Purpose of Review To describe the possible neuroinvasion pathways of Severe Acute Respiratory Syndrome-related Coronavirus-2 (SARS-CoV-2), the virus responsible for the Coronavirus disease-19 (Covid-19) pandemic. Recent Findings We present data regarding the family of Coronaviruses (CoVs) and the central nervous system (CNS), and describe parallels between SARS-CoV-2 and other members of the family, which have been investigated in more depth and combine these findings with the recent advancements regarding SARS-CoV-2. Summary SARS-CoV-2 like other CoVs is neuroinvasive, neurotropic and neurovirulent. Two main pathways of CNS penetration seem to be the strongest candidates, the hematogenous and the neuronal. Τhe olfactory route in particular appears to play a significant role in neuroinvasion of coronaviruses and SARS-CoV-2, as well. However, existing data suggest that other routes, involving the nasal epithelium in general, lymphatic tissue and the CSF may also play roles in SARS-CoV-2 invasion into the CNS.

BackgroundSleep disorders and circadian dysregulation appear to be associated with primary headache disorders.ObjectiveThe aim of this study was to review the existing evidence for the deployment of melatonin in migraine prophylaxis. Initially, case‐control studies investigating nocturnal melatonin and 6‐sulphatoxymelatonin (aMT6s, melatonin metabolite discarded by the urine) levels in patients with migraine and healthy controls (HC) would be reviewed and meta‐analyzed. Second, results from randomized controlled trials (RCTs) and non‐randomized studies evaluating the use of melatonin in migraine would be synthesized.MethodsMEDLINE EMBASE, CENTRAL, PsycINFO, trial registries, Google Scholar, and OpenGrey were comprehensively searched. The quality of studies was assessed according to the Newcastle‐Ottawa Scale (case‐control studies) and the Risk‐of‐Bias Cochrane tool (RCTs). Random‐effects (RE) or fixed‐effects (FE) model was used based on heterogeneity among studies (homogeneity assumed when PQ > 0.1 and I2 < 30%). Publication bias was assessed by funnel plots.ResultsLiterature search provided 11 case‐control studies. Evidence was compatible with lower nocturnal serum [5 of 6 studies were synthesized due to deficient reporting of 1 abstract, migraine n = 197, HC n = 132, RE MD = −12.29 pg/ml, 95%CI = (−21.10, −3.49)] and urinary melatonin [3 studies, migraine n = 30, HC n = 29, RE MD = −0.12 nmol/nocturnal (12 hours) urinary collection, 95%CI = (−0.22, −0.03)], as well as urine aMT6s levels [1 study, migraine n = 146, HC n = 74, MD = −11.90 μg/nocturnal (12 hours) urine collection, 95%CI = (−19.23, −4.57)] in adult migraine patients compared to HC [1 study involving children did not reveal any difference regarding nocturnal urine aMT6s, n = 18 per group, MD = −6.00 μg/nocturnal (12 hours) urine collection, 95%CI = (−21.19, 9.19)]. Regarding the treatment‐prevention of migraine, 7 RCTs and 9 non‐randomized studies were retrieved. Data synthesis was not feasible for the comparison of melatonin and placebo due to the existing clinical and methodological heterogeneity of the 5 relevant RCTs. Overall, melatonin was more efficacious and equally safe with placebo in the prevention of migraine in adults (3 of 4 RCTs provided superior efficacy results for melatonin, 1 RCT revealed no difference regarding Headache Frequency ‐HF‐), while there are limited data for children (1 RCT revealed no difference against placebo regarding HF). Additionally, no difference was revealed between melatonin and amitriptyline (1 RCT), sodium valproate (1 RCT) or propranolol (1 non‐randomized study) with respect to their efficacy in adults with migraine, while melatonin was more effective than pizotifen (1 RCT). In children with migraine, amitriptyline is more efficacious regarding most assessed parameters (2 studies, n = 85 per group, HF: RE MD = 4.03, 95%CI = (2.64, 5.42), Headache Duration: RE MD = 0.72, 95%CI = (0.41, 1.03), Headache Severity: FE MD = 1.57, 95%CI = (1.13, 2.00), Response to Treatment: FE MD = 0.33, 95%CI = (0.16, 0.69), Headache Induced Disability Severity: RE MD = 6.07, 95%CI = (−11.87, 24.01 ), Analgesic Consumption – assessed in 1 study, n = 40 per group – MD = 1.11, 95%CI = (−0.10, 2.32)), although melatonin presents a superior safety profile than amitriptyline both in adults and in children.ConclusionsMelatonin may be of potential benefit in the treatment‐prevention of migraine in adults, but complementary evidence from high‐quality RCTs is required.

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