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INTRODUCTION
Trigeminal neuralgia is a painful chronic condition involving the trigeminal nerve, and its development has been linked to COVID-19. Trigeminal neuralgia is characterised by chronic and sharp neuropathic pain (sometimes described as similar to an electric shock) on one side of the face, resulting from spontaneous excitation of one or more of the trigeminal nerve branches (Bendtsen et al., 2019). Radiating pain in trigeminal neuralgia can be aggravated by non-radiating pain or stimuli from a region that is not innervated by the trigeminal nerve, and the unilateral effect can last between one second and two minutes (Headache Classification Committee of the International Headache Society (IHS), 2018) which assists clinicians in diagnosis. The diagnosis is based on the prevalence of causes. The lifetime prevalence of trigeminal neuralgia in population- based studies is between 0.16 % and 0.3 % (Mueller et al.,2011). The annual incidence rate of trigeminal neuralgia is between 0.0004 and 0.0013 %, and incidence increases with age (Yadav et al., 2017), potentially reaching as high as 0.07 % over 50 years (Headache Classification Committee of the International Headache Society (IHS), 2018; Jones et al., 2019).
The trigeminal nerve is the fifth paired cranial nerve that originates from the pons or the middle part of the brainstem. It travels lateral to the cavernous sinus and carries facial sensations to three sensory nuclei (mesencephalic, principal sensory, and spinal nuclei) that extend through the brainstem and into the high cervical spinal cord. Additionally, one associated motor nucleus extends into the brainstem to control mastication muscles (masseter, temporalis, and lateral and medial pterygoids, in addition to the tensor veli palatini, mylohyoid, tensor tympani, and anterior belly of digastric muscles). The trigeminal nerve divides into ophthalmic, maxillary, and mandibular branches, located in the skull via the superior orbital fissure, foramen rotundum, and foramen ovale, respectively (Huff et al., 2020). Therefore, ophthalmic neuralgia is a part of trigeminal neuralgia.
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was originally discovered in Wuhan, China in 2019 (Veritti et al., 2020). The resulting condition was named coronavirus disease 2019 (COVID-19), and a global pandemic was declared on March 11, 2020 (Khalili et al., 2020). By December 31, 2022, 665,000,000 people had contracted SARS-CoV-2, over 6,700,000 of whom passed away from COVID-19 or its adverse health consequences (Worldometer, 2020). Case studies of trigeminal neuralgia in COVID-19 patients have been reported (Narasimhalu et al., 2021; Santovito & Pinna, 2021; Kaya & Kaya, 2022; Onoda et al., 2022), but “the link between trigeminal neuralgia and COVID-19 is not yet well understood”. This meta-analysis highlights the different clinical features of trigeminal neuralgia that are present in patients with COVID-19, and it describes the neuroanatomical mechanisms of associated and radiating pain.
MATERIAL AND METHOD
The current study is a meta-analysis study that does not require ethical approval. Studies concerning trigeminal nerve involvement in COVID-19 were obtained from the PubMed and Google Scholar databases, yielding 252 and 607 articles, respectively. Almost 900 articles were published on this topic in 2020 alone. The articles were found and selected using the English-language keywords ‘trigeminal neuralgia’, ‘ocular pain’, ‘coronavirus’, and ‘COVID-19’. Out of 900 articles, 7705 COVID-19 cases (including 728 trigeminal neuralgia cases) from 2019 to 2022 were found to be relevant to this study, but some of these were excluded due to non-sufficient clinical data or study design; ultimately, 7561 COVID-19 cases (including 628 cases of COVID-19 and trigeminal neuralgia) were included for analysis. We further classified the trigeminal neuralgia cases into those with known or unknown causes for associated ocular pain. The data were collected and analysed via Statistical Package for the Social Sciences, version 21.0 which provides the incidence rate of trigeminal neuralgia in 638 cases COVID-19 cases.
RESULTS
We reviewed 7561 cases of COVID-19 and selected 638 cases due to either trigeminal or ophthalmic neuralgia, 638 cases with trigeminal neuralgia (8.4 %); of these, 570 patients (7.8 %) with trigeminal neuralgia presented with COVID-19 and the involvement of ophthalmic neuroglia as a clear reason for ocular pain, while 48 patients (0.6 %) with trigeminal neuralgia and COVID-19 demonstrated ocular pain but with no clear cause. Overall, the patients with ophthalmic glial involvement (92.5 %) outnumbered the patients with no clear cause for ocular pain (7.5 %; Table I, Fig. 1).
DISCUSSION
This meta-analysis found the overall incidence of trigeminal neuralgia (including those with known and unknown reasons for ocular pain, based on history and clinical examination) to be 8.4 % (Table I). The Ocular pain is a symptom of trigeminal neuralgia. Ocular pain was a presenting feature of COVID-19 in 0.8 % to 48.6 % of cases (Table I, Fig. 1), likely caused by the involvement of ophthalmic glia; only Nasiri et al. (2021) reported an incidence consistent with our finding of 7.8 % for this group. This study also found 48 cases with unknown causes of trigeminal neuralgia and no ocular pain or symptoms reported during or after COVID-19 (for an incidence of 0.6 %): Kasimov et al. (2022) reported 28 cases of post-COVID cavernous sinus thrombosis involving the ophthalmic division of the trigeminal nerve, Bohania et al. (2021) reported four cases; Vasanthpuram & Badakere (2021), Ferreira et al. (2020), Zhang et al. (2020), Molina-Gil et al. (2021), Emami & Margolin (2021), and Maksimova et al. (2022) each reported one case; Caggia et al. (2021) reported 10 cases.
Several case studies of trigeminal neuralgia in COVID-19 patients have been reported (Narasimhalu et al., 2021; Kaya & Kaya, 2022; Onoda et al., 2022); these three patients were older than 45 years and presented with a history of comorbid chronic conditions such as diabetes, hypertension with or without hyperlipidaemia, scoliosis, or lasting effects from recurrent brain surgeries. This suggests that trigeminal neuropathy can be the result of other chronic diseases, though Santovito & Pinna (2021) presented a case in which the COVID-19 vaccine was believed to induce trigeminal neuropathy, owing to no other significant findings in history or clinical investigation.
There are several theories to explain the neuropathological mechanism of this interaction. COVID-19 may infect neurons and glial cells (astrocytes and microglia), activating an innate reaction that produces a high serum protein S100B level associated with blood-brain barrier (BBB) permeability resulting in the severity of tissue injury (Aceti et al., 2020). As the viral infection becomes systemic, large amounts of inflammatory mediators such as cytokines, chemokines, interleukins, and antibodies are released, resulting in neural damage and downstream consequences (Klein et al., 2019). During the pandemic, severe COVID-19 was found to be the main cause of mucormycosis infection in 88 % of COVID-19 intensive care unit patients because of compromised immunity; of these cases, 57 % involved the peripheral nervous system (Carlos and Pablo, 2021), 64 % involved the infraorbital nerve, and 52 % involved the maxillary branch of the trigeminal nerve (Bhuskute et al., 2022). Moreover, COVID-19 may infiltrate the nervous system through trans-synaptic neurons or other immunological or meningeal mechanisms affecting the cranial nerves (including the trigeminal nerves), and respiratory and enteric routes can circulate the virus into the brainstem nuclei via the hematogenous route (Franca et al., 2021). The virus can cause trigeminal neuralgia by attacking the trigeminal nuclei located in the brainstem. COVID-19 can also invade the nasal epithelium by binding to ACE2 receptors near the trigeminal nerve sensory branches (Fodoulian et al., 2020), irritation of the maxillary branch leading to redirection of pain to the trigeminal nuclei and neuralgia. Therefore, several mechanisms may explain trigeminal neuralgia in COVID-19.
Based on anatomical interpretation by Al Dorazi & Al Talalwah (2021), COVID-19 may lead to vasculitis, resulting in thrombosis, which can damage the trigeminal nerve. The vessel is lined with a simple squamous endothelial cell as COVID-19 binds to the ACE2 receptor and result in endothelial damage, therefore, the cell does not produce nitric oxide and prostacyclin, which prevents thrombosis. As COVID- 19 binds to the endothelium of Vasa nervorum (the minor artery that supplies the trigeminal nerve or its branches) it produces trigeminal neuralgia. Further, thrombosis of the artery or vein due to COVID-19 causes dilatation, which compresses the nerve. Trigeminal neuralgia may result from vascular compression, as the trigeminal nerve travels along the thrombosing superior and anterior inferior cerebellar arteries and the superior petrosal veins (Hong et al., 2011).
Recently, COVID-19 was found to be a risk fac- tor for cerebral vein thrombosis when combined with a fungal infection or when coronavirus binds with ACE2 receptors, resulting in vasculitis (Al Dorazi & Al Talalwah, 2021). The cavernous sinus and vein are lined by simple squamous endothelial cells, and as COVID-19 binds to the ACE2 receptor, it results in endothelial injury therefore the cell does not produce nitric oxide and prostacyclin which prevent thrombosis. Therefore, cavernous sinus thrombosis is a cerebral vein thrombosis caused by the transmission of the COVID-19 infection through the venous system (either superficial or deep veins such as facial or sinus veins); venous thrombosis can then result in vein engorgement, compressing the trigeminal nerve and leading to neuralgia. Cavernous sinus thrombosis can result from several other conditions, including an infection spread by the ethmoidal veins or sphenoid sinuses (Zhang & Stringer, 2010), changes to the cerebral, meningeal and diploic veins associated with dental procedures (Patel et al., 2020), or improper draining of the superior and inferior alveolar veins into cavernous sinuses. Cerebral vein thrombosis occurs in 13 persons per million annually, while cerebral vein thrombosis including cavernous sinus thrombosis occurs in 22-157 per ten million, and more often in females than in males (Devasagayam et al., 2016) due to hormonal imbalance leading to coagulopathy in several conditions contraceptive use, pregnancy, post- partum changes perimenopause and postmenopause.
Based on the basic venous draining system (Standring, 2005), pathogenic COVID-19 infection transmission can cause cavernous sinus thrombosis through superficial veins that transmit the infection through the facial skin via the superior and inferior ophthalmic veins, as well as through the scalp skin via the supraorbital and supra trochlear veins into the superior ophthalmic veins. Ocular pain is a symptom of COVID-19 (Sen et al., 2021), presenting in 10.3 % to % of cases (Aggarwal et al., 2020; Rokohl et al., 2020). Furthermore, orbital fissure syndrome involving ophthalmoplegia is estimated to occur in 30 % of post- COVID cases of cavernous sinus thrombosis (Kasimov et al., 2022). A maxillary sinus infection can also occur due to COVID-19 infection if the maxillary veins drain backwards into the pterygoid plexus, and then into the cavernous sinuses via the emissary veins. As a result, post-COVID cavernous sinus thrombosis could compress the lateral wall of the trigeminal nerve and produce clinical features or cranial neurological deficits, such as dysfunction of the extraocular muscle, which is innervated by the oculomotor and trochlear nerves and the ophthalmic and maxillary branches of the trigeminal nerve. The trigeminal nerve also innervates the meninges above the tentorium; therefore, a headache can be caused by referred pain from trigeminal irritation or as a result of residual damage to the branch distributions from COVID-19 infection. However, because of its proximity to the cerebral veins, a headache can also be a serious sign of cerebral vein thrombosis if the vein becomes dilated and irritates the meninges. Therefore, physicians should examine the eye and other areas innervated by the cranial nerves using computerised tomography (CT) to exclude or document cavernous thrombosis, which can result in blindness.
Our results suggest that trigeminal neuralgia in these patients is due to compression of the trigeminal nerve by the lateral wall of the cavernous sinuses, and is likely a manifestation of COVID-19. Physicians should be aware of a patient’s risk of developing trigeminal neuralgia during a COVID-19 infection. Awareness of neurologists or neurosurgeons may prevent chronic trigeminal neuralgia caused by COVID- 19, through early medical or surgical intervention treatment. Further, ophthalmologists must be careful when examining patients presenting with trigeminal neuralgia, and they should use adequate personal protective equipment to avoid any spread of infection. The results of this study should also alert health administrators of further risks or potential consequences of a COVID-19 outbreak between medical staff and patients. The limitation of the study is that neurological deficits can develop for up to a year, and irregular follow-up may hide the fact of COVID-19 complications that may become a long-term condition in chronic disease.
