We reported cranial nerve abnormalities as seen by MRI of six confirmed cases of COVID-19. One participant had bilateral gadolinium-enhancement in the olfactory bulb, associated with anosmia; one patient had left optic neuritis; one case presented with a lesion in the right abducens nerve nucleus; two participants had facial palsy, one unilaterally, and the other bilaterally; and one case had bilateral facial palsy associated with the Guillain-Barré syndrome.
Although COVID-19 can have a series of neurological complications, it is still unclear if SARS-CoV-2 is neurotropic in humans. However, there are some plausible hypotheses for viral neural entry, such as via the olfactory bulb, through the vascular endothelium, by leukocyte migration across the blood–brain barrier, and by transsynaptic transfer across infected neurons (Zubair et al. 2020). It has been proposed that SARS-CoV-2 binds by spike proteins expressed on its surface to the angiotensin-converting enzyme 2 (ACE2) to enter into the host’s cells (Hoffmann et al. 2020). ACE2 is expressed in the airway epithelium, kidney cells, small intestine, lung parenchyma, vascular endothelium, and widely throughout the CNS, including the substantia nigra, ventricles, middle temporal gyrus, posterior cingulate cortex, and olfactory bulb (Zubair et al. 2020). Several other viruses can use the olfactory nerve as a shortcut into the CNS, such as influenza A virus, herpesvirus, poliovirus, paramyxovirus, rabies virus, parainfluenza virus, adenovirus, Japanese encephalitis virus, West Nile virus, and chikungunya virus, among others (van Riel et al. 2015).
Previous studies have demonstrated imaging alterations in the olfactory bulb and/or adjacent gyrus rectus, secondary to COVID-19, in patients with anosmia, using T1-weighted imaging with fat suppression, pregadolinium and postgadolinium, and FLAIR, corroborating that the olfactory bulb is a potential entry site into the CNS for SARS-CoV-2 (Aragão et al. 2020; Politi et al. 2020; Vargas-Gandica et al. 2020; Klironomos et al. 2020). Similarly, in our case series, one patient presented with MRI-detected alterations in the olfactory bulb, seen in fat saturation post-gadolinium T1-weighted imaging.
We also presented five cases of confirmed COVID-19 with lesions in other cranial nerves that did not present associated anosmia, suggesting that the neuronal injury in this disease goes beyond the invasion of the olfactory bulb. Previous authors reported COVID-19-related facial palsy (Lima et al. 2020; Klironomos et al. 2020). Similarly, we reported one patient with unilateral facial nerve palsy. In addition, we also reported two cases with bilateral facial nerve palsy. Facial nerve palsy, unilateral or bilateral, is associated with several other infections, such as by herpes simplex virus, varicella zoster, human immunodeficiency virus, influenza virus, poliomyelitis virus, human T-cell lymphotrophic virus, mycobacterium tuberculosis, infectious mononucleosis, Lyme disease, and syphilis, as well as with non-infectious causes, including sarcoidosis and neoplasms (Goh et al. 2020; Jain et al. 2006). The exact pathogenesis of acute facial nerve palsy remains unclear in COVID-19, but in association with neurotropic viruses, one can hypothesize that it is related with axonal spread and viral replication leading to inflammation and demyelination (Goh et al. 2020; Lima et al. 2020). However, previous authors have failed to detect SARS-CoV-2 in the CSF, so cranial neuropathies are probably related to immune-mediated injury from proinflammatory cytokines, with or without molecular mimicry (Fotuhia et al. 2020), rather than direct viral neurotropism (Gutiérrez-Ortiz et al. 2020). In addition, it is important to remember that not all facial nerve enhancement is pathological. Mild enhancement in the geniculate ganglion, tympanic, or mastoid segments can be normal, presumably secondary to the circumneural venous plexus in these segments. However, when asymmetrical, correlated with symptoms, associated with other facial nerve segments enhancement, or with other abnormalities, such as facial canal expansion, it can be considered pathological (Raghavan et al. 2009). Brain MRI of our case 3 demonstrated gadolinium-enhancement in the mastoid portion of the right facial nerve. Although this finding could be related to the circumneural facial venous plexus, as it correlated with clinical symptoms, and it was asymmetric in relation to the left side, we could consider it as a pathological finding.
Abducens nerve palsy has also been previously reported, in the context of Miller Fisher syndrome, but without imaging evidence of nerve involvement (Dinkin et al. 2020; Gutiérrez-Ortiz et al. 2020). We presented a case with involvement of the abducens nucleus in the pons associated with facial palsy, but not related to the Miller Fischer syndrome, since the patient did not preset ataxia or hyporeflexia.
Several studies have associated COVID-19 with Guillain-Barré syndrome with axonal neuropathy, demyelination, or cranial nerve lesions, which probably occurs due to molecular mimicry (Fotuhia et al. 2020; Toscano et al. 2020). In the present study, we reported one case of Guillain-Barré syndrome with bilateral facial palsy by MRI. Guillain-Barré syndrome diagnosis is confirmed by clinical parameters, CSF study, and electroneuromyography. MRI can be performed to exclude other causes of flaccid paralysis and show contrast enhancement in the cauda equina nerve roots. However, nerve root enhancement can be seen in several causes of radiculitis and is not pathognomonic.
Dinkin et al. (2020) presented a COVID-19 case with contrast enhancement in the optic nerve perineural sheath without involvement of the nerve substance. The authors interpreted this finding as a possible viral leptomeningeal invasion, though nonspecific. Other authors have reported prominent subarachnoid spaces around the optic nerves, probably due to increased intracranial pressure in COVID-19 (Klironomos et al. 2020). On the other hand, we presented a case with hyperintense signal in the optic nerve substance associated with contrast enhancement. Coronaviruses can cause clinical entities such as conjunctivitis, anterior uveitis, retinitis, and optic neuritis in feline and murine models (Seah et al. 2020). Previous case reports have described CNS demyelinating lesions induced by a delayed immune response secondary to viremia, complicating COVID-19 (Zanin et al. 2020; Corrêa et al. 2020). Also, experimental models using human coronavirus have indicated a potential link between coronavirus infection and the development of demyelinating diseases (Montalvan et al. 2020). Although there is only sparse evidence, optic neuritis may also be considered a demyelinating lesion, and may be induced by a delayed immune response.
Although cranial nerve lesions can complicate COVID-19, this association has been reported only in case reports or short case series, as in the present study. Therefore, the real prevalence of this type of neurological complication is not known. A limitation of this work is that we did not perform lumbar punctures on all of our patients. However, since all participants had mild and self-limiting respiratory symptoms and neurological complications appeared after improvement of the initial symptoms, there was a marked temporal relationship with the SARS-CoV-2 infection. Also, all participants had their SARS-CoV-2 infection confirmed by RT-PCR and tested negative for other respiratory viruses.
In conclusion, although the full neurological features of SARS-CoV-2 infection are still to be characterized, cranial nerve lesions are part of this spectrum, and MRI can help to detect these abnormalities. Further research is still needed to describe the incidence of cranial nerve lesions in COVID-19.