Primary headaches prevalence, characteristics, and healthcare utilization in Italian medical students.

BACKGROUND: Among university students, migraine is notably prevalent and is linked to compromised academic performance and daily functioning. Medical students are a particularly vulnerable category due to the demanding nature of their training, as they are often exposed to headache trigger factors. We therefore aimed to determine the prevalence, characteristics, and healthcare-seeking practices of primary headaches among Italian medical students. METHODS: We conducted a cross-sectional study among medical students attending the Università Cattolica del Sacro Cuore in Rome who completed a self-administered questionnaire designed following the International Classification of Headache Disorders-3 criteria. The questionnaire assessed sociodemographic and headache features, healthcare utilization, the use of symptomatic and preventive treatment, and headache trigger factors. RESULTS: Five hundred thirty-six students filled out the questionnaire. The lifetime and last-year prevalence of headache in this cohort was 76.7% (n = 411). Among the students surveyed, migraine had a prevalence of 26.9%, probable migraine of 12.9%, and tension-type headache (TTH)/probable TTH of 36.9%. Two hundred and forty-six students (59.8%) reported that their headache worsened after starting university. All students reporting headache had at least one trigger factor. In students fulfilling the criteria for migraine (n = 144), 137 (95.1%) had previously used acute non-prescription treatments, and eight concurrently used a preventive treatment. Thirty-five students fulfilling the criteria for migraine underwent a brain MRI scan (24.3%), 43 performed a neurological evaluation (29.9%), 36 received a diagnosis of migraine (25%), and 20 (13.9%) accessed the emergency room. DISCUSSION: Migraine and TTH are common among medical students in Italy despite low healthcare resource utilization. These results support the need to promote public health policies and strategies in order to reduce the disability and burden associated with primary headaches among medical students.

Exploring the emotional and behavioural profile in paediatric narcolepsy type 1: A case-control study.

Narcolepsy type 1 (NT1) is a central disorder of hypersomnolence often arising in childhood and adolescence. NT1 has a significant, but poorly defined, psychological impact. We aimed to investigate the psycho-social functioning of children and adolescents with NT1. We performed a cross-sectional, child and parent-reported questionnaire survey in 37 children and adolescents (6-17 years) with NT1, compared with age- and sex-matched controls. Questionnaires (SSHS, ESS-CHAD, CDI, MASC, CBCL, CRS-R, and SNAP-IV) evaluated various aspects of behavioural and emotional profiles, sleep habits, and daytime sleepiness. Subsequently, NT1 intra-group analysis was performed to investigate the effect of sex (males vs females) and pharmacological treatment (treated vs non-treated) on psychological features. The NT1 questionnaires total scores were then correlated with the clinical characteristics (age, body mass index [BMI], ESS-CHAD score, cerebrospinal hypocretin-1 [Hcrt-1] levels, and diagnostic delay). Patients with NT1 showed a higher tendency to depressive symptoms, anxiety, somatisation, inattention, hyperactivity, oppositional/defiant problems, and other maladaptive behaviours compared with controls. Among NT1 patients, females showed a higher propensity to anxiety, and non-treated patients displayed higher depressive symptoms. Psychological symptoms increased with age, BMI, and daytime sleepiness in patients with NT1, while a younger age was associated with more frequent somatisation symptoms. Lower cerebrospinal Hcrt-1 levels correlated with poorer social competencies, daily activities, and inattention. Diagnostic delay was associated with a higher impact of depressive symptoms and behavioural problems. NT1 in children and adolescents is associated with poorer functioning in multiple psychological domains calling for a multidisciplinary approach and monitoring to reduce disease burden and to prevent psychiatric consequences.

Autoimmune encephalitis during pregnancy: A diagnostic and therapeutic challenge-A systematic review with individual patients' analysis and clinical recommendations.

Several reports have described the autoimmune encephalitis' (AE) possible onset during pregnancy. In this systematic review, we summarize the available data on the diagnostic and therapeutic approach to AE during pregnancy, highlighting the associated maternal and fetal clinical outcomes. A systematic search of the literature was performed. The following databases were used: PubMed, Google Scholar, EMBASE, and CrossRef. The revision was registered on the PROSPERO platform (CRD42022336357). Forty-nine patients were included. AE onset was mainly observed during the first and the second trimester of pregnancy with psychiatric manifestations and seizures as main onset symptoms. CSF analysis showed AE-specific autoantibody positivity in 33 patients (anti-NMDA receptor as the most frequent). EEG generally showed normal findings. MRI revealed pathological findings in less than half of patients. Tumor screening was positive in 14 cases. First-line immunotherapy (single or combined) was generally employed while second line was administered in a minority of patients. Levetiracetam was the most used antiseizure medication. Cesarean section was performed in 18 women. Most of the women had an excellent early outcome after delivery but 22 showed persistent neurological deficits in long-term follow-up. Fetal outcome was positive in 33 cases, whereas 12 cases of fetal death were reported. A logistic regression showed that no variable significantly influenced the odds of good/bad maternal and fetal clinical outcome. Diagnosis and treatment of AE during pregnancy is challenging. The rate of miscarriage in women with AE seems to be higher than the general population. In addition, mothers may show long-term neurological deficits.

Microvascular involvement in migraine: an optical coherence tomography angiography study.

OBJECTIVE: The aim of this study was to evaluate the microvasculature of the macula and the optic nerve in patients affected by migraine with aura (MA) and without aura (MO) by optical coherence tomography angiography (OCTA), comparing the findings with healthy controls (HC). METHODS: We collected data from ocular and orthotic examinations, including eye motility, intraocular pressure measurement, best-corrected visual acuity (BCVA) measurement, objective refraction measurement, fundus examination, macular and optic disk OCTA examination. All subjects were imaged with solix fullrange OCT. The following OCTA parameters were recorded: macular vessel density (VD), inside disc VD, peripapillary VD, disc whole image VD, fovea choriocapillaris VD, fovea VD, parafovea VD, peripapillary thickness, fovea thickness, parafovea thickness, macular full retinal thickness, and foveal avascular zone (FAZ) parameters. Clinical and demographical data about migraine patients were collected by a neurologist. RESULTS: We included 56 eyes from 28 patients with a diagnosis of MO, 32 eyes from 16 patients with a diagnosis of MA, and 32 eyes from 16 HC subjects. The FAZ area was 0.230 ± 0.099 mm2 in the MO group, 0.248 ± 0.091 mm2 in the MA group and 0.184 ± 0.061 mm2 in the control group. The FAZ area was significantly larger in the MA group than in the HC group (p = 0.007). The foveal choriocapillaris VD was significantly lower in MA patients (63.6 ± 2.49%) when compared with MO patients (65.27 ± 3.29%) (p = 0.02). CONCLUSION: An impairment of retinal microcirculation can be detected in patients with MA, as demonstrated by the enlargement of FAZ. Moreover, the study of choroid circulation may reveal microvascular damage in patients with migraine with aura. OCTA is a useful non-invasive screening tool for the detection of microcirculatory disturbance in patients with migraine.

A retrospective multicentric study on the effectiveness of intravenous brivaracetam in seizure clusters: Data from the Italian experience.

OBJECTIVE: Nearly half of people with epilepsy (PWE) are expected to develop seizure clusters (SC), with the subsequent risk of hospitalization. The aim of the present study was to evaluate the use, effectiveness and safety of intravenous (IV) brivaracetam (BRV) in the treatment of SC. METHODS: Retrospective multicentric study of patients with SC (≥ 2 seizures/24 h) who received IV BRV. Data collection occurred from January 2019 to April 2022 in 25 Italian neurology units. Primary efficacy outcome was seizure freedom up to 24 h from BRV administration. We also evaluated the risk of evolution into Status Epilepticus (SE) at 6, 12 and 24 h after treatment initiation. A Cox regression model was used to identify outcome predictors. RESULTS: 97 patients were included (mean age 62 years), 74 (76%) of whom had a history of epilepsy (with drug resistant seizures in 49% of cases). BRV was administered as first line treatment in 16% of the episodes, while it was used as first or second drug after benzodiazepines failure in 49% and 35% of episodes, respectively. On the one hand, 58% patients were seizure free at 24 h after BRV administration and no other rescue medications were used in 75 out of 97 cases (77%) On the other hand, SC evolved into SE in 17% of cases. A higher probability of seizure relapse and/or evolution into SE was observed in patients without a prior history of epilepsy (HR 2.0; 95% CI 1.03 - 4.1) and in case of BRV administration as second/third line drug (HR 3.2; 95% CI 1.1 - 9.7). No severe treatment emergent adverse events were observed. SIGNIFICANCE: In our cohort, IV BRV resulted to be well tolerated for the treatment of SC and it could be considered as a treatment option, particularly in case of in-hospital onset. However, the underlying etiology seems to be the main outcome predictor.

Heart rate variability modification as a predictive factor of sudden unexpected death in epilepsy: How far are we? A systematic review and meta-analysis.

BACKGROUND: Sudden unexpected death in epilepsy (SUDEP) is a sudden, unexpected death in people with epilepsy, with or without evidence of an epileptic seizure. The pathophysiological mechanism underlying SUDEP appears to be partly associated with an autonomic nervous system (ANS) dysfunction. Heart rate variability (HRV) analysis is a reliable, non-invasive method for detecting fluctuations in the ANS. In this systematic review we analyzed the data available in the literature on changes in HRV parameters in patients with SUDEP. METHODS: We carried out a systematic search of the literature to identify the quantitative variations of HRV in epileptic patients with SUDEP. The following databases were used: Pubmed, Google Scholar, EMBASE, and CrossRef. A pooled analysis was carried out, and the results obtained were compared using mean difference (MD). The review was registered on the PROSPERO platform (CRD42021291586). RESULTS: Seven articles were included, with a total of 72 SUDEP cases associated with altered HRV parameters. Generally, a reduction of SDNN (standard deviation of the RR intervals) and RMSSD (root mean square differences of successive RR intervals) was reported in most SUDEP patients. According to MD, the SUDEP patients showed no differences in time and frequency domain parameters compared to controls. However, a trend toward increased low frequency and high frequency ratio (LF/HF) was observed in the SUDEP patients. CONCLUSIONS: HRV analysis is a valuable method for assessing cardiovascular risk and cardioautonomic impairment. Although a possible association between HRV variation and SUDEP has been reported, further studies are needed to assess the potential role of HRV modifications as a SUDEP biomarker.

Association of Obstructive Sleep Apnea and Atrial Fibrillation in Acute Ischemic Stroke: A Cross-Sectional Study.

Background: There is a growing body of evidence suggesting a link between obstructive sleep apnea (OSA) and atrial fibrillation (AF). The primary objective of this study is to evaluate the association between OSA and AF in acute ischemic stroke. The secondary objective is to describe the clinical features of patients with acute ischemic stroke and concomitant OSA. Methods: We enrolled consecutive patients with acute ischemic stroke. All patients underwent full-night cardiorespiratory polygraphy. To determine if there is an association between AF and OSA, we compared the observed frequency of this association with the expected frequency from a random co-occurrence of the two conditions. Subsequently, patients with and without OSA were compared. Results: A total of 174 patients were enrolled (mean age 67.3 ± 11.6 years; 95 males). OSA and AF were present in 89 and 55 patients, respectively. The association OSA + AF was observed in 33/174 cases, which was not statistically different compared to the expected co-occurrence of the two conditions. Patients with OSA showed a higher neck circumference and body mass index, a higher prevalence of hypertension and dysphagia, and a higher number of central apneas/hypoapneas. In the multivariate analysis, dysphagia and hypertension were independent predictors of OSA. A positive correlation was observed between OSA severity, BMI, and neck circumference. The number of central apneas/hypoapneas was positively correlated with stroke severity. Conclusions: Our data suggest that OSA and AF are highly prevalent but not associated in acute stroke. Our findings support the hypothesis that OSA acts as an independent risk factor for stroke.

Heart rate variability modifications in adult patients with early versus late-onset temporal lobe epilepsy: A comparative observational study.

OBJECTIVES: Temporal lobe epilepsy (TLE) is the most frequent form of focal epilepsy. TLE is associated with cardio-autonomic dysfunction and increased cardiovascular (CV) risk in patients over the fifth decade of age. In these subjects, TLE can be classified as early-onset (EOTLE; i.e., patients who had developed epilepsy in their youth) and late-onset (LOTLE; i.e., patients who developed epilepsy in adulthood). Heart rate variability (HRV) analysis is useful for assessing cardio-autonomic function and identifying patients with increased CV risk. This study compared changes in HRV occurring in patients over the age of 50, with EOTLE or LOTLE. METHODS: We enrolled twenty-seven adults with LOTLE and 23 with EOTLE. Each patient underwent a EEG and EKG recording during 20-minutes of resting state and a 5-minutes hyperventilation (HV). Short-term HRV analysis was performed both in time and frequency domains. Linear Mixed Models (LMM) were used to analyze HRV parameters according to the condition (baseline and HV) and group (LOTLE and EOTLE groups). RESULTS: Compared to the LOTLE group, the EOTLE group showed significantly decreased LnRMSSD (natural logarithm of the root mean square of the difference between contiguous RR intervals) (p-value=0.05), LnHF ms2 (natural logarithm of high frequency absolute power) (p-value=0.05), HF n.u. (high frequency power expressed in normalized units) (p-value=0.008) and HF% (high frequency power expressed in percentage) (p-value=0.01). In addition, EOTLE patients exhibited increased LF n.u. (low frequency power expressed in normalized units) (p-value=0.008) and LF/HF (low frequency/high frequency) ratio (p-value=0.007). During HV, the LOTLE group exhibited a multiplicative effect for the interaction between group and condition with increased LF n.u. (p = 0.003) and LF% (low frequency expressed in percentage) (p = 0.05) values. CONCLUSIONS: EOTLE is associated with reduced vagal tone compared to LOTLE. Patients with EOTLE may have a higher risk of developing cardiac dysfunction or cardiac arrhythmia than LOTLE patients.

Validation of the Italian version of the Cluster Headache Impact Questionnaire (CHIQ).

BACKGROUND: The Cluster Headache Impact Questionnaire (CHIQ) is a specific and easy-to-use questionnaire to assess the current impact of cluster headache (CH). The aim of this study was to validate the Italian version of the CHIQ. METHODS: We included patients diagnosed with episodic CH (eCH) or chronic CH (cCH) according to the ICHD-3 criteria and included in the "Italian Headache Registry" (RICe). The questionnaire was administered to patients through an electronic form in two sessions: at first visit for validation, and after 7 days for test-retest reliability. For internal consistency, Cronbach's alpha was calculated. Convergent validity of the CHIQ with CH features and the results of questionnaires assessing anxiety, depression, stress, and quality of life was evaluated using Spearman's correlation coefficient. RESULTS: We included 181 patients subdivided in 96 patients with active eCH, 14 with cCH, and 71 with eCH in remission. The 110 patients with either active eCH or cCH were included in the validation cohort; only 24 patients with CH were characterized by a stable attack frequency after 7 days, and were included in the test-retest cohort. Internal consistency of the CHIQ was good with a Cronbach alpha value of 0.891. The CHIQ score showed a significant positive correlation with anxiety, depression, and stress scores, while showing a significant negative correlation with quality-of-life scale scores. CONCLUSION: Our data show the validity of the Italian version of the CHIQ, which represents a suitable tool for evaluating the social and psychological impact of CH in clinical practice and research.

Treatment of benzodiazepine-refractory status epilepticus: A retrospective, cohort study.

INTRODUCTION: Status epilepticus (SE) is a frequent neurological emergency, derived from the failure of mechanisms responsible for seizure termination. The present study aims to compare the efficacy of the most common antiseizure medications (ASMs) employed for the treatment of benzodiazepine-refractory SE. METHODS: We performed a retrospective cohort study of all SE episodes treated in our hospital between January 2016 and December 2020. Inclusion criteria were: age ≥ 18 years; a diagnosis of status epilepticus. Exclusion criteria were: status epilepticus resolved by initial therapy with benzodiazepines; impossibility to retrieve medical records. We considered as effective the ASM that was the last drug introduced or increased in dose before termination of SE and without changes in the co-medication. RESULTS: A total of 244 episodes in 219 patients were included in the study. The mean age of the final study cohort was 63.6 ± 19.2, with 108 (49%) men. In the total cohort, phenytoin (PHT) showed the highest response rate (57.6%), followed by lacosamide (LCM) (40.7%) and valproate (VPA) (39.8%). The comparative efficacy among the different drugs was significantly different (p < 0.001). In the pairwise comparisons, VPA was superior to levetiracetam (LEV) (response rate: 39.75% vs 24.71%; p = 0.004), but not to LCM. Phenytoin had a significantly higher resolution rate compared to VPA (response rate: 57.63% vs 39.75%; p = 0.02) and LEV (response rate: 57.63% vs 24.71; p < 0.001). The clinical predictors of anaesthetics administration were a disorder of consciousness upon clinical presentation, previous diagnosis of epilepsy, and younger age. CONCLUSION: In our cohort of SE, PHT showed higher effectiveness in terminating established SE, as well as refractory SE in the subgroup of patients treated with anaesthetics.

Antiseizure Medications for the Prophylaxis of Migraine during the Anti- CGRP Drugs Era.

Migraine and epilepsy are fundamentally distinct disorders that can frequently coexist in the same patient. These two conditions significantly differ in diagnosis and therapy but share some widely- used preventive treatments. Antiseizure medications (ASMs) are the mainstay of therapy for epilepsy, and about thirty different ASMs are available to date. ASMs are widely prescribed for other neurological and non-neurological conditions, including migraine. However, only topiramate and valproic acid/valproate currently have an indication for migraine prophylaxis supported by high-quality evidence. Although without specifically approved indications and with a low level of evidence or recommendation, several other ASMs are used for migraine prophylaxis. Understanding ASM antimigraine mechanisms, including their ability to affect the pro-migraine calcitonin gene-related peptide (CGRP) signaling pathway and other pathways, may be instrumental in identifying the specific targets of their antimigraine efficacy and may increase awareness of the neurobiological differences between epilepsy and migraine. Several new ASMs are under clinical testing or have been approved for epilepsy in recent years, providing novel potential drugs for migraine prevention to enrich the treatment armamentarium and drugs that inhibit the CGRP pathway.

Psychogenic non-epileptic seizures (PNES) in the COVID-19 pandemic era: A systematic review with individual patients' analysis.

OBJECTIVE: Psychogenic non-epileptic seizures (PNES) resemble epileptic seizures but are not due to underlying epileptic activity and in some cases coexist alongside epilepsy. We described the clinical characteristics of patients with PNES as reported in the literature from the outbreak of the COVID-19 pandemic. We evaluated differences between patients with a diagnosis made immediately before the pandemic (pPNES) and those newly diagnosed during it (nPNES). METHODS: A systematic search with individual patient analysis of PNES cases published since the COVID-19 pandemic outbreak was performed. Differences between pPNES and nPNES were analyzed using Chi-square or Fisher exact test. RESULTS: Eleven articles were included, with 133 patients (106 pPNES and 27 nPNES). In the pPNES group, PNES frequency increased during the pandemic in 20/106 patients, whereas in 78/106, the frequency remained stable or decreased. nPNES was associated with higher risks of SARS-CoV-2 infection and epilepsy diagnosis, whereas psychiatric comorbidities were less frequent. CONCLUSIONS: During the pandemic, most patients with pPNES remained stable or improved, whereas nPNES was associated with a lower burden of psychiatric comorbidities. These intriguing findings suggest that, at least in some patients, the COVID-19 pandemic may not necessarily lead to worsening in the frequency of PNES and quality of life.

Validation Study of the Richards-Campbell Sleep Questionnaire in Patients with Acute Stroke.

Sleep disorders are frequent in acute stroke. The Richards-Campbell Sleep Questionnaire (RCSQ) is a validated scale for the sleep assessment in intensive care unit. The aim of the present study is to validate RCSQ for use in patients with acute stroke. We performed a validation study by comparing the RCSQ with polysomnography (PSG), the standardized measure of sleep. Inclusion criteria were age ≥ 18 years and a radiologically confirmed diagnosis of stroke. Exclusion criteria were global aphasia, extreme severity of clinical conditions and inability to attend PSG. All patients underwent PSG in a stroke unit, the day after a subjective sleep assessment by means of the RCSQ. The RCSQ was compared with PSG parameters to assess the degree of concordance of the two measures. The cohort consisted of 36 patients. Mean RCSQ score was 61.5 ± 24.8. The total score of the RCSQ showed a good degree of concordance with the sleep efficiency index of PSG. Accuracy of the RCSQ was 70%, sensitivity 71% and specificity 68%. The RCSQ is a good tool for screening the sleep quality in the setting of a stroke unit. Therefore, it could be useful to select the patients who might beneficiate from an instrumental sleep evaluation.

Preventive migraine treatment in mitochondrial diseases: a case report of erenumab efficacy and literature review.

Migraine is a common condition in mitochondrial diseases, with a higher prevalence than in the general population. Although several clinical studies support the hypothesis that mitochondrial dysfunction plays a central role in the pathophysiology of migraine, currently there are few data in the literature regarding the efficacy and safety of drugs for the treatment and prophylaxis for this condition in patients with primary mitochondrial disorders. We report a 37-year-old woman affected by mitochondrial disease with progressive external ophthalmoplegia phenotype (PEO) associated with POLG mutation effectively treated with erenumab, in the absence of side effects. Monoclonal antibodies against the calcitonin gene-related peptide (CGRP) or against its receptor are innovative and specific therapies for migraine prophylaxis. This class of drugs is particularly suitable for subjects, such as those suffering from genetically determined mitochondrial dysfunction, in which pharmacological management can represent a challenge due to the nature of these neurogenetic disorders and/or the frequently associated comorbidities.

Theory of Mind in migraine and medication-overuse headache: A cross-sectional study.

Background: Theory of Mind (ToM) is the ability to predict and anticipate others' behaviors through the mental state attribution process. This study aims to investigate the ToM in patients with medication-overuse headache (MOH) and episodic migraine (EM) and to compare it with healthy controls (HC). Methods: This study enrolled patients with MOH, patients with EM, and HC. ToM was assessed through the Theory of Mind Assessment Scale (ThOMAS), which includes four subscales: Scale A, I-Me, Scale B, Other-Self, Scale C, I-Other, and Scale D, Other-Me, through the Reading the Mind in the Eyes test (RMET), which measures complex emotion recognition, and through the Toronto Alexithymia Scale (TAS-20), which measures alexithymia. Concomitant psychiatric disturbances were evaluated through the Hamilton Anxiety Rating Scale, the Hamilton Depression Rating Scale, and the Dissociative Experiences Scale-II. Results: The study involved 21 patients with EM, 22 patients with MOH, and 18 HC. In all the four subscales of the ThOMAS, there was a significant difference between HC, EM, and MOH patients: Scale A (p = 0.009), Scale B (p = 0.004), Scale C (p = 0.039), and Scale D (p = 0.008). In the RMET, MOH patients had worse performances than EM patients and HC (p = 0.039). MOH group exhibited higher levels of alexithymia when compared to the HC (p = 0.033) and higher levels of anxiety than HC (p = 0.001). Conclusion: MOH patients showed a subtle psychopathological pattern characterized by impaired social adaptation.

Impact of delirium on the outcome of stroke: a prospective, observational, cohort study.

INTRODUCTION: Delirium is an acute fluctuating disorder of attention and awareness, which often complicates the clinical course of several conditions, including acute stroke. The aim of the present study was to determine whether delirium occurrence impacts the outcome of patients with acute stroke. METHODS: The study design is single center, prospective, observational. We consecutively enrolled patients admitted to the stroke unit from April to October 2020. Inclusion criteria were age ≥ 18 years and diagnosis of acute stroke. Exclusion criteria were stroke mimics, coma, and terminal conditions. All patients were screened for delirium upon admission, within 72 h, and whenever symptoms suggesting delirium occurred by means of the Confusion Assessment Method for Intensive Care Unit and the Richmond Agitation Sedation Scale. Outcomes were evaluated with the 90-days modified Rankin Scale (mRS) by telephone interview. RESULTS: The final study cohort consisted of 103 patients (62 men; median age 75 years, interquartile range 63-81). Thirty-one patients (30%) developed delirium. In the multivariate ordinal logistic regression, patients with delirium had higher mRS scores at 3 months (DLR + : mRS = 4 (3-6); DLR-: mRS = 1 (1-3); adjusted odds ratio = 4.83; CI = 1.88-12.35; p = 0.006). Delirium was a risk factor for death (mRS = 6) in the univariate logistic regression (OR 4.5, CI = 1.44-14.07; p = 0.010), but not in the adjusted analysis (OR 3.45; CI = 0.66-17.95; p = 0.142). Survival time during 90-days follow-up was shorter in the delirium group (Log Rank χ2 3.89; p = 0.048). CONCLUSION: Delirium negatively impacts the prognosis of patients with acute stroke. Patients with post-stroke delirium have a worse functional outcome and a shorter survival.

Prevalence of gastrointestinal disorders in individuals with RASopathies: May RAS/MAP/ERK pathway dysfunctions be a model of neuropathic pain and visceral hypersensitivity?

RASopathies are a group of neurodevelopmental syndromes caused by germline variants in genes of the Ras/MAP/ERK pathway. Growth failure, neurological involvement, and pain represent the main features of these conditions. ERK signaling cascade plays a crucial role in nociception and visceral pain and it is likely implicated in the genesis of neuropathic pain and maintenance of altered pain states. We studied the prevalence of abdominal pain and functional gastrointestinal (GI) disorders in a large sample of individuals with RASopathies. A brief pain inventory questionnaire and semi-structured dedicated interview were used to investigate presence and localization of pain. A Rome IV questionnaire was used to screen for functional GI disorders. Eighty patients with clinical and molecular diagnoses of RASopathy were recruited (42 with Noonan syndrome; 17 with Costello Syndrome and 21 with cardio-facio-cutaneous syndrome). Overall, the prevalence of abdominal pain was 44% and prevalence of functional GI disorders was 78% with constipation, abdominal pain, and aerophagia being the most frequently detected ones. A significant association was found between pain and irritable bowel syndrome, functional constipation and aerophagia. Children with RASopathies have a high prevalence of functional gastrointestinal disorders. These children could represent a good in vivo model to study neuropathic pain, visceral hypersensitivity and gut-brain axis disorders.

Perampanel enhances the cardiovagal tone and heart rate variability (HRV) in patients with drug-resistant temporal lobe epilepsy.

OBJECTIVE: The temporal lobe plays a central role in the regulation of the "Central Autonomic Network" and cardiovascular functions. The blockade of glutamatergic pathways in the temporal lobe affects cardio-autonomic control. Perampanel (PER) is a non-competitive agonist of the AMPA receptor. This study evaluated PER effects on cardiac autonomic control in patients affected by drug-resistant TLE (DRTLE). METHODS: We enrolled 40 adults with DRTLE treated with PER as add-on therapy (PER group) and 32 DRTLE age, sex, and seizure-frequency matched controls treated with different additional anti-seizure medication (ASM) as add-on therapy (No-PER group). HRV analysis was performed on 5-minute EKG recording in resting state before and 6-months after the introduction of add-on ASM. Linear Mixed Models (LMM) were used to analyzed HRV variables according to time (baseline and 6-months follow-up) and groups. RESULTS: At baseline no differences were detected between PER group and No-PER group according to time-domain and frequency-domain HRV parameters. At the follow-up, in PER group a multiplicative effect for the interaction between treatment and time was observed for MeanRR (ms) (p=0.03), LnRMSSD (ms) (p=0.04), LnHF (ms2) (p<0.001), HF n.u. (p=0.001), HF% (p=0.002) with increased values, and for LnLF (ms2) (p=0.001), LF n.u. (p=0.001), LF% (p=0.01), and LF/HF (p<0.001) with reduced values. The change in seizure frequency after add-on therapy was comparable between the two groups (p=0.81) CONCLUSIONS: Our data support the notion that PER increases the vagal tone in DRTLE. This activity may exert a cardioprotective effect by reducing the risk of developing cardiac arrhythmias. Furthermore, given the correlations between HRV modifications and the occurrence of SUDEP, future studies will need to test the protective effects of PER on SUDEP.