The Role of the Autonomic Nervous System in Epilepsy and Migraine: A Narrative Review.

Autonomic symptoms may be local and general clinical manifestations of both epilepsy and migraine caused by the dysfunction of brain areas best known as the central autonomic network. Despite their prevalence, autonomic signs are often misdiagnosed and their treatment is undervalued. This review aims to describe the autonomic manifestations reported during seizures and migraineur attacks according to their presentation, focusing on the role of the central autonomic network (CAN) and on the parasympathetic outflow that often-induced cranial autonomic symptoms (CAS) during migraineur attacks. Further, our purpose is to analyze the pathophysiological meanings and whether their presence influences the prognosis and therapy of these disorders.

Cranial Autonomic Symptoms and Migraine: What Relationship and What Meaning? A Review.

Cranial autonomic symptoms (CAS) have been usually associated with trigeminal autonomic cephalalgias (TAC's), however in the last few years several reports in adult and pediatric population have reported important presence of the CAS in migraine. Also several evidences experimentally show that the increased parasympathetic outflow can enhance the sensitization of nociceptive receptors involved in migraine. The presence of CAS suggests an activation of the trigeminal-autonomic reflex, probably related to an over-activation of the trigeminal afferent arm. For these reasons identifing and understanding of these symptoms in migraine may be important to help in the diagnosis and effective management. The purpose of this review is, analyzing the literature data, to discuss the prevalence of these CAS in migraine, the pathophysiological meaning in the pathogenesis of migraine and whether their presence influences the prognosis and therapy of migraine in adult and pediatric age.

Are Mutations in the DHRS9 Gene Causally Linked to Epilepsy? A Case Report.

The DHRS9 gene is involved in several pathways including the synthesis of allopregnanolone from progesterone. Allopregnanolone is a positive modulator of gamma aminobutyric acid (GABA) action and plays a role in the control of neuronal excitability and seizures. Whole-exome sequencing performed on a girl with an early onset epilepsy revealed that she was a compound heterozygote for two novel missense mutations of the DHRS9 gene likely to disrupt protein function. No previous studies have reported the implication of this gene in epilepsy. We discuss a new potential pathogenic mechanism underlying epilepsy in a child, due to a defective progesterone pathway.

PACAP38 and PAC1 receptor blockade: a new target for headache?

Pituitary adenylate cyclase activating polypeptide-38 (PACAP38) is a widely distributed neuropeptide involved in neuroprotection, neurodevelopment, nociception and inflammation. Moreover, PACAP38 is a potent inducer of migraine-like attacks, but the mechanism behind this has not been fully elucidated.Migraine is a neurovascular disorder, recognized as the second most disabling disease. Nevertheless, the antibodies targeting calcitonin gene-related peptide (CGRP) or its receptor are the only prophylactic treatment developed specifically for migraine. These antibodies have displayed positive results in clinical trials, but are not effective for all patients; therefore, new pharmacological targets need to be identified.Due to the ability of PACAP38 to induce migraine-like attacks, its location in structures previously associated with migraine pathophysiology and the 100-fold selectivity for the PAC1 receptor when compared to VIP, new attention has been drawn to this pathway and its potential role as a novel target for migraine treatment. In accordance with this, antibodies against PACAP38 (ALD 1910) and PAC1 receptor (AMG 301) are being developed, with AMG 301 already in Phase II clinical trials. No results have been published so far, but in preclinical studies, AMG 301 has shown responses comparable to those observed with triptans. If these antibodies prove to be effective for the treatment of migraine, several considerations should be addressed, for instance, the potential side effects of long-term blockade of the PACAP (receptor) pathway. Moreover, it is important to investigate whether these antibodies will indeed represent a therapeutic advantage for the patients that do not respond the CGRP (receptor)-antibodies.In conclusion, the data presented in this review indicate that PACAP38 and PAC1 receptor blockade are promising antimigraine therapies, but results from clinical trials are needed in order to confirm their efficacy and side effect profile.

Blocking CGRP in migraine patients - a review of pros and cons.

Migraine is the most prevalent neurological disorder worldwide and it has immense socioeconomic impact. Currently, preventative treatment options for migraine include drugs developed for diseases other than migraine such as hypertension, depression and epilepsy. During the last decade, however, blocking calcitonin gene-related peptide (CGRP) has emerged as a possible mechanism for prevention of migraine attacks. CGRP has been shown to be released during migraine attacks and it may play a causative role in induction of migraine attacks. Here, we review the pros and cons of blocking CGRP in migraine patients. To date, two different classes of drugs blocking CGRP have been developed: small molecule CGRP receptor antagonists (gepants), and monoclonal antibodies, targeting either CGRP or the CGRP receptor. Several trials have been conducted to test the efficacy and safety of these drugs. In general, a superior efficacy compared to placebo has been shown, especially with regards to the antibodies. In addition, the efficacy is in line with other currently used prophylactic treatments. The drugs have also been well tolerated, except for some of the gepants, which induced a transient increase in transaminases. Thus, blocking CGRP in migraine patients is seemingly both efficient and well tolerated. However, CGRP and its receptor are abundantly present in both the vasculature, and in the peripheral and central nervous system, and are involved in several physiological processes. Therefore, blocking CGRP may pose a risk in subjects with comorbidities such as cardiovascular diseases. In addition, long-term effects are still unknown. Evidence from animal studies suggests that blocking CGRP may induce constipation, affect the homeostatic functions of the pituitary hormones or attenuate wound healing. However, these effects have so far not been reported in human studies. In conclusion, this review suggests that, based on current knowledge, the pros of blocking CGRP in migraine patients exceeds the cons.

Pediatric Migraine and Visual Cortical Excitability: A Prospective Observational Study with Sound-Induced Flash Illusions.

The pathophysiological mechanisms underlying migraine are more difficult to investigate in children than in the adult population. Abnormal cortical excitability turns out to be one of the most peculiar aspects of migraine, accounting for the manifestations of migraine attacks. Recently, visual cortical excitability has been explored effectively in adult migraineurs with a technique based on cross-modal audio-visual illusions (with sound-induced flash illusions (SIFIs) being reduced in migraineurs compared to non-migraineur subjects). On such a basis, in this study, we investigated visual cortical excitability in children with migraine using SIFIs using combinations of visual and sound stimuli presented randomly. We evaluated 26 children with migraine without aura and 16 healthy children. Migraineurs did not differ from the age-matched healthy subjects regarding fission or fusion illusions but perceived more flashes in trials of multiple flashes with or without beeps. The higher number of SIFIs in migraineur children compared to adults may be due to a greater propensity of visual stimulation to be driven by auditory stimuli (i.e., acoustic dominance). The increased ability to perceive flashes reveals a hyperfunctional visual cortex, demonstrating that the use of SIFIs is a valid tool for assessing visual cortical responsiveness even in pediatric migraine.

Exploring Headaches in Pediatric Behçet Disease: Prevalence, Clinical Impact, and Management.

Behçet's Disease (BD), also recognized as Behçet Syndrome, manifests uniquely in pediatric populations as Pediatric Behçet's Disease (PBD), characterized by multisystemic inflammatory symptoms including recurrent oral and genital aphthae, and diverse ocular, vascular, and neurological involvements. This review elucidates the prevalence, burden, and management strategies of headaches in children with PBD, focusing on both primary headaches, such as migraine and tension-type headaches, and secondary headaches linked to systemic disease manifestations. It explores the pathophysiological underpinnings specific to PBD-related headaches and discusses the intricate relationship between systemic inflammatory processes and neurological symptoms. By examining the literature from 2004 to 2024, this study highlights the high frequency of headache in PBD patients, underscoring its diagnostic and clinical significance. We aim to provide a detailed understanding of headache management in PBD, emphasizing tailored therapeutic strategies that address the unique challenges faced by this patient population. This review also underscores the importance of comprehensive clinical evaluations to optimize outcomes and mitigate long-term sequelae, proposing that awareness and understanding of headache in PBD can significantly enhance both diagnosis and management.

A Narrative Review of Visual Hallucinations in Migraine and Epilepsy: Similarities and Differences in Children and Adolescents.

Since the earliest descriptions of the simple visual hallucinations in migraine patients and in subjects suffering from occipital lobe epilepsy, several important issues have arisen in recognizing epileptic seizures of the occipital lobe, which often present with symptoms mimicking migraine. A detailed quantitative and qualitative clinical scrutiny of timing and characteristics of visual impairment can contribute to avoiding mistakes. Differential diagnosis, in children, might be challenging because of the partial clinical, therapeutic, and pathophysiological overlaps between the two diseases that often coexist. Ictal elementary visual hallucinations are defined by color, shape, size, location, movement, speed of appearance and duration, frequency, and associated symptoms and their progression. The evaluation of the distinctive clinical features of visual aura in migraine and visual hallucinations in occipital epilepsy could contribute to understanding the pathogenetic mechanisms of these two conditions. This paper aims to critically review the available scientific evidence on the main clinical criteria that address diagnosis, as well as similarities and differences in the pathophysiological mechanisms underlying the visual impairment in epilepsy and migraine.

Evolution of Pediatric Migraine Patients Admitted at an Emergency Department after a 10-Year Follow-Up.

BACKGROUND: Despite its high prevalence, the clinical course of pediatric migraine has not been fully understood, and previous studies present conflicting results. We present here the findings of a 10-year follow-up study involving children with severe migraine pain admitted to our emergency department. Furthermore, all studies were carried out on selected outpatient clinical case studies. Our aim was to evaluate a population of migraine children admitted to an emergency department because of increased severity or frequency of pain or even because of very anxious parents concerning their child's headache in order to describe their long-term outcomes, whether it differed from that of outpatient populations and to identify possible predictors of prognosis. METHODS: We recruited 80 subjects with migraine headaches (mean age 8 years with a range of 4-14 years, 50% females), attending the baseline examination of a population admitted for a headache to the Emergency Department in the first half year of 2012. Of the 80 subjects, 48 (60%) were eligible for follow-up in 2022. We included in our study only patients diagnosed with migraine, according to the diagnostic criteria of the International Classification of Headache Disorders. All were contacted by telephone, and a semi-structured questionnaire was provided to them by email. The association between several possible prognostic factors (gender, familiar neurologic disorders, prenatal and perinatal disorders, social activities, sleep disorders, etc.) and the long-term persistence of migraine headaches were explored using logistic regression analysis. RESULTS: Of 48 subjects with migraine headaches at baseline, 31 (65%) had persistent migraine, and 17 (35%) experienced remission. The preliminary results showed that the presence of neurologic disorders in parents (p < 0.01-odds ratio 9.34 (2.53-41.64) and sleep disorders (p < 0.01-odds ratio 13.18 (2.25-252.74) significantly predicted the 10-year persistence of migraine headaches, while the other considered predictors were found not to influence prognosis. CONCLUSIONS: To our knowledge, this was the first study conducted on a selected pediatric population upon admission to the emergency room. Our study suggests that a population of pediatric migraine selected for admission to the emergency department also shows a favorable long-term prognosis, like the studies conducted in the outpatient sample. Familial neurological comorbidity and sleep disorders were unfavorable factors for predicting good outcomes.

New-onset headache following COVID-19: An Italian multicentre case series.

OBJECTIVE: To describe the characteristics of patients with new-onset headache following SARS-CoV-2 infection. BACKGROUND: SARS-CoV-2 infection leads to several neurological manifestations, and headache is a frequent and disabling symptom, both exacerbating pre-existing headache syndromes and causing new-onset ones. METHODS: Patients with new-onset headache after SARS-CoV-2 infection with consent to participate were included, while those ones with previous headaches were excluded. The temporal latency of headache after infection, pain characteristics, and concomitant symptoms were analysed. Moreover, the efficacy of acute and preventive medications was explored. RESULTS: Eleven females (median age 37.0 [10.0-60.0] years old) were included. In most cases, headache onset occurred with the infection, the location of pain varied, and the quality was either pulsating or tightening. Headache was persistent and daily in 8 patients (72.7%), while it occurred in episodes in the remaining subjects. Baseline diagnoses were new daily persistent headache (36.4%), probable new daily persistent headache (36.4%), probable migraine (9.1%), and migraine-like headache secondary to COVID-19 (18.2%). Ten patients received one or more preventive treatments and six of them showed an improvement. CONCLUSION: New-onset headache following COVID-19 is a heterogenous condition with uncertain pathogenesis. This type of headache can become persistent and severe, with a wide spectrum of manifestations (new daily persistent headache being the most represented one) and variable response to treatment.

Idiopathic Non-Dental Facial Pain Syndromes in Italian Children: A Clinical Case Series.

BACKGROUND: The orofacial pain syndromes (OFPs) are a heterogeneous group of syndromes characterized by painful attacks involving the orofacial structures. They may be summarily subdivided into two great categories: (1) orofacial pain mainly attributed to dental disorders such as dentoalveolar and myofascial orofacial pain or temporomandibular joint (TM) pain; (2) orofacial pain mainly attributed to non-dental pain as neuralgias, facial localization of primary headaches or idiopathic orofacial pain. The second group is uncommon, often described by single case reports, can often show overlapping symptoms with the first group, and represents a clinical challenge, carrying the risk of undervaluation and possibly invasive odontoiatric treatment. We aimed to describe a clinical pediatric series of non-dental orofacial pain and better to underline some topographic and clinical features associated with them. We retrospectively collected the data of children admitted to our headache centers (Bari, Palermo, Torino) from 2017 to 2021. Our inclusion criterion was the presence of non-dental orofacial pain following the topographic criteria of 3° International Classification of Headache Disorders (ICHD-3), and exclusion criteria included the pain syndromes attributed to the dental disorders and pain syndromes due to the secondary etiologies Results. Our sample comprised 43 subjects (23/20 M/F, in the range of ages 5-17). We classified them int: 23 primary headaches involving the facial territory during attacks, 2 facial trigeminal autonomic cephalalgias, 1 facial primary stabbing headache, 1 facial linear headache, 6 trochlear migraines, 1 orbital migraine 3 red ear syndrome and 6 atypical facial pain. All patients described debilitating pain for intensity (moderate/severe), 31 children had episodic attacks, and 12 had continuous pain. Almost all received drugs for acute treatment (less than 50% were satisfied), and some received non-pharmacological treatment associated with drug therapy Conclusion. Although rare OFP can occur in pediatric age, it can be debilitating if unrecognized and untreated, affecting the psychophysical well-being of young patients. We highlight the specific characteristics of the disorder for a more correct and earlier identification during the diagnostic process, already difficult in pediatric age, and to define the approach and possible treatment to prevent negative outcomes in adulthood.