Headache as a Symptom of COVID-19: Narrative Review of 1-Year Research.

PURPOSE OF REVIEW: Headache is a common symptom of COVID-19 with emerging literature being published on the subject. Although it may seem unspecific, scientific evidence has allowed a better definition of this headache type, revealing relevant associations with other COVID-19 symptoms and prognoses. We therefore sought to highlight the most remarkable findings concerning headache secondary to COVID-19, specifically focusing on epidemiology, characteristics, pathophysiology, and treatments. RECENT FINDINGS: The real prevalence of headache as a symptom of COVID-19 is still unclear ranging from 10 to 70%. Headache mainly has a tension-type-like phenotype, although 25% of individuals present with migraine-like features that also occur in patients without personal migraine history. This finding suggests that a likely pathophysiological mechanism is the activation of the trigeminovascular system. SARS-CoV-2 neurotropism can occur by trans-synaptic invasion through the olfactory route from the nasal cavity, leading to anosmia which has been associated with headache. SARS-CoV-2 protein has been found not only in olfactory mucosa and bulbs but also in trigeminal branches and the trigeminal ganglion, supporting this hypothesis. However, other mechanisms such as brain vessels inflammation due to SARS-CoV-2 damage to the endothelium or systemic inflammation in the context of cytokine storm cannot be ruled out. Interestingly, headache has been associated with lower COVID-19 mortality. No specific treatment for COVID-19 headache is available at present. Studies show that investigating COVID-19 headache represents an opportunity not only to better understand COVID-19 in general but also to advance in the knowledge of both secondary and primary headaches. Future research is therefore warranted.

Characterization of Headache in COVID-19: a Retrospective Multicenter Study.

Headache is the most common neurological symptom in COVID-19, reported in 6.5 to 34% of patients. Few studies have analyzed its characteristics, and some of them included cases without laboratory confirmation or reported only critical patients. We aimed to analyze the clinical characteristics of COVID-19 associated headache in laboratory-confirmed cases. We conducted a retrospective evaluation of patients with COVID-19 and neurological symptoms. Patients who reported headache answered an interview about its clinical characteristics. Twenty-four patients with COVID-19 associated headache completed the interview. Mean age of patients was 53.8 (standard deviation-17.44), and 14 out of 24 (58.3%) were male. The majority (75%) had no previous history of headache. Fever was documented in 19 out of the 24 patients (79.1%). Headache was predominantly bifrontal or holocranial, in pressure, during hours, worsening with cough or physical activity. COVID-19 headache tends to appear in the first days of symptoms, be either frontal or holocranial and last for days. The quality of pain in pressure and the worsening with cough or physical activity were reported in most cases. We have not found any characteristic that could differentiate COVID-19 associated headache from other causes of headache, possibly because of its multifactorial mechanism.

Trigeminal herpes zoster and Ramsay Hunt syndrome in an elderly adult: Presentation with prodromal toothache.

OBJECTIVE: This article describes an atypical herpes zoster (HZ) infection heralded by prodromic dental pain. BACKGROUND: Trigeminal HZ is associated with any of the three divisions of the trigeminal nerve, and Ramsay Hunt syndrome is a rare variant of HZ infection of the ear, often accompanied with unilateral facial nerve palsy. MATERIALS AND METHODS: An 87-year-old man sought remedy for tooth-like pain. Within a week, he developed cutaneous, intraoral and otic eruptions, hearing loss, and mild facial palsy. RESULTS: After ruling out odontogenic pain, he was diagnosed with trigeminal HZ and Ramsay Hunt syndrome. CONCLUSION: Herpes zoster infection should be included as a possible aetiologic factor with atypical presentations of odontogenic pain. Diagnosis of trigeminal HZ infection and the Ramsay Hunt syndrome may lead to timely intervention with antivirals and improved patient outcomes.

Herpes zoster ophthalmicus caught in the (Tr)act!

To emphasize the utility of contrast enhanced MRI for identifying the extent of disease in herpes zoster ophthalmicus with intracranial extension to help determine proper management. We present a rare case of herpes zoster ophthalmicus (HZ/HZO) with intracranial extension and MRI demonstration of involvement of the trigeminal nerve, the trigeminal nucleus, and the spinal trigeminal nucleus and tract. Herpes zoster is caused by reactivation of varicella zoster virus. Herpes zoster ophthalmicus with involvement of the ophthalmic division of the trigeminal nerve has been estimated to account for 10-20% of the cases (Yawn et al. in Mayo Clin Proc 88:562-570, 2013). While postherpetic neuralgia is the most common complication, HZ/HZO can rarely manifest in a more sinister manner resulting in multi-dermatomal involvement, disseminated disease, cranial arteritis (Walker in Radiology 107:109-110, 1973), cranial nerve paresis (O.d in Clinical Eye and Vision Care 11:75-80, 1999), hemiplegia (Cavaletti in The Italian Journal of Neurological Sciences 11:297-300, 1990), ocular/dysfunction (Kocaoglu in Türk Oftalmoloji Dergisi 48:42-46, 2018), and intracranial extension (Chen in BMC Infectious Diseases 17:213, 2017; Yawn in Mayo Clin Proc. 88:562-570, 2013). Contrast enhanced MRI (CE-MRI) can be of great benefit to elucidate the extent of disease and intracranial involvement for institution of more aggressive management to prevent further complications.

Vaccine-strain herpes zoster found in the trigeminal nerve area in a healthy child: A case report.

A previously healthy 2-year-old girl, vaccinated for varicella at 17 months, was admitted because of left-sided facial herpes zoster caused by vaccine-strain varicella-zoster virus (VZV). She recovered fully with no complication after intravenous treatment using acyclovir. Earlier reports have described that herpes zoster (HZ) rashes caused by vaccine-strain VZV tend to occur on the dermis corresponding to the skin area where the varicella vaccine was received. However, rashes appeared on this girl only in the trigeminal nerve area, which is unrelated to the vaccinated site. Results underscore the importance of distinguishing vaccine-strain VZV from wild-type VZV whenever encountering HZ cases after vaccination, even in immunocompetent children, irrespective of the skin lesion site. Monitoring vaccine-strain HZ incidence rates is expected to elucidate many aspects of varicella vaccine safety.

Diffusion tensor magnetic resonance imaging of trigeminal nerves in relapsing herpetic keratouveitis.

BACKGROUND: Corneal hypoesthesia is the landmark of HSV and VZV keratitis and can lead to neurotrophic keratitis. Diffusion tensor imaging (DTI) is a new magnetic resonance imaging (MRI) derived technique, which offers possibilities to study axonal architecture. We aimed at assessing the potential impact of recurrent HSV or VZV-related keratitis on the axonal architecture of trigeminal nerves using DTI. DESIGN: Prospective non-interventional study. PARTICIPANTS: Twelve patients and 24 controls. METHODS: DTI using MRI of the trigeminal fibers and corneal esthesiometry using the Cochet-Bonnet esthesiometer were acquired for patients affected by unilateral and recurrent HSV or VZV-related keratitis (3 months after the last corneal inflammatory event), and control subjects with no history of ocular or neuronal disease affecting the trigeminal pathways. MAIN OUTCOME MEASURES: Fractional anisotropy (FA) and apparent diffusion coefficient (ADC) were compared between the 2 eyes of both patients and controls, and correlated with corneal esthesiometry. RESULTS: FA was lower in the trigeminal fibers ipsilateral to the affected eye compared to the non-affected side (0.39±0.02 versus 0.46±0.04, P=0.03). This difference was more important than the intra-individual variability observed in controls. Concomitantly, the asymmetry in ADC results was significantly correlated with the loss of corneal sensitivity in the affected eye. CONCLUSIONS: Corneal hypoesthesia related to HSV and VZV keratitis is associated with persistent modifications in the architecture and functionality of the trigeminal fibers. These results add further explanation to the pathogenesis of HSV and VZV-induced neurotrophic keratitis, which may occur despite an apparent quiescence of the disease.

Trigeminal herpes zoster: early recognition and treatment are crucial.

Reactivation of varicella zoster virus (VZV) is not uncommon in older patients, particularly in cases of chronic autoimmune disorders and in patients taking immunosuppressant drugs. We present a case of a 57-year-old woman presenting with severe herpes zoster infection, involving the maxillary and ophthalmic branches of the trigeminal nerve. Despite an initial delay in instigating crucial antiviral treatment, the patient achieved an excellent recovery, with only some mild scarring at 2 months postinfection. Trigeminal herpes zoster is a potentially devastating clinical occurrence, and is associated with severe long-term neurological sequelae, including encephalitis, vision loss and postherpetic neuralgia. Physicians must be aware of risk factors and treatment modalities.

Effects of antiviral medications on herpetic epithelial keratitis in mice.

PURPOSE: Aciclovir (ACV), valaciclovir (VACV) and famciclovir (FCV) are used for systemic infections caused by herpes virus. In Japan, only topical ACV is permitted for use against herpetic keratitis. We investigated the effectiveness of topical ACV, oral VACV and oral FCV on mouse epithelial herpetic keratitis. METHODS: C57/BL76 mice were inoculated with HSV-1 McKrae strain in the cornea. Once infection was confirmed 4 days after inoculation, topical ACV, oral VACV and FCV were started and administered for 5 days. Control groups were given either topical or oral saline. On days 2, 4, 6 and 10 after medication started, tears, eyeballs, and trigeminal ganglia were examined using viral culture and real-time PCR. RESULTS: Viral culture of tears detected no HSV in the topical ACV group on day 4 after administration start; with similar results for the oral VACV group on day 4; and the oral FCV group on day 6. Real-time PCR of the eyeballs showed significant decrease of HSV DNA copy number in the topical ACV group on days 4 and 6 compared to the topical saline group. Real-time PCR of the trigeminal ganglia showed significant decrease of HSV DNA copy number in the oral VACV group on days 4 and 6, and in the oral FCV group on day 6 compared to the oral saline group. CONCLUSION: We suggest that 5-day administration of topical ACV, oral VACV and oral FCV are effective for mouse epithelial herpetic keratitis and sufficiently decrease HSV amounts in the ocular surface and eyeballs.

Rare involvement of herpes zoster in the mandibular branch of the trigeminal nerve: A case report and review of the literature.

Herpes zoster (HZ) infections rarely affect the mandibular branches of the trigeminal nerve. When the mandibular branches are involved, lesions may appear on the face, in the mouth, in the eye, or on the tongue. Additionally, this condition may be associated with devitalized teeth, internal resorption and spontaneous exfoliation of the teeth, and osteomyelitis of the alveolar bone. In this paper, the treatment of a case HZ of the mandibular branch of the trigeminal nerve is reported, and 22 articles on HZ cases with involvement of the mandibular branch are reviewed. This is the first literature review of HZ cases involving only the mandibular branch of the trigeminal nerve.

Lesión del núcleo del trigémino por virus herpes simple / Lesion of the trigeminal nucleus caused by herpes simplex virus

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[Head and neck space infection presenting with Herpes Simplex virus]. / Bas boyun alan enfeksiyonu ile Herpes Simpleks virüs birlikteligi.

A six-year-old girl was admitted to our clinic with the complaints of swelling, trismus, pain in the submandibular, submental and masticator area and vesicular lesions on the mandibular branch of trigeminal nerve (C5, V3). We present this case of head and neck space infection presenting with Herpes Simplex virus, as it is rarely seen.

An ocular infection model using suckling hamsters inoculated with equine herpesvirus 9 (EHV-9): kinetics of the virus and time-course pathogenesis of EHV-9-induced encephalitis via the eyes.

By using a new member of the neurotropic equine herpesviruses, EHV-9, which induced encephalitis in various species via various routes, an ocular infection model was developed in suckling hamsters. The suckling hamsters were inoculated with EHV-9 via the conjunctival route and were sacrificed after 6, 12, 24, 36, 48, 72, 96, 120, and 144 hours (h) post inoculation (PI). Three horizontal sections of the brains, including the eyes and cranial cavity, were examined histologically to assess the viral kinetics and time-course neuropathological alterations using a panoramic view. At 6 to 24 h PI, there were various degrees of necrosis in the conjunctival epithelial cells, as well as frequent mononuclear cell infiltrations in the lamina propria and the tarsus of the eyelid, and frequent myositis of the eyelid muscles. At 96 h PI, encephalitis was observed in the brainstem at the level of the pons and cerebellum. EHV-9 antigen immunoreactivity was detected in the macrophages circulating in the eyelid and around the fine nerve endings supplying the eyelid, the nerves of the extraocular muscles, and the lacrimal glands from 6 h to 144 h PI. At 96 h PI, the viral antigen immunoreactivity was detected in the brainstem at the level of the pons and cerebellum. These results suggest that EHV-9 invaded the brain via the trigeminal nerve in addition to the abducent, oculomotor, and facial nerves. This conjunctival EHV-9 suckling hamster model may be useful in assessing the neuronal spread of neuropathogenic viruses via the eyes to the brain.

Segmental vitiligo following encephalitis.

We describe a rare account of a patient who developed segmental vitiligo within several months of an episode of viral encephalitis. This case provides further support to the neuronal hypothesis in the etiology of segmental vitiligo. A literature review of the neuronal theory and pathogenesis of vitiligo is further discussed.

Echinacea purpurea polysaccharide reduces the latency rate in herpes simplex virus type-1 infections.

OBJECTIVE: During the latency period of herpes simplex virus type-1 (HSV-1), the virus can occasionally reactivate, travel back to the eye and cause recurrent ocular disease. As this condition arises from the ability of HSV-1 to produce a dormant infection, effective medication to prevent the virus enter a latent state should prevent it. In this study, we applied Echinacea polysaccharide (EP) fraction as prophylactic mediator for latency prevention. METHODS: In order to investigate the protective properties of EP, we evaluated its immunostimulatory functions on different immune aspects that play important roles in latency prevention (particularly IFN-gamma as one of the main indicators of cellular immunity and latency). Finally, we assessed establishment of latency by detection of thymidine kinase gene in trigeminal ganglia of BALB/c mice. RESULTS: We demonstrated that EP promotes immune response, leading to a reduced latency rate, and it has a promising effect on latency prevention. CONCLUSION: EP was able to exert an antiviral action on the development of recurrent HSV-1 disease when supplied prior to infection.

Fewer latent herpes simplex virus type 1 and cytotoxic T cells occur in the ophthalmic division than in the maxillary and mandibular divisions of the human trigeminal ganglion and nerve.

Following primary infection of the mouth, herpes simplex virus type 1 (HSV-1) travels retrogradely along the maxillary (V2) or mandibular (V3) nerve to the trigeminal ganglion (TG), where it establishes lifelong latency. Symptomatic HSV-1 reactivations frequently manifest as herpes labialis, while ocular HSV-1 disease is rare. We investigated whether these clinical observations are mirrored by the distribution of latent HSV-1 as well as cytotoxic T-cell infiltration around the nerve cell bodies and in the nerve fibers. The three divisions of the TG were separated by using neurofilament staining and carbocyanine dye Di-I tracing and then screened by in situ hybridization for the presence of HSV-1 latency-associated transcript (LAT). The T-cell distribution and the pattern of cytolytic molecule expression were evaluated by immunohistochemistry. The Di-I-labeled neurons were largely confined to the nerve entry zone of the traced nerve branches. Very few Di-I-labeled neurons were found in adjacent divisions due to traversing fiber bundles. LAT was abundant in the V2 and V3 divisions of all TG but was scarce or totally absent in the ophthalmic (V1) division. CD8(+) T cells were found in all three divisions of the TG and in the respective nerves, clearly clustering in V2 and V3, which is indicative of a chronic inflammation. Only T cells surrounding neurons in the V2 and V3 ganglionic divisions expressed granzyme B. In conclusion, the large accumulation of LAT and cytotoxic T cells in the V2 and V3 but not in the V1 division of the TG reflects the sites supplied by the sensory fibers and the clinical reactivation patterns.

Trigeminal trophic syndrome with extensive ulceration following herpes zoster.

The trigeminal trophic syndrome is a rare complication following central or peripheral injury of the trigeminal nerve typically characterized by unilateral distribution of anaesthesia, paraesthesia and ulceration. In one third of cases it is preceded by an iatrogenic damage of the trigeminal nerve, in another third by a history of stroke. Other causes include head trauma, intracranial tumours, herpes virus infection, degenerative diseases of the CNS and idiopathic. Little is known about the pathogenesis. Contribution of neurotrophic factors and an altered sympathetic activity is assumed but a pivotal role of self-mutilation is generally accepted. We report a case of a patient who developed a strictly unilateral crescent ulcer of the ala nasi in addition to an extensive ulceration of the forehead and scalp following herpes zoster ophthalmicus.