There are consolidated data about multiple sclerosis (MS)–dependent retinal neurodegeneration occurring in the optic disk and the macula, although it is unclear whether other retinal regions are affected. Our objective is to evaluate, for the first time, the involvement of the entire retinal posterior pole in patients diagnosed with relapsing remitting multiple sclerosis (RRMS) unaffected by optic neuritis using Spectral Domain–Optical Coherence Tomography (SD–OCT). The study protocol was approved by Tor Vergata Hospital Institutional Ethics Committee (Approval number 107/16), and conforms to the tenets of the Declaration of Helsinki. After a comprehensive neurological and ophthalmological examination, 53 untreated RRMS patients (aged 37.4 ± 10) and 53 matched controls (aged 36.11 ± 12.94) were enrolled. In addition, each patient underwent an examination of the posterior pole using the SD-OCT built-in Spectralis posterior pole scanning protocol. After segmentation, the mean thickness, as well as the thickness of the 64 single regions of interest, were calculated for each retinal layer. No statistically significant difference in terms of average retinal thickness was found between the groups. However, MS patients showed both a significantly thinner ganglion cell layer (p < 0.001), and, although not statistically significant, a thinner inner nuclear layer (p = 0.072) and retinal nerve fiber layer (p = 0.074). In contrast, the retinal pigment epithelium (p = 0.014) and photoreceptor layers p < 0.001) resulted significantly thicker in these patients. Interestingly, the analysis of the region of interest showed that neurodegeneration was non-homogeneously distributed across each layer. This is the first report that suggests a complex rearrangement that affects, layer by layer, the entire retinal posterior pole of RRMS retinas in response to the underlying neurotoxic insult.

Introduction: Refractory and super-refractory status epilepticus are medical emergencies that must be promptly treated in consideration of their high mortality and morbidity rate. Nevertheless, the available evidence of effective treatment for these conditions is scarce. Among novel antiseizure medications (ASMs), highly purified cannabidiol (hpCBD) has shown noteworthy efficacy in reducing seizures in Lennox-Gastaut syndrome, Dravet syndrome, and Tuberous Sclerosis Complex. Case Presentation: Here, we present two cases of effective use of hpCBD in both refractory and super- refractory status epilepticus. The administration of the nasogastric tube permitted the resolution of status epilepticus without adverse events. At 6-month follow-up, both patients were on hpCBD treatment, which continued to be efficacious for treating seizures. Conclusion: According to our experience, hpCBD should be taken into consideration as an add-on therapy of RSE and SRSE while also considering the possibility of maintaining this treatment during the follow-up of patients. However, more studies and real-world experiences are needed to better understand its effectiveness in this setting and the interaction with other ASMs.

We've read with remarkable interest the paper "Adverse event reports of seizure for insomnia medication from 1967 to 2023" published on Scientific Reports in July 2025, in which Authors investigated the risk to induce seizures of different drugs used for the treatment of insomnia. (Kim et al., 2025) In this study, the Authors reported the results of the American Insomnia Survey done in 2020 (in which up to 22% of responders met the criteria for insomnia) and highlighted how clinicians very frequently tend to treat insomnia with hypnotic medications, especially in consideration of the lack of accessibility to cognitive behavioural therapy for insomnia (CBT-i) (Dopheide et al., 2020). The common practice to prescribe hypnotics happens despite the lack of robust randomized trials, that must always be conducted to minimize drug-related side effects. The authors reviewed a vast dataset deriving from the reports of adverse events related to medications used for the treatment of insomnia from 140 countries between 1967 and 2013, evaluating the seizure risk associated with these medications measured as reported odds ratio (ROR). They found that seizures were significantly associated with various hypnotic medications including benzodiazepines, Z-drugs, antidepressants, melatonin, atypical antipsychotics and first-generation H1 antagonists. No association was found between seizures risk and melatonin receptor agonists and dual orexin receptor antagonists (DORAs).The presented study is one of the most valuable in the field, in considerations of the huge number of case reports and adverse events reviewed. Nevertheless, the authors do not explore the underlying pathophysiological mechanisms useful to explain why some drugs are associated to seizure risk (like benzodiazepines, Z-drugs and antipsychotic) and others are not (like DORAs). Moreover, the Authors did not discuss about the controversial results regarding the increased risk for seizures of melatonin and the lack of association between melatonergic receptor agonists and seizure occurrence.Insomnia is a high common sleep disorder in the general population. Chronic insomnia may affect approximately 10% to 12% of adults, with an additional 15% to 20% reporting occasional insomnia symptoms (Morin et al., 2024;van Straten et al., 2025, Benjafield et al., 2025;Jeste et al., 2022;Winkelman et al., 2015;Rosenberg et al., 2021). When broader definitions are used, such as any insomnia symptoms or sleep dissatisfaction, prevalence rates can reach up to one-third of adults (Jeste et al., 2022, Ohayon 2022).Translating the results of the study in the common clinical practice, the importance of these findings also regards the frequency of sleep disorders in people with epilepsy (PwE) and the importance of promoting sleep without increasing the risk of seizures in PwE.Therefore, to complete the discussion of the study "Adverse event reports of seizure for insomnia medication from 1967 to 2023", we do believe that both preclinical and clinical evidence should be cited in order to explain the Authors' findings.Orexin (hypocretin) neurons, located in the lateral hypothalamus, play an extensive role in the regulation of the sleep-wake cycle. During wakefulness it can be registered the highest orexinergic activity, which then decreases during slow-wave sleep and is virtually absent during rapid eye movement (REM) sleep. (Schwartz and Kilduff, 2015) This circadian rhythm mirrors oscillations in the activity of cortical ad subcortical brain structures. The high firing of orexinergic neurons stabilizes wakefulness through cortical desynchronization, on the contrary a weak orexinergic activity consolidates slow-wave sleep enhancing the thalamocortical synchronization (Scammell, 2015). Since seizures are often associated with transitions from wakefulness to sleep and vice versa, sleep stability should be targeted for preventing the risk for nocturnal seizures. Moreover, sleep exerts beneficial effects on epileptogenesis and therefore maintaining the sleep-wake cycle regularity and the regulation of the physiological sleep are both targets for reducing the risk for seizures in PwE.According to this, we may hypothesize that the pharmacological antagonism to orexin receptors, exerted by DORAs, might reduce the risk of seizures. Accordingly, both preclinical and clinical studies suggests that DORAs do not increase seizure risk and may play an anticonvulsant role instead.Experiments in animal models showed, indeed, that orexinergic agonism produces proconvulsant effects and conversely orexinergic antagonism, that mirrors the neuronal silence observed in REM sleep (a state characterized by low seizure susceptibility) exerts anticonvulsant effects. The direct administration of orexin-A and orexin-B into the cortex increases epileptiform activity, measured in terms of spike number, amplitude, and EEG spectral power, as well as seizure-related motor manifestations. (Kortunay et al., 2012) At the cellular level, orexins enhance hippocampal neuronal excitability and increase excitatory neurotransmitter release (Chen et al., 2017). In experimental rats exposed to proconvulsant agents such as pilocarpine, pentylenetetrazol (PTZ), and maximal electroshock induced seizures, it has been demonstrated an upregulation in orexin expression in the hippocampus (Morales et al., 2006, Socała et al., 2016). In contrast, both orexin-1 receptor (OX1R) antagonists (e.g., SB-334867) and orexin-2 receptor (OX2R) antagonists (e.g., TCS OX2 29) attenuate seizure severity and duration in PTZ models when administered intrahippocampally or intracerebroventricularly (Goudarzi et al., 2015).DORAs, including suvorexant, an FDA-approved therapy for insomnia, significantly reduce seizure duration in PTZ mice. Suvorexant may exert additional modulatory effects via GABA-A and glutamate receptors (Razavi et al., 2020). Furthermore, in sleep-deprived Wistar rats, both OX1R and OX2R antagonists delayed...

• Agomelatine and escitalopram improved depressive symptoms in people with epilepsy. • Seizure frequency, sleep and daytime alertness were unaffected by antidepressant treatment. • Escitalopram showed more consistent benefits on mood and quality of life.