Magnetic resonance imaging features of COVID-19-related cranial nerve lesions.

The complete features of the neurological complications of coronavirus disease 2019 (COVID-19) still need to be elucidated, including associated cranial nerve involvement. In the present study we describe cranial nerve lesions seen in magnetic resonance imaging (MRI) of six cases of confirmed COVID-19, involving the olfactory bulb, optic nerve, abducens nerve, and facial nerve. Cranial nerve involvement was associated with COVID-19, but whether by direct viral invasion or autoimmunity needs to be clarified. The development of neurological symptoms after initial respiratory symptoms and the absence of the virus in the cerebrospinal fluid (CSF) suggest the possibility of autoimmunity.

Metagenomic next-generation sequencing of viruses, bacteria, and fungi in the epineurium of the facial nerve with Bell's palsy patients.

Bell's palsy (BP) represents a major cause leading to facial paralysis in the world. The etiology of BP is still unknown, and virology is the prevailing theory. The purpose of this study is to explore the pathogenic microorganisms that may be related to BP, and it is of great significance to study the pathogenesis and treatment of BP. Metagenomic next-generation sequencing (mNGS) detection was performed in the epineurium of the facial nerve of 30 BP patients who underwent facial nerve epineurium decompression. A total of 84 pathogenic microorganisms were detected in 30 clinical samples, including 4 viruses, 10 fungi, and 70 bacteria. The species with the highest detection frequency in virus was human betaherpesvirus 7 (HHV-7). The species with the highest detection frequency in Fungi was Malassezia restricta. The species with the highest detection frequency in Bacteria was Pseudomonas aeruginosa. In this study, mNGS method was firstly used to detect the pathogenic microorganisms in the epineurium of the facial nerve with BP patients. We have for the first time identified HHV-7 and aspergillus in the epineurium of the facial nerve of BP patients. These results suggest that these two pathogenic microorganisms should be considered in the pathogenesis of BP.

A systematic review of Bell's Palsy as the only major neurological manifestation in COVID-19 patients.

BACKGROUND: Bell's palsy is an acute idiopathic paralysis of the facial nerve. The disease is caused by many viruses like Herpes simplex virus-1, Varicella zoster, Epstein-bar virus, Cytomegalovirus, Usutu virus, Human immunodeficiency virus, etc. Literature has reported few cases of COVID-19 patients with Bell's palsy as the only major neurological manifestation indicating the possible role of another virus in the etiopathogenesis of Bell's Palsy. This paper aims to evaluate the reported cases of COVID-19 positive patients, presented with Bell's palsy as the only major neurological manifestation from March 2020 to December 2020, and to investigate the association of SARS-CoV2 and Bell's palsy. MATERIALS AND METHODS: A systematic review of the published literature was performed using an electronic search in PubMed/Medline, Science Direct, Web of Science, Embase, J- STAGE, Google Scholar, China National Knowledge Infrastructure (CKNI) and Scopus databases, from March 2020 to Dec 2020 using keywords like 'COVID-19', 'SARS-CoV-2', 'Coronavirus', 'Bell's palsy', 'Facial nerve', 'First', 'Only',' Neurological', 'Manifestation'. The studies reviewed were case series and case reports regarding the subject. RESULTS: Search strategy revealed thirteen articles from March 2020 to Dec 2020 with a total of 20 cases of COVID-19 with Bell's palsy as the only major neurological manifestation. CONCLUSION: Evidence of Bell's palsy as the only major neurological manifestation in COVID-19 patients signifies an important clinical finding but robust research is needed to investigate their association and the exact mechanisms by which SARS-CoV2 causes Bell's Palsy.

The presence of herpes simplex-1 and varicella zoster viruses is not related with clinical outcome of Bell's Palsy.

Bell's Palsy is the most frequent acute neuropathy of cranial nerves; it has been associated in various reports to herpes viruses. In a prospective study we searched the presence of DNA from five herpes viruses (HSV-1 and 2, VZV, EBV and HHV-6) in 79 patients at the acute phase of Bell's Palsy. Results were related with various parameters; age, gender and clinical outcome. We found the significant presence (p˂0.001) of HSV-1 and VZV in 39% and 42% of patients. However, a large percentage of cases were negative. When comparisons were made between subgroups according to gender and age no differences were found with viral findings nor with clinical outcome of palsy, which was of clinical remission in most cases (78%). Our results suggest that herpes viruses might participate in the complex mechanisms of autoimmunity of Bell's Palsy but not as determinant etiological element.

Failure of postexposure prophylaxis in a girl child attacked by rabid dog severing her facial nerve causing possible direct entry of rabies virus into the facial nerve.

On January 4, 2019 an eight-year-old girl child was bitten by a suspected rabid dog over the left parotid region. After a 17-h delay, the child was brought for rabies postexposure prophylaxis (PEP) at Civil Hospital Theog and was administered complete PEP. On January 29, 2019, the child was again brought to Theog Hospital with complaints of having fever, difficulty in walking, neck drop, and ptosis. On examination, pediatrician found photophobia, phonophobia, and hydrophobia and subsequently the patient died of cardiac arrest. On postmortem examination, the facial nerve was found dissected and injured at the inner end of the parotid gland. A severed end toward the brain was swollen and edematous. The entire brain was extracted and sent to Central Research Institute Kasauli for confirmation of rabies, where it tested positive for rabies by Fluorescent Antibodies Test and Biological Test. In situations where sensitive parts such as the face are involved, a thorough wound wash with soap and water and application of antiseptics along with immediate PEP may save some lives by not allowing the virus enough time to attach to and infect the nerve cells.

Typical or Atypical Ramsay-Hunt Syndrome in Delayed Facial Palsy After Stapedectomy?

OBJECTIVES: The aim of this study was to define the typical pattern for varicella zoster virus (VZV) reactivation in delayed facial palsy (DFP) after stapedectomy for otosclerosis. MATERIALS AND METHODS: Review of the relevant literature, personal casistics, and case-report. RESULTS: In total, 48 cases of DFP after stapes surgery have been described so far, including the reported case with exclusive manifestation of atypical Ramsay Hunt syndrome (RH); in the personal series of 1253 stapedectomies, DFP occurred in only one case (0.08%). Complete DFP (House-Brackmann grade VI) rapidly developed 12 days after surgery; RH appeared 2 days later, confirming the role of VZV. The DFP started improving after 8 weeks and completely recovered 6 months later. CONCLUSION: Acute otalgia prior to DFP should raise the suspicion of VZV reactivation. Atypical RH is the most frequent pattern that occurs in DFP after stapedectomy.

Facial paralysis induced by ear inoculation of herpes simplex virus in rat.

OBJECTIVE: Bell's palsy is caused by the reactivation of herpes simplex virus type 1 (HSV-1). Using Balb/c mice inoculated with the KOS strain of HSV-1, we previously developed an animal disease model that simulated mild Bell's palsy. The current study developed an animal disease model of more severe facial palsy than that seen in the mouse model. METHODS: Three-week-old female Wister rats weighing 60-80g were inoculated on the auricle with HSV-1 and acyclovir was administered intraperitoneally to deactivate the infected HSV-1. Instead of HSV-1, phosphate-buffered saline was used for inoculation as a negative control. Quantitative polymerase chain reaction (PCR), behavior testing (blink reflex), electroneuronography, histopathology of the peripheral nerve, and immunohistochemistry of the facial nerve nucleus were evaluated. RESULTS: Facial palsy occurred 3-5 days after virus inoculation, and the severity of the facial palsy progressed for up to 7 days. Quantitative PCR showed an increase in HSV-1 DNA copies in the facial nerve from 24 to 72h, suggesting that HSV-1 infection occurred in the nerve. Electroneuronography values were 33.0±15.3% and 110.0±18.0% in HSV-1-inoculated and control rats, respectively. The histopathology of the peripheral nerve showed demyelination and loss of the facial nerve, and the facial nerve nucleus showed degeneration. CONCLUSION: Facial palsy developed in Wister rats following inoculation of the KOS strain of HSV-1 onto the auricles. The behavioral, histopathological, and electroneuronography data suggested that the severity of facial palsy was greater in our rats than in animals in the previous mouse disease model.

Bell's palsy and Herpes simplex virus: fact or mystery?

HYPOTHESIS AND BACKGROUND: In recent years, progress has been made in the understanding of Bell's palsy, the most common form of acute facial weakness. Herpes simplex virus (HSV) reactivation within the geniculate ganglion with subsequent inflammation and entrapment of the nerve at the meatal foramen has been proposed to be the pathogenetic mechanism. We challenged its accuracy by analyzing our own data on the presence of viral genomic DNA of HSV-1 and 2, human herpes virus (HHV)-6A/B, as well as varizella zoster virus (VZV) in patients with Bell's palsy and in control patients without the disease. METHODS: Polymerase chain reaction was performed with primer sets specific for viral genomic DNA of HSV-1, HSV-2, and VZV in facial muscle biopsy specimens from patients with Bell's palsy. As control specimens, the Scarpa's ganglion of patients with Meniere's disease and the geniculate ganglion harvested at autopsy from patients without history of facial palsy. In a second study, we used polymerase chain reaction with primers specific for HSV-1, -2, and HHV-6A, -6B to analyze for the presence of these viruses in tear fluid samples from control patients and patients with acute Bell's palsy. RESULTS: HSV-1 and VZV genomic DNA were detected in 86 and 43%, respectively, of geniculate ganglion preparations from control specimen. We were not able to detect the presence of HSV-1, HSV-2, or VZV genomic DNA in ganglion scarpae or muscle biopsy results in control and Bell's palsy patients. HHV-6A could be detected in tear fluid samples in 40% of control patients and 30% of Bell's palsy patients. CONCLUSIONS: The sole presence of HSV genomic DNA within the sensory ganglion along the facial nerve does not explain the direct association with Bell's palsy. The missing link would be the identification of an active replicating virus, an investigation that has not yet been carried out.

Adenoviral vector-mediated gene expression in the nervous system of immunocompetent Wistar and T cell-deficient nude rats: preferential survival of transduced astroglial cells in nude rats.

In the present paper, we examined the effect of the adenoviral vector dosage, the role of T cells, and the influence of the presence of replication-competent adenovirus (RCA) in adenoviral vector stocks, on the efficacy of adenoviral vector-directed transgene expression in the facial nucleus of immunocompetent Wistar and athymic nude rats. A small number of motor neurons and glial cells was transduced at low dosages of viral vector (1 x 10(6) pfu) and in the absence of RCA, and transgene-expressing cells persisted throughout the 3-week period of observation. Intraparenchymal infusion of 2 x 10(7) pfu of a recombinant adenoviral vector free of RCA was required for optimal transduction of facial motor neurons. In Wistar rats, a biphasic immune response occurred at higher dosages of the vector (5 x 10(6) and 2 x 10(7) pfu) that was characterized by early infiltration of macrophages and the occurrence of T cells during the second week after injection of the vector. The immune response was associated with the loss of transduced neural cells. In nude rats, administration of an adenoviral vector free of RCA resulted in a macrophage response comparable to that in the Wistar rat and long-term survival of transduced astroglial cells. However, transduced motor neurons degenerated according to a similar time course as observed in Wistar rats. Small amounts of RCA (2 x 10(5) pfu) injected with 2 x 10(7) pfu recombinant viral vector particles resulted in an accelerated T cell response and a rapid elimination of transduced cells within 1 week in Wistar rats, whereas in nude rats transgene expression continued during this period. Taken together, these observations suggest that at the high viral vector loads necessary to achieve optimal transduction of the facial nucleus, T cells play a role in the degeneration of adenoviral vector-transduced astroglial cells. The adverse effects on neurons appear to be due to the observed inflammatory response or to direct adenoviral vector toxicity.

Rapid diagnosis of varicella zoster virus infection in acute facial palsy.

Patients with zoster sine herpete and Ramsay Hunt syndrome without pathognomonic vesicles at the initial visit are often misdiagnosed with Bell's palsy and treated without antiviral agents. With PCR, we found that varicella zoster virus genomes were frequently detectable in auricular skin exudate from patients with zoster sine herpete or Ramsay Hunt syndrome before the appearance of vesicles.

Neuronal propagation of HSV1 from the oral mucosa to the eye.

PURPOSE: To identify possible neuronal pathways leading to herpetic ocular disease after primary oral infection in mice. METHODS: The SC16 strain of herpes simplex virus (HSV)-1 (10(6) plaque-forming units) was injected into the mucocutaneous border of the left upper lip. Animals were killed 2 to 10 days postinoculation (DPI). Spread of the virus in neural structures was studied by immunochemistry. RESULTS: HSV1 first replicated at the site of inoculation and then at the superior cervical ganglion (at 2 DPI). The trigeminal ganglion and the facial nerve fibers were infected by 4 DPI. Infection of the ciliary body and iris occurred at 6 DPI, together with several brain stem nuclei belonging to the autonomic or sensory pathways. Between 8 and 10 DPI, the neural infection gradually cleared up, except for the ipsilateral sympathetic ganglion, and ipsilateral keratitis appeared in some animals. CONCLUSIONS: The pattern of viral dissemination in this mouse model suggests that infection of iris and ciliary body results from transfer of virus in the superior cervical ganglion from sympathetic neurons innervating the lip to neighboring neurons innervating the anterior uvea. Later, zosteriform spread of virus from the trigeminal system may have contributed to the clinical and histologic findings.

HSV1 latency sites after inoculation in the lip: assessment of their localization and connections to the eye.

PURPOSE: To localize the sites of HSV1 latency in mice after a primary infection induced by injection into the lip and to assess their connection to the eye. METHODS: The SC16 strain of HSV1, or a recombinant virus containing the HSV1 latency-associated transcript (LAT)-promoter driving expression of the LacZ reporter gene, were injected into the left upper lip. Tissues from animals killed at 6, 28, 180, and 720 days postinoculation (dpi) were analyzed for LATs, either by in situ hybridization (ISH) or by identifying LAT-promoter-driven transgene expression. HSV1 antigens were detected by immunochemistry. RESULTS: At 28 dpi, all the neurologic structures that were acutely infected at 6 dpi exhibited a pattern of virus gene expression consistent with HSV1 latency--that is, LATs with no detectable HSV1 antigens. LAT staining differed among structures: intense and widespread within trigeminal neurons, intermediate within the sympathetic intermediolateral cell group of the spinal cord and the facial motor nucleus, and weak in other sites. Long-term expression of LATs (positive at 180 and 720 days) was observed only in tissues where the staining was intense or intermediate at 28 dpi. CONCLUSIONS: After inoculation into the upper lip of mice, HSV1 established latency in several nervous system structures that have direct or indirect connections with ocular tissues. These results suggest that after an oral primary infection, the most frequent in humans, HSV1 may establish latency in several sites connected to the eye and may finally result in herpetic ocular disease involving the cornea, the iris, or even the retina.

Bell's palsy and herpes simplex virus.

Bell's palsy, which is defined as idiopathic peripheral facial paralysis of sudden onset, accounts for > 50% of all cases of facial paralysis. Different theories on the etiology of Bell's palsy have been proposed and investigated. Various clinical studies have suggested an etiological link between Bell's palsy and herpes simplex virus (HSV). In addition, animal experiments have shown the ability of HSV to induce facial paralysis. In our opinion, the possible link between Bell's palsy and HSV can only be explored properly by studying the human facial nerve, and especially the geniculate ganglion itself. Different groups have tried to detect hypothetically reactivated and hypothetically latent HSV in the facial nerves of Bell's palsy patients and control patients, respectively. The isolation of infectious HSV from facial nerve tissue by conventional cell culture methods appeared to be very difficult, also when Bell's palsy patients were tested. Instead, modern molecular methods, such as in situ hybridization and the polymerase chain reaction (PCR) could easily detect HSV DNA in geniculate ganglia. The detection of HSV-specific latency-associated transcripts in the ganglia of control patients provided further evidence for the hypothetically latent state of HSV in the geniculate ganglia in these patients. Recent PCR experiments performed by a Japanese group strongly suggest that the area adjacent to the geniculate ganglia does not usually contain any HSV at all, except in patients with Bell's palsy. This well-controlled study provides conclusive evidence that reactivation of HSV genomes from the geniculate ganglia is the most important cause of Bell's palsy. Consequently, it has been suggested that "Bell's palsy" be renamed as "herpetic facial paralysis".

Adenovirus-mediated gene transfer in neurons: construction and characterization of a vector for heterologous expression of the axonal cell adhesion molecule axonin-1.

By homologous recombination, a first-generation adenovirus-based gene transfer vector, AdCMVax-1, was constructed as a means of manipulating the expression level of the axonal cell adhesion molecule axonin-1 in neurons and glial cells. AdCMVax-1 harbours the entire coding region of the chicken axonin-1 cDNA under the transcriptional control of the Cytomegalovirus enhancer/promoter in the early-region 1 of the viral genome. Characterization of AdCMVax-1 in vitro revealed highly efficient gene transfer and expression of recombinant axonin-1 in neurons and glial cells of dissociated rat dorsal root ganglia. Similar to its native counterpart, virus-derived axonin-1 was detected on the cell body, neurites, and growth cones of transduced neurons, occurred in a secreted and membrane-associated form, and could be cleaved from the membrane with phosphatidylinositol-specific phospholipase C. Functional characterization of recombinant axonin-1 revealed the same binding properties as previously reported for native axonin-1 isolated from the vitreous fluid of chicken embryos. In vivo gene transfer was studied by stereotactic injection of AdCMVax-1 in the dentate gyrus of the hippocampus and the facial nucleus in the brainstem of adult Wistar rats and revealed high level expression of recombinant axonin-1 in a subset of hippocampal neurons and motor neurons in the facial nucleus.

Herpes virus reactivation and gadolinium-enhanced magnetic resonance imaging in patients with facial palsy.

OBJECTIVE: This study investigated whether magnetic resonance imaging (MRI) patterns were different between patients with Bell's palsy and those with herpetic facial palsy in whom varicella-zoster virus (VZV) or herpes simplex virus type 1 (HSV-1) reactivation had been confirmed by polymerase chain reaction (PCR) or serologic assay. STUDY DESIGN: A retrospective study of 15 patients with acute peripheral facial palsy was performed to compare virologic tests and gadolinium (Gd)-enhanced MRI findings. RESULTS: Ramsay Hunt syndrome was diagnosed in one patient. By use of virologic tests, zoster sine herpete (VZV reactivation without zoster) was diagnosed in four patients and HSV-1 reactivation in three. Bell's palsy was diagnosed in the remaining seven patients. No significant difference in the frequency of Gd-enhanced MRI was observed between herpetic facial palsy and Bell's palsy. However, in those patients who underwent MRI on the day viral reactivation was confirmed by PCR, Gd enhancement of the meatal fundus was observed infrequently. In addition, when MRI was performed within 10 days of the onset of palsy, Gd enhancement was not detected at the geniculate ganglion in any patients with herpetic facial palsy. By contrast, both the meatal fundus and the geniculate ganglion were enhanced in all patients with Bell's palsy, regardless of when MRI was performed with respect to the onset of palsy. CONCLUSION: This study shows a difference in the pattern of Gd enhancement at the meatal fundus and the geniculate ganglion between patients with Bell's palsy and those with herpetic facial palsy. The results suggest that the meatal fundus or the geniculate ganglion may be affected first by virus reactivation in patients with herpetic facial palsy.

Pathophysiology of facial nerve paralysis induced by herpes simplex virus type 1 infection.

Herpes simplex virus type 1 (HSV-1) has been proven to be a cause of Bell's palsy; however, the underlying pathophysiology of the facial nerve paralysis is not fully understood. We established a mouse model with facial nerve paralysis induced by HSV-1 infection simulating Bell's palsy and investigated the pathophysiology of the facial nerve paralysis. The time course of the R1 latency in the blink reflex tests paralleled the recovery of the facial nerve paralysis well, whereas electroneurographic recovery tended to be delayed, compared to that of the paralysis; these responses are usually seen in Bell's palsy. On histopathologic analysis, intact, demyelinated, and degenerated nerves were intermingled in the facial nerve in the model. The similarity of the time course of facial nerve paralysis and the electrophysiological results in Bell's palsy and the model strongly suggest that the pathophysiological basis of Bell's palsy is a mixed lesion of various nerve injuries.

Role of herpes simplex virus infection in the pathogenesis of facial paralysis in mice.

To clarify the role and site of herpes simplex virus (HSV) infection in the pathogenesis of facial paralysis, we examined the viral genome by the polymerase chain reaction and the neutralization antibody titer using microplates in an animal model. Following inoculation with HSV type 1 of the KOS strain into mouse auricles, HSV DNA appeared in the ipsilateral facial nerve on the 3rd day, and in bilateral facial nerves and the brain stem on the 10th day only in animals with facial paralysis. In animals without facial paralysis, no HSV DNA was detected in these tissues. The neutralization antibody titer was elevated between 4 and 20 days in all animals, with or without facial paralysis. Facial paralysis developed only on the inoculated side, even though HSV DNA was also present in the contralateral facial nerve. We conclude that HSV infection in the facial nerve and brain stem is prerequisite for facial paralysis, and suggest that an immunologic reaction following viral infection plays a key role in the pathogenesis.

Polymerase chain reaction amplification of herpes simplex viral DNA from the geniculate ganglion of a patient with Bell's palsy.

Bell's palsy is the most common cause of facial paralysis. In this study, we demonstrate the presence of herpes simplex viral type 1 (HSV-1) genomic DNA in the geniculate ganglion of a patient who had Bell's palsy. This association suggests that in this patient, HSV-1 may have caused Bell's palsy. If HSV-1 is a cause of Bell's palsy, treatment with acyclovir may be beneficial. Additional studies should be done to establish the prevalence of HSV-1 as an etiologic agent of Bell's palsy.

Varicella-zoster virus DNA level and facial paralysis in Ramsay Hunt syndrome.

We have investigated whether the copy number of varicella-zoster virus (VZV) in saliva correlates with the clinical symptoms in patients with Ramsay Hunt syndrome. A real-time quantitative polymerase chain reaction assay was used to examine the VZV DNA copy number in saliva samples from 37 patients. We detected VZV DNA in 6 of the 7 patients with oropharyngeal zoster lesions (86%) and in 17 of the 30 patients who had zoster lesions only on the skin (57%). Patients with oropharyngeal zoster lesions had a high VZV load in their saliva, and the difference between the copy number in patients with oropharyngeal zoster lesions and those without was around 10,000 copies per 50 microL. In addition, patients with oropharyngeal zoster lesions showed worse recovery of facial function than those without. It seems that the VZV DNA level in saliva reflects the kinetics of viral reactivation in the facial nerve, as well as in the oropharyngeal epithelium, in patients with Ramsay Hunt syndrome.

Immunologic aspects of facial nerve paralysis induced by herpes simplex virus infection in mice.

This immunologic aspects of facial nerve paralysis due to herpes simplex virus type 1 (HSV-1) infection were investigated in a mouse model system. Half of the 4- to 5-week-old mice developed facial nerve paralysis, whereas none of the 6-week-old mice died or developed facial nerve paralysis on inoculation with HSV-1. Six-week-old mice showed significantly higher titers of anti-HSV-1 neutralizing antibody than did 4-week-old animals. Passive transfer of either anti-HSV-1 antibody or HSV-1-immunized splenic T cells into 4-week-old mice 3 hours after HSV-1 inoculation prevented development of facial nerve paralysis and death, whereas such transfers 48 or 96 hours after HSV-1 inoculation did not prevent or exacerbate facial nerve paralysis. These results demonstrate that the age and the immunologic potency of mice are closely related to the pathogenesis of facial nerve paralysis. That facial nerve paralysis developed even in 6-week-old mice whose T-cell function was suppressed with anti-CD3 antibody suggests that virus-induced cellular demyelination is unlikely as a cause of facial nerve paralysis in this animal model.