, or ongoing health problems that people experience four or more weeks after being infected with the COVID-19 virus. Syndromes of post-viral manifestations have previously been reported in other pandemic events, such as severe acute respiratory syndrome (SARS) [33. Augustin M, Schommers P, Stecher M, Dewald F, Gieselmann L, Gruell H. Post-COVID syndrome in non-hospitalised patients with COVID-19: A longitudinal prospective cohort study. Lancet Reg Health Eur. 2021 Jul 1;6:100122.].

COVID-19 is a systemic disease that predominantly affects the respiratory system [44. Lago VC, Prudente RA, Luzia DA, Franco ET, Cezare TJ, Peralta A, Ferreira EVM, Albuquerque ALP, Okoshi MP, Baldi BG, Tanni SE. Persistent interstitial lung abnormalities in post-COVID-19 patients: a case series. J Venom Anim Toxins incl Trop Dis. 2021 Apr 14;27:e20200157. doi: 10.1590/1678-9199-JVATITD-2020-0157.
https://doi.org/10.1590/1678-9199-JVATIT... ]. However, neurological changes may result from systemic complications of the disease, the direct effect of the virus on neurons, or an inflammation of the nervous system [55. Ellul MA, Benjamin L, Singh B, Lant S, Michael BD, Easton A, Kneen R, Defres S, Sejvar J, Solomon T. Neurological associations of COVID-19. Lancet Neurol. 2020;19(9):767-83.]. It is known that the SARS-CoV-2 infection is related to encephalopathies, central nervous system inflammatory syndromes, ischemic stroke, and peripheral neurological disorders; this relationship continues even after the acute phase of COVID-19 [66. Paterson RW, Brown RL, Benjamin L, Nortley R, Wiethoff S, Bharucha T, Jayaseelan DL, Kumar G, Raftopoulos RE, Zambreanu L, Vivekanandam V, Khoo A, Geraldes R, Chinthapalli K, Boyd E, Tuzlali H, Price G, Christofi G, Morrow J, McNamara P, McLoughlin B, Lim ST, Mehta PR, Levee V, Keddie S, Yong W, Trip SA, Foulkes AJM, Hotton G, Miller TD, Everitt AD, Carswell C, Davies NWS, Yoong M, Attwell D, Sreedharan J, Silber E, Schott JM, Chandratheva A, Perry RJ, Simister R, Checkley A, Longley N, Farmer SF, Carletti F, Houlihan C, Thom M, Lunn MP, Spillane J, Howard R, Vincent A, Werring DJ, Hoskote C, Jäger HR, Manji H, Zandi MS. The emerging spectrum of COVID-19 neurology: Clinical, radiological and laboratory findings. Brain. 2020 Oct 1;143(10):3104-20., 77. Guerrero J, Barragán L, Martínez J, Montoya J, Peña A, Mejía F Sobrino, Tovar-Spinoza Z, Ghotme K. Central and peripheral nervous system involvement by COVID-19: A systematic review of the pathophysiology, clinical manifestations, neuropathology, neuroimaging, electrophysiology, and cerebrospinal fluid findings. BMC Infect Dis. 2021 Jun 2;21(1):515.]. Peripheral facial paralysis (PFP) occurs when there is a dysfunction of the facial nerve, usually affected in an inflammatory way, resulting in total or partial paralysis of facial movement. It is characterized by the involvement of the upper and lower areas of the face, which differentiates it from central peripheral paralysis, which only affects the lower portion [88. Pons Y, Ukkola-Pons E, Ballivet de Régloix S, Champagne C, Raynal M, Lepage P, Kossowski M. Peripheral facial nerve palsy. J Fr Ophtalmol. 2013;36:548-53.]. It can be primarily referred to as Bell’s palsy, with an incidence rate of 15 to 30 cases per 100,000 inhabitants [99. Ozonoff A, Nanishi E, Levy O. Bell’s palsy and SARS-CoV-2 vaccines. Lancet Infect Dis. 2021;21:450-2.] or secondary, caused by metabolic, cerebrovascular, and mainly infectious factors [1010. Rivkees SA, Carlson LL, Reppert SM. Guanine nucleotide-binding protein regulation of melatonin receptors in lizard brain. Proc Natl Acad Sci U S A. 1989 May;86:3882-6. ].

This type of paralysis has been associated with viral infections, mainly herpes virus [8]. More recently, the association of PFP with SARS-CoV-2 has been reported [5, 1111. Homma Y, Watanabe M, Inoue K, Moritaka T. Coronavirus disease-19 pneumonia with facial nerve palsy and olfactory disturbance. Intern Med. 2020 Jul 15;59(14):1773-5.-1313. Derollez C, Alberto T, Leroi I, Mackowiak MA, Chen Y. Facial nerve palsy: An atypical clinical manifestation of COVID-19 infection in a family cluster. Eur J Neurol. 2020 Dec;27(12):2670-2.]. The diagnosis is made by observing the signs and symptoms. It is not necessary to employ imaging devices because, in this case, the benefits do not outweigh the harm when performing these tests [1414. Baugh RF, Basura GJ, Ishii LE, Schwartz SR, Drumheller CM, Burkholder R, Deckard NA, Dawson C, Driscoll C, Gillespie MB, Gurgel RK, Halperin J, Khalid AN, Kumar KA, Micco A, Munsell D, Rosenbaum S, Vaughan W. Clinical practice guideline: Bell’s palsy. Otolaryngol Head Neck Surg. 2013Nov;149(3 Suppl):S1-27.].

In the present study, we report two cases of late PFP that occurred after COVID-19 in healthcare professionals, along with results of a review of the current literature evaluating PFP patients’ demographics, clinical characteristics, treatment, and outcomes of COVID-19.

2. Methods

The CARE guidelines [1515. Case Report Guidelines CARE [internet]. Checklist of information to include when writing a case report. [cited 2022 Jun 2]. Available from: Available from: https://www.care-statement.org/checklist .
https://www.care-statement.org/checklist... ] were used in the present case reports. Patients provided informed consent for publication of the cases, and the project was approved by the Institutional Review Board of Federal University de Mato Grosso do Sul, Brazil (protocol number 4.754.351).

2.1. Literature search strategy

A rapid systematic review was conducted, as recommended by Habby et al. [1616. Haby MM, Chapman E, Clark R, Barreto J, Reveiz L, Lavis JN. What are the best methodologies for rapid reviews of the research evidence for evidence-informed decision making in health policy and practice: A rapid review. Health Res Policy Syst. 2016 Nov 25;14|(1):83.]. The searches were conducted on PubMed, Embase, and Cochrane Library on August 30, 2021. The rapid review protocol was registered under number 242075 on PROSPERO (International Prospective Register of Systematic Reviews). The search strategy consisted of different combinations of the following search terms: (“COVID-19” OR “SARS-CoV-2”) AND (“Bell Palsy” [MeSH Terms] OR “Facial Paralysis”). The review did not have date or language restrictions. The articles in which PFP was characterized as Guillain-Barré syndrome (GBS) were excluded. The complete search strategies can be found in ^{Additional file 1}Additional file 1Systematic review search strategy.

Additional file 1. Systematic review search strategy.

2.2. Data extraction

One reviewer conducted the screening by titles, abstracts, and descriptors to identify articles for analysis. A second reviewer screened all excluded abstracts, and any conflicts that arose were resolved. Data extraction was done by one reviewer and checked (“checked” value = “1”) for correctness and completeness by a second reviewer. A table was used to characterize the articles using the following information: article identification (by year, study site, and authors) and methodological profile of the article. When available, individuals’ data were included: patient demographics (age, gender, number of evaluated subjects, differential diagnosis, and probable diagnosis) and country of study origin. When the data were not available in the articles, they were requested from the author.

2.3. Statistical analyses

Descriptive analysis is expressed as frequencies and percentages for categorical variables and median and range for continuous variables. We present the results without meta-analysis due to the small numbers of studies currently available, considerable heterogeneity across studies and the high risk at bias that. Otherwise, the meta-analysis would produce a seemingly more accurate estimate than the underlying evidence is able to provide at this point in time.

2.4. Risk of bias assessment

Risk of bias assessment was carried out by one reviewer using the guidelines [1515. Case Report Guidelines CARE [internet]. Checklist of information to include when writing a case report. [cited 2022 Jun 2]. Available from: Available from: https://www.care-statement.org/checklist .
https://www.care-statement.org/checklist... ] recommended by the Joanna Briggs Institute. Full verification of all judgments was performed by a second reviewer.

3. Results

Our search yielded 127 cases of PFP after COVID-19 in 43 studies. Most of the cases were reported in Turkey (5.46%) and the USA (5.46%), followed by Spain (4.68%) and France (3.12%). Hospitals were the primary study settings in 22.65%. Males accounted for 42.19% of cases. For 23 cases, the gender of the patient was not reported. The youngest patient was 15 months old, and the oldest one was 90 years old. One patient was primigravida, at 39 weeks’ gestation (Table 1).

Physical therapy based on facial exercises, ocular hydration and eye protection were indicated as non-drug treatment [1717. Casas E, Barbosa A, Rubio-García E, Cebrián J, Díaz-Pérez C, de la Fuente E, Vivancos J, López-Manzanares L. Isolated peripheral facial paralysis in a patient with COVID-19. Rev Neurol. 2020 Jul 1;71(1):40-1., 1818. García Ochoa-Fernández EG, Víllora-Morcillo N, Táboas-Pereira MA. Peripheral facial palsy in a paediatric patient with no risk factors within the context of infection by SARS-CoV-2. Rev Neurol. 2021 Mar 1;72(5):177-8., 3232. Kumar V, Narayanan P, Shetty S, Mohammed AP. Lower motor neuron facial palsy in a postnatal mother with COVID-19. BMJ Case Rep. 2021 Mar 1;14(3):10-2., 3333. Neo WL, Ng JCF, Iyer NG. The great pretender-Bell’s palsy secondary to SARS-CoV-2? Clin Case Rep. 2021Feb 12;9(3):1175-77., 5555. Figueiredo R, Falcão V, Pinto MJ, Ramalho C. Peripheral facial paralysis as presenting symptom of COVID-19 in a pregnant woman. BMJ Case Rep. 2020 Aug 11;13(8):13-5. ].

Three papers described the occurrence of Bell’s palsy in patients more than 30 days from their COVID-19 diagnosis [1919. Doblan A, Kaplama ME, Ak S, Basmacı N, Tarini EZ, Göktaş ŞE, Güler S, Müderris T. Cranial nerve involvement in COVID-19. Am J Otolaryngol. 2021 Sep-Oct;42(5):102999., 3939. Koh JS, De Silva DA, Quek AML, Chiew HJ, Tu, TM, Seet CYH, Hoe RHM, Saini M, Hui ACF, Angon J, Ker JR, Yong MH, Goh Y, Yu WY, Lim TCC, Tan BYQ, Ng KWP, Yeo LLL, Pang YZ, Prakash KM, Ahmad A, Thomas T, Lye DCB, Tan K, Umapathi T. Neurology of COVID-19 in Singapore. J Neurol Sci. 2020 Nov 15;418:117118., 4444. Kerstens J, Deschuytere L, Schotsmans K, Maréchal E. Bilateral peripheral facial palsy following asymptomatic COVID-19 infection: a case report. Acta Neurol Belg. 2021;121(3):815-6.]. Two articles were not included in the median calculation as they did not report this result. In the aforementioned two articles, the mean time between COVID-19 and PFP ranged from 7 to 12 days for three patients [4747. Egilmez OK, Gündoğan ME, Yılmaz MS, Güven M. Can COVID-19 cause peripheral facial nerve palsy? SN Compr Clin Med. 2021;3(8):1707-13.] and from 2 to 10 days in five patients [3838. Lima MA, Silva MTT, Soares CN, Coutinho R, Oliveira HS, Afonso L, Espíndola O, Leite AC, Araujo A. Peripheral facial nerve palsy associated with COVID-19. J Neurovirol. 2020 Dec;26(6):941-4.]. In a study reporting 21 cases of nerve facialis [1919. Doblan A, Kaplama ME, Ak S, Basmacı N, Tarini EZ, Göktaş ŞE, Güler S, Müderris T. Cranial nerve involvement in COVID-19. Am J Otolaryngol. 2021 Sep-Oct;42(5):102999.], some patients presented associated diseases such as hypertension, diabetes mellitus, cardiac diseases, asthma, and Behçet’s disease, but the study did not report the distribution of these diagnoses. One patient was empirically treated with doxycycline for suspected borreliosis [3434. Dahl EH, Mosevoll KA, Cramariuc D, Vedeler CA, Blomberg B. COVID-19 myocarditis and postinfection Bell’s palsy. BMJ Case Rep. 2021 Jan 11;14(1):e240095.]. The other treatments as well as clinical features of patients with PFP after COVID-19 are presented in Table 2. In 38 (29.68%) cases of PFP, the information regarding the recovery was not described and, in 35 (27.35%) cases patients did not recover.

4. Case Report 1

A female patient (37 years old; a resident of Campo Grande, MS, Brazil; married; nursing technician; brown) started experiencing a headache and runny nose on September 16, 2020 and developed diarrhea, myalgia, anosmia, and adynamia. The patient underwent oro-nasopharyngeal swab sample collection on September 18 for an RT-qPCR test using the Allplex 2019-nCoV real-time RT-qPCR kit (Seegene, Seoul, Korea). This multiplex assay uses oligonucleotides for the RdRP-gene (RNA-dependent RNA polymerase), N-gene (nucleocapsid), and E-gene (envelope) as viral targets, and RNase P-gene (ribonuclease P) as the internal control. CT values ≤ 38 were considered positive. CT values were 26 for E-gene, 28 for RdRP-gene, 36 for N-gene, and 26 for RNase P-gene, confirming the positive result for SARS-CoV-2 infection. A serology for the detection of anti-SARS-CoV-2 IgG antibodies by CLIA (Abbott) was performed on September 30, 2020 with a positive result.

There was a progressive regression of symptoms and, on September 25, 2020, she became asymptomatic. One hundred and ten days after the onset of symptoms of COVID-19, the patient presented severe squeezing pain in the left ear for six hours, with an intensity of 10/10, which radiated to the temporal and zygomatic regions. The pain ceased with the use of dipyrone (the patient could not recall the dosage). The next morning, she noticed lip rhyme deviation, went to an emergency care unit close to her home, and received a clinical diagnosis of Bell’s palsy on the left side. She had no history of previous facial paralysis, labial or genital herpes, or other comorbidities. According to the House-Brackmann classification system, the damage resulted in moderately severe dysfunction in the patient (Grade IV).

The following drugs were prescribed orally: acyclovir 400 mg every four hours for 10 days; prednisone 60 mg for the first five days; prednisone 30 mg for the final five days; and prednisone 15 mg for five days. The patient underwent facial physiotherapy, with progressive improvement in her condition. Symptoms ceased in 15 days. The following laboratory tests were performed: serology for HIV (non-reactive), brucellosis 1^st and 2^nd samples (non- reactive), cytomegalovirus IgG (reactive) and IgM (non- reactive), Lyme IgG (non- reactive), and Lyme IgM (non- reactive). No imaging exams were performed.

5. Case Report 2

A female patient (39 years old; resident of Campo Grande, MS, Brazil, for 28 years; married; nurse; white) received a confirmed diagnosis of SARS-CoV-2 infection on September 19, 2020 through a real-time RT-qPCR test, performed for infection surveillance. The Allplex 2019-nCoV real-time RT-qPCR kit (Seegene, Seoul, Korea) was used and the CT values were 29 for E-gene, 29 for RdRP-gene, 30 for N-gene, and 28 for RNase P-gene. The patient was asymptomatic for four days after the test was collected, when she declared that she was experiencing myalgia, nausea, adynamia, nasal congestion, anosmia, headache, and cough. On September 27, 2020, she was clinically evaluated and complained of right chest pain, with a diagnosis of pneumonia; prednisolone 10 mg was prescribed for five days. On October 9, 2020, the patient manifested tiredness, fatigue, headache, and presented tachycardia on physical examination. A beta-blocker (bisoprolol 2.5 mg daily) was prescribed due to tachycardia, with partial improvement. Subsequently, the patient continued to report anosmia and migraine. After 103 days since the COVID-19 diagnosis, the patient had mild paralysis on the right side of her face, and she was clinically diagnosed with Bell’s palsy. According to the House-Brackmann classification system, the damage resulted in mild dysfunction (Grade 2). The patient had no history of previous facial paralysis, labial or genital herpes, or comorbidities.

The patient took 300 mg of dipyrone monohydrate, 35 mg of orphenadrine citrate, and 50 mg of anhydrous caffeine, orally, every eight hours for five days for pain and relief of muscle contracture of the mandible contralateral to the paralysis. She also underwent facial physiotherapy at home. In consultation with an otolaryngologist, due to tinnitus and right ear pain on December 8, 2020, she started using inhaled corticosteroids (fluticasone furoate nasal spray, 27.5 mcg) for 14 days, and noticed an improvement in her migraine and otological symptoms. Her facial paralysis lasted for 10 days, and her symptoms progressively improved with partial recovery up to the time of this report.

A cranial MRI performed to investigate persistent migraine did not show any changes. The following serology tests were performed: HIV (non-reactive), brucellosis 1^st and 2^nd samples (non-reactive), cytomegalovirus IgG (reactive), IgM (non-reactive), Lyme IgG (non-reactive), and Lyme IgM (non-reactive).

6. Discussion

This study describes two cases of late PFP after confirmed COVID-19 infections. In the literature search, we retrieved 43 articles reporting patients with acute paralysis or idiopathic facial weakness associated with SARS-CoV-2 infection. Numerous late cases of Bell’s palsy weeks after the COVID-19 diagnosis have likely not been published as related to Sars-CoV-2. In this case, it is necessary to take into account the publication bias [5656. Dwan K, Altman DG, Arnaiz JA, Bloom J, Chan AW, Cronin E, Decullier E, Easterbrook PJ, Elm EV, Gamble C, Ghersi D, Ioannidis JPA, Simes J, Williamson PR. Systematic review of the empirical evidence of study publication bias and outcome reporting bias. PloS One. 2008 Aug 28;3(8):e3081.]. Although a problem may be relevant to the scientific community, many studies are published or not depending on the results.

Although facial paralysis has no gender predilection, our two reports involved female patients, as indicated in recent reports on the subject [1111. Homma Y, Watanabe M, Inoue K, Moritaka T. Coronavirus disease-19 pneumonia with facial nerve palsy and olfactory disturbance. Intern Med. 2020 Jul 15;59(14):1773-5., 1212. Ribeiro BNF, Marchiori E. Facial palsy as a neurological complication of SARS-CoV-2. Arq Neuropsiquiatr. 2020;78:667., 2424. Goh Y, Beh DLL, Makmur A, Somani J, Chan ACY. Pearls & Oy-sters: Facial nerve palsy in COVID-19 infection. Neurology. 2020 Aug 25;95(8):364-7., 55]. The pathophysiology of the disease may be related to increased viral replication and dissemination in the axon, leading to demyelination and inflammation [5757. Eviston TJ, Croxson GR, Kennedy PG, Hadlock T, Krishnan AV. Bell’s palsy: Aetiology, clinical features and multidisciplinary care. J Neurol Neurosurg Psychiatry. 2015 Dec;86(12):1356-61.]. The severity of this condition can be measured by the addition of more neurological events, intensification of initial symptoms, ocular symptoms, and incomplete recovery after three months [55. Ellul MA, Benjamin L, Singh B, Lant S, Michael BD, Easton A, Kneen R, Defres S, Sejvar J, Solomon T. Neurological associations of COVID-19. Lancet Neurol. 2020;19(9):767-83.].

In general, the cases we have reported had benign courses with some degree of facial involvement. Patient 1 was classified as grade III, according to an assessment of facial movement using the House-Brackmann scale [5858. Fonseca KM, Mourão AM, Motta AR, Vicente LC. Scales of degree of facial paralysis: Analysis of agreement. Braz J Otorhinolaryngol. 2015 May-Jun;81(3):288-93.], with no movement in the forehead, incomplete eye closure with effort, and asymmetry of the mouth with maximum effort. Patient 2 was classified as grade II, with moderate to good forehead function, complete eye closure with minimal effort, and mild asymmetry in the mouth. As a result of this systematic review, most cases were grade III [1717. Casas E, Barbosa A, Rubio-García E, Cebrián J, Díaz-Pérez C, de la Fuente E, Vivancos J, López-Manzanares L. Isolated peripheral facial paralysis in a patient with COVID-19. Rev Neurol. 2020 Jul 1;71(1):40-1., 2525. Zammit M, Markey A, Webb C. A rise in facial nerve palsies during the coronavirus disease 2019 pandemic. J Laryngol Otol. 2020 Oct 1:1-4., 3838. Lima MA, Silva MTT, Soares CN, Coutinho R, Oliveira HS, Afonso L, Espíndola O, Leite AC, Araujo A. Peripheral facial nerve palsy associated with COVID-19. J Neurovirol. 2020 Dec;26(6):941-4., 4444. Kerstens J, Deschuytere L, Schotsmans K, Maréchal E. Bilateral peripheral facial palsy following asymptomatic COVID-19 infection: a case report. Acta Neurol Belg. 2021;121(3):815-6.], which means that a large number of patients affected by paralysis had moderate symptoms.

The cases presented here diverge from the literature regarding temporality and the symptom itself; in other reports, paralysis has generally been described as the only symptom or as an initial symptom [1111. Homma Y, Watanabe M, Inoue K, Moritaka T. Coronavirus disease-19 pneumonia with facial nerve palsy and olfactory disturbance. Intern Med. 2020 Jul 15;59(14):1773-5., 1818. García Ochoa-Fernández EG, Víllora-Morcillo N, Táboas-Pereira MA. Peripheral facial palsy in a paediatric patient with no risk factors within the context of infection by SARS-CoV-2. Rev Neurol. 2021 Mar 1;72(5):177-8., 2020. Zain S, Petropoulou K, Mirchia K, Hussien A, Mirchia K. COVID-19 as a rare cause of facial nerve neuritis in a pediatric patient. Radiol Case Rep. 2021 Jun;16(6):1400-4., 2222. Pinna P, Grewal P, Hall JP, Tavarez T, Dafer RM, Garg R, Osteraas ND, Pellack DR, Asthana A, Fegan K, Patel V, Conners JJ, John S, Silva I. Neurological manifestations and COVID-19: Experiences from a tertiary care center at the Frontline. J Neurol Sci. 2020 Aug 15;415:116969., 3333. Neo WL, Ng JCF, Iyer NG. The great pretender-Bell’s palsy secondary to SARS-CoV-2? Clin Case Rep. 2021Feb 12;9(3):1175-77., 3636. Theophanous C, Santoro JD, Itani R. Bell’s palsy in a pediatric patient with hyper IgM syndrome and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Brain Dev. 2021 Feb ;43(2):357-9., 3838. Lima MA, Silva MTT, Soares CN, Coutinho R, Oliveira HS, Afonso L, Espíndola O, Leite AC, Araujo A. Peripheral facial nerve palsy associated with COVID-19. J Neurovirol. 2020 Dec;26(6):941-4., 3939. Koh JS, De Silva DA, Quek AML, Chiew HJ, Tu, TM, Seet CYH, Hoe RHM, Saini M, Hui ACF, Angon J, Ker JR, Yong MH, Goh Y, Yu WY, Lim TCC, Tan BYQ, Ng KWP, Yeo LLL, Pang YZ, Prakash KM, Ahmad A, Thomas T, Lye DCB, Tan K, Umapathi T. Neurology of COVID-19 in Singapore. J Neurol Sci. 2020 Nov 15;418:117118., 5555. Figueiredo R, Falcão V, Pinto MJ, Ramalho C. Peripheral facial paralysis as presenting symptom of COVID-19 in a pregnant woman. BMJ Case Rep. 2020 Aug 11;13(8):13-5. ].

The cases described in this work presented other manifestations, such as cough, body pain, and myalgia. The paralysis occurred four months after symptoms and the COVID-19 diagnosis. The persistence of symptoms after the acute phase of COVID-19 has been discussed and the term long COVID is used for this purpose: when there are lasting effects of the infection after three weeks from the time of diagnosis. The virus can cause permanent damage to various organs, such as the heart, lung, and brain [5959. Mendelson M, Nel J, Blumberg L, Madhi SA, Dryden M, Stevens W, Venter FWD. Long-COVID: An evolving problem with an extensive impact. S Afr Med J. 2020 Nov 23;111(1):10-2.]. Therefore, we classify the cases presented here as long COVID.

Except for the anosmia presented by the two patients, the association of other neurological manifestations concomitant with the paralysis was not observed. In recent reports, the involvement of the facial nerve - during or after COVID-19 infection - was associated with the absence of deep tendon reflexes, ataxia, hypoesthesia, or paresthesia in the upper and lower limbs, being characteristic signs of Guillain-Barré syndrome (GBS) [6060. Bigaut K, Mallaret M, Baloglu S, Nemoz B, Morand P, Baicry F, Godon A, Voulleminot P, Kremer L, Chanson JB, de Seze J. Guillain-Barré syndrome related to SARS-CoV-2 infection. Neurol Neuroimmunol Neuroinflamm. 2020;7(5).-6363. Paybast S, Gorji R, Mavandadi S. Guillain-Barré syndrome as a neurological complication of novel COVID-19 infection: A case report and review of the literature. Neurologist. 2020 Jul;25(4):101-3.].

The World Health Organization, in April 2020, determined that cases with acute disseminated encephalomyelitis, GBS, and other acute neuropathies could be associated with SARS-CoV-2 infection [55. Ellul MA, Benjamin L, Singh B, Lant S, Michael BD, Easton A, Kneen R, Defres S, Sejvar J, Solomon T. Neurological associations of COVID-19. Lancet Neurol. 2020;19(9):767-83.]. Our reported cases do not coincide with the concepts of probable and possible association described in the literature [6464. Numbers SIN. Coronavirus disease 2019 (COVID-19);2019.]. However, this definition of temporal association can be changed as new events have been reported throughout the pandemic [6565. World Health Organization. Coronavirus disease 2019 (COVID-19): Situation report, 61. https://apps.who.int/iris/handle/10665/331605. WHO. 2020.
https://apps.who.int/iris/handle/10665/3... ].

Additionally, no changes in taste have been reported, although ageusia has emerged as one of the common symptoms of COVID-19 and these manifestations are present in cases of peripheral paralysis, when the topography of the lesion reaches the chorda tympani nerve, a branch of the facial nerve [6666. Valença MM, Valença LPAdA, Lima MCM. Paralisia facial periférica idiopática de Bell: A propósito de 180 pacientes. Arq Neuro-Psiquiatr. 2001 Set;59(3B):733-9. ].

Treatment for paralysis aims to improve the facial mimicry of these patients and prevent sequelae. There is evidence that physiotherapy sessions can offer benefits for recovering facial mobility and improving the functionality of facial expressions, accelerating the recovery process [6767. Ferraria L, Silva I, Rosa H, Antunes L. Tipo de terapêutica e fatores de prognóstico na paralisia de Bell: Estudo retrospectivo de cinco anos em um hospital português. Sci Med. 2016 Jan-Mar;26(1):21384.]. In addition to physiotherapy sessions, the study patients used corticosteroids. One corticosteroid was associated with an antiviral. In the review, eight patients received the association of antivirals and corticotherapy, in consideration of a possible HSV infection [2424. Goh Y, Beh DLL, Makmur A, Somani J, Chan ACY. Pearls & Oy-sters: Facial nerve palsy in COVID-19 infection. Neurology. 2020 Aug 25;95(8):364-7., 3232. Kumar V, Narayanan P, Shetty S, Mohammed AP. Lower motor neuron facial palsy in a postnatal mother with COVID-19. BMJ Case Rep. 2021 Mar 1;14(3):10-2., 3333. Neo WL, Ng JCF, Iyer NG. The great pretender-Bell’s palsy secondary to SARS-CoV-2? Clin Case Rep. 2021Feb 12;9(3):1175-77., 3636. Theophanous C, Santoro JD, Itani R. Bell’s palsy in a pediatric patient with hyper IgM syndrome and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Brain Dev. 2021 Feb ;43(2):357-9., 3838. Lima MA, Silva MTT, Soares CN, Coutinho R, Oliveira HS, Afonso L, Espíndola O, Leite AC, Araujo A. Peripheral facial nerve palsy associated with COVID-19. J Neurovirol. 2020 Dec;26(6):941-4.]. Another 17 patients used antiviral drugs such as lopinavir/ritonavir, valacyclovir, and acyclovir to treat paralysis [1111. Homma Y, Watanabe M, Inoue K, Moritaka T. Coronavirus disease-19 pneumonia with facial nerve palsy and olfactory disturbance. Intern Med. 2020 Jul 15;59(14):1773-5., 2525. Zammit M, Markey A, Webb C. A rise in facial nerve palsies during the coronavirus disease 2019 pandemic. J Laryngol Otol. 2020 Oct 1:1-4., 5151. Tawfik HM, Shaaban HM, Tawfik AM. Post-COVID-19 Syndrome in Egyptian Healthcare Staff: Highlighting the Carers Sufferings. Electron J Gen Med. 2021;18(3)., 5353. Hasibi M, Seyed Ahadi M, Abdollahi H, Jafari M. Protracted COVID-19 during treatment of facial palsy. Case Rep Neurol Med. 2021 Jun 4;2021:5569841.].

Finally, concerning the duration of symptoms mentioned in other articles on the subject, which ranged from six days for complete recovery [1111. Homma Y, Watanabe M, Inoue K, Moritaka T. Coronavirus disease-19 pneumonia with facial nerve palsy and olfactory disturbance. Intern Med. 2020 Jul 15;59(14):1773-5.] to 30 days for partial recovery [3838. Lima MA, Silva MTT, Soares CN, Coutinho R, Oliveira HS, Afonso L, Espíndola O, Leite AC, Araujo A. Peripheral facial nerve palsy associated with COVID-19. J Neurovirol. 2020 Dec;26(6):941-4.], the total recovery of the facial mimicry of patients described in our report has an uncertain but promising prognosis.

There is a notable increase in described neurological manifestations including facial paralysis cases, with an onset time that can vary from two days to 60 days. Different from the observed in the rapid review, the two cases are considered late peripheral facial paralysis after COVID-19 because the onset of symptoms occurs more than 100 days after the onset of the disease.

The limitations of our study are inherent to the types of research included in the rapid review, which do not describe their limitations, making it difficult to compare with cases related globally. Additionally, the difficulty in differentiating isolated paralysis and facial paralysis associated with GBS is detected in the included articles. In our report, it was not possible to perform HSV serology due to lack of a kit in the reference laboratory. Also, MRIs were not performed in the acute period of the onset of facial paralysis. Due to the low CT, it was not possible to perform genetic sequencing of the virus.

7. Conclusion

In conclusion, cases of peripheral facial paralysis have been described in the literature, but they are limited to acute cases with descriptions of up to 60 days in duration. There is a wide variety of clinical protocols and treatments. We report two cases of PFP after confirmed COVID-19 infection, both presenting some symptoms related to COVID-19, with late neurological alteration. Considering that these two cases had no history of labial or genital herpes and that both cases had positive serology (IgG) for cytomegalovirus, this late symptomatology is a hypothesis that it is caused by Sars-Cov-2. The benign course of the disease demonstrated the diversity of complications caused by SARS-CoV-2 and the need for outpatient follow-up to observe possible late manifestations of FPF.

Acknowledgments

The authors thank Maria Luiza L. Moreira, Coordinator of the Laboratory of Serology, COVID-19 Diagnosis Support Unit (UNADIG-RJ) for her support with the laboratory tests. Thanks are also due to the authors of studied articles who answered our questions, namely: Ahmet Doblan, Matthew Zammit, Oguz Egilmez, Pranusha Pinna, and Yuce Islamoglu.

References

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Additional file 1Systematic review search strategy.

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