Migraine - a borderland disease to epilepsy: near it but not of it.

BACKGROUND: Migraine and epilepsy are two paroxysmal chronic neurological disorders affecting a high number of individuals and being responsible for a high individual and socioeconomic burden. The link between these disorders has been of interest for decades and innovations concerning diagnosing and treatment enable new insights into their relationship. FINDINGS: Although appearing to be distinct at first glance, both diseases exhibit a noteworthy comorbidity, shared pathophysiological pathways, and significant overlaps in characteristics like clinical manifestation or prophylactic treatment. This review aims to explore the intricate relationship between these two conditions, shedding light on shared pathophysiological foundations, genetic interdependencies, common and distinct clinical features, clinically overlapping syndromes, and therapeutic similarities. There are several shared pathophysiological mechanisms, like CSD, the likely underlying cause of migraine aura, or neurotransmitters, mainly Glutamate and GABA, which represent important roles in triggering migraine attacks and seizures. The genetic interrelations between the two disorders can be observed by taking a closer look at the group of familial hemiplegic migraines, which are caused by mutations in genes like CACNA1A, ATP1A2, or SCN1A. The intricate relationship is further underlined by the high number of shared clinical features, which can be observed over the entire course of migraine attacks and epileptic seizures. While the variety of the clinical manifestation of an epileptic seizure is naturally higher than that of a migraine attack, a distinction can indeed be difficult in some cases, e.g. in occipital lobe epilepsy. Moreover, triggering factors like sleep deprivation or alcohol consumption play an important role in both diseases. In the period after the seizure or migraine attack, symptoms like speech difficulties, tiredness, and yawning occur. While the actual attack of the disease usually lasts for a limited time, research indicates that individuals suffering from migraine and/or epilepsy are highly affected in their daily life, especially regarding cognitive and social aspects, a burden that is even worsened using antiseizure medication. This medication allows us to reveal further connections, as certain antiepileptics are proven to have beneficial effects on the frequency and severity of migraine and have been used as a preventive drug for both diseases over many years. CONCLUSION: Migraine and epilepsy show a high number of similarities in their mechanisms and clinical presentation. A deeper understanding of the intricate relationship will positively advance patient-oriented research and clinical work.

Don't eat me/eat me signals as a novel strategy in cancer immunotherapy.

Cancer stands as one of the prominent global causes of death, with its incidence burden continuously increasing, leading to a substantial rise in mortality rates. Cancer treatment has seen the development of various strategies, each carrying its drawbacks that can negatively impact the quality of life for cancer patients. The challenge remains significant within the medical field to establish a definitive cancer treatment that minimizes complications and limitations. In the forthcoming years, exploring new strategies to surmount the failures in cancer treatment appears to be an unavoidable pursuit. Among these strategies, immunology-based ones hold substantial promise in combatting cancer and immune-related disorders. A particular subset of this approach identifies "eat me" and "Don't eat me" signals in cancer cells, contrasting them with their counterparts in non-cancerous cells. This distinction could potentially mark a significant breakthrough in treating diverse cancers. By delving into signal transduction and engineering novel technologies that utilize distinct "eat me" and "Don't eat me" signals, a valuable avenue may emerge for advancing cancer treatment methodologies. Macrophages, functioning as vital components of the immune system, regulate metabolic equilibrium, manage inflammatory disorders, oversee fibrosis, and aid in the repair of injuries. However, in the context of tumor cells, the overexpression of "Don't eat me" signals like CD47, PD-L1, and beta-2 microglobulin (B2M), an anti-phagocytic subunit of the primary histocompatibility complex class I, enables these cells to evade macrophages and proliferate uncontrollably. Conversely, the presentation of an "eat me" signal, such as Phosphatidylserine (PS), along with alterations in charge and glycosylation patterns on the cellular surface, modifications in intercellular adhesion molecule-1 (ICAM-1) epitopes, and the exposure of Calreticulin and PS on the outer layer of the plasma membrane represent universally observed changes on the surface of apoptotic cells, preventing phagocytosis from causing harm to adjacent non-tumoral cells. The current review provides insight into how signaling pathways and immune cells either stimulate or obstruct these signals, aiming to address challenges that may arise in future immunotherapy research. A potential solution lies in combination therapies targeting the "eat me" and "Don't eat me" signals in conjunction with other targeted therapeutic approaches. This innovative strategy holds promise as a novel avenue for the future treatment of cancer.

Debate: differences and similarities between tension-type headache and migraine.

Tension-type headache (TTH) and migraine are two common primary headaches distinguished by clinical characteristics according to the 3rd edition of the International Classification of Headache Disorders. Migraine is identified by specific features such as being more prevalent in females, being aggravated by physical activity, certain genetic factors, having photophobia, phonophobia, nausea, vomiting, or aura, and responding to specific drugs. Nonetheless, TTH and migraine share some common characteristics, such as onset occurring in the 20 s, and being triggered by psychological factors like stress, moderate pain severity, and mild nausea in chronic TTH. Both conditions involve the trigeminovascular system in their pathophysiology. However, distinguishing between TTH and migraine in clinical practice, research, and epidemiological studies can be challenging, as there is a lack of specific diagnostic tests and biomarkers. Moreover, both conditions may coexist, further complicating the diagnostic process. This review aims to explore the similarities and differences in the pathophysiology, epidemiology, burden and disability, comorbidities, and responses to pharmacological and non-pharmacological treatments of TTH and migraine. The review also discusses future research directions to address the diagnostic challenges and improve the understanding and management of these conditions.

Future targets for migraine treatment beyond CGRP.

BACKGROUND: Migraine is a disabling and chronic neurovascular headache disorder. Trigeminal vascular activation and release of calcitonin gene-related peptide (CGRP) play a pivotal role in the pathogenesis of migraine. This knowledge has led to the development of CGRP(-receptor) therapies. Yet, a substantial proportion of patients do not respond to these treatments. Therefore, alternative targets for future therapies are warranted. The current narrative review provides a comprehensive overview of the pathophysiological role of these possible non-CGRP targets in migraine. FINDINGS: We covered targets of the metabotropic receptors (pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), amylin, and adrenomedullin), intracellular targets (nitric oxide (NO), phosphodiesterase-3 (PDE3) and -5 (PDE5)), and ion channels (potassium, calcium, transient receptor potential (TRP), and acid-sensing ion channels (ASIC)). The majority of non-CGRP targets were able to induce migraine-like attacks, except for (i) calcium channels, as it is not yet possible to directly target channels to elucidate their precise involvement in migraine; (ii) TRP channels, activation of which can induce non-migraine headache; and (iii) ASICs, as their potential in inducing migraine attacks has not been investigated thus far. Drugs that target its receptors exist for PACAP, NO, and the potassium, TRP, and ASIC channels. No selective drugs exist for the other targets, however, some existing (migraine) treatments appear to indirectly antagonize responses to amylin, adrenomedullin, and calcium channels. Drugs against PACAP, NO, potassium channels, TRP channels, and only a PAC1 antibody have been tested for migraine treatment, albeit with ambiguous results. CONCLUSION: While current research on these non-CGRP drug targets has not yet led to the development of efficacious therapies, human provocation studies using these targets have provided valuable insight into underlying mechanisms of migraine headaches and auras. Further studies are needed on these alternative therapies in non-responders of CGRP(-receptor) targeted therapies with the ultimate aim to pave the way towards a headache-free future for all migraine patients.

The sense of stopping migraine prophylaxis.

INTRODUCTION: Migraine prophylactic therapy has changed over recent years with the development and approval of monoclonal antibodies (mAbs) targeting the calcitonin gene-related peptide (CGRP) pathway. As new therapies emerged, leading headache societies have been providing guidelines on the initiation and escalation of such therapies. However, there is a lack of robust evidence looking at the duration of successful prophylaxis and the effects of therapy discontinuation. In this narrative review we explore both the biological and clinical rationale for prophylactic therapy discontinuation to provide a basis for clinical decision-making. METHODS: Three different literature search strategies were conducted for this narrative review. These include i) stopping rules in comorbidities of migraine in which overlapping preventives are prescribed, notably depression and epilepsy; ii) stopping rules of oral treatment and botox; iii) stopping rules of antibodies targeting the CGRP (receptor). Keywords were utilized in the following databases: Embase, Medline ALL, Web of Science Core collection, Cochran Central Register of Controlled Trials, and Google Scholar. DISCUSSION: Reasons to guide decision-making in stopping prophylactic migraine therapies include adverse events, efficacy failure, drug holiday following long-term administration, and patient-specific reasons. Certain guidelines contain both positive and negative stopping rules. Following withdrawal of migraine prophylaxis, migraine burden may return to pre-treatment level, remain unchanged, or lie somewhere in-between. The current suggestion to discontinue CGRP(-receptor) targeted mAbs after 6 to 12 months is based on expert opinion, as opposed to robust scientific evidence. Current guidelines advise the clinician to assess the success of CGRP(-receptor) targeted mAbs after three months. Based on excellent tolerability data and the absence of scientific data, we propose if no other reasons apply, to stop the use of mAbs when the number of migraine days decreases to four or fewer migraine days per month. There is a higher likelihood of developing side effects with oral migraine preventatives, and so we suggest stopping these drugs according to the national guidelines if they are well tolerated. CONCLUSION: Translational and basic studies are warranted to investigate the long-term effects of a preventive drug after its discontinuation, starting from what is known about the biology of migraine. In addition, observational studies and, eventually, clinical trials focusing on the effect of discontinuation of migraine prophylactic therapies, are essential to substantiate evidence-based recommendations on stopping rules for both oral preventives and CGRP(-receptor) targeted therapies in migraine.

Genetics of migraine: where are we now?

Migraine is a complex brain disorder explained by the interaction of genetic and environmental factors. In monogenic migraines, including familial hemiplegic migraine and migraine with aura associated with hereditary small-vessel disorders, the identified genes code for proteins expressed in neurons, glial cells, or vessels, all of which increase susceptibility to cortical spreading depression. The study of monogenic migraines has shown that the neurovascular unit plays a prominent role in migraine. Genome-wide association studies have identified numerous susceptibility variants that each result in only a small increase in overall migraine risk. The more than 180 known variants belong to several complex networks of "pro-migraine" molecular abnormalities, which are mainly neuronal or vascular. Genetics has also highlighted the importance of shared genetic factors between migraine and its major co-morbidities, including depression and high blood pressure. Further studies are still needed to map all of the susceptibility loci for migraine and then to understand how these genomic variants lead to migraine cell phenotypes.

Primary headache epidemiology in children and adolescents: a systematic review and meta-analysis.

INTRODUCTION: Headache is the most prevalent neurological manifestation in adults and one of the leading causes of disability worldwide. In children and adolescents, headaches are arguably responsible for a remarkable impact on physical and psychological issues, yet high-quality evidence is scarce. MATERIAL AND METHODS: We searched cross-sectional and cohort studies in Embase, Medline, Web of Science, and Cochrane databases from January 1988 to June 2022 to identify the prevalence of headaches in 8-18 years old individuals. The risk of bias was examined with the Joanna Briggs Institute (JBI) scale. A random-effects model was used to estimate the pooled prevalence of pediatric headache. Subgroup analyses based on headache subtypes were also conducted. RESULTS: Out of 5,486 papers retrieved electronically, we identified 48 studies that fulfilled our inclusion criteria. The pooled prevalence of primary headaches was 11% for migraine overall [95%CI: 9-14%], 8% for migraine without aura (MwoA) [95%CI: 5-12%], 3% for migraine with aura (MwA) [95%CI:2-4%] and 17% for tension-type headache (TTH) [95% CI: 12-23%]. The pooled prevalence of overall primary headache in children and adolescents was 62% [95% CI: 53-70%], with prevalence in females and males of 38% [95% CI: 16-66%] and 27% [95% CI: 11-53%] respectively. After the removal of studies ranked as low-quality according to the JBI scale, prevalence rates were not substantially different. Epidemiological data on less common primary headaches, such as trigeminal autonomic cephalalgias, were lacking. CONCLUSION: We found an overall remarkably high prevalence of primary headaches in children and adolescents, even if flawed by a high degree of heterogeneity. Further up-to-date studies are warranted to complete the picture of pediatric headache-related burden to enhance specific public interventions.

Characteristics and comorbidities of headache in patients over 50 years of age: a cross-sectional study.

BACKGROUND: Although headache is a common complaint in younger individuals, it is one of the most common complaints among persons over the age of 50 and is a significant cause of morbidity. As there are differences in the causes and types of headache, the diagnosis and management of headache in older adults differ from that in younger individuals. METHODS: In this cross-sectional study, 570 patients ≥ 50 years were recruited at a university affiliated tertiary headache center between 2016 and 2019. Demographic data, headache characteristics, and comorbid medical conditions were recorded. The presence of depression was explored using the Beck Depression Inventory. The patients were evaluated using the STOP-BANG scale to determine the risk of obstructive sleep apnea. RESULTS: The mean age of the patients was 57.7 years. Seventy-three percent of the patients had primary headache disorders, with the most prevalent types being migraine, followed by tension-type headache. Secondary headaches were primarily the result of overuse of medication, cervical spine disease, and hypertension. Patients with medication-overuse headache were significantly more likely to suffer from hypothyroidism and gastrointestinal problems such as bleeding/ulcers. Irritable bowel syndrome was also more common in patients with medication-overuse headaches and migraines. The risk for obstructive sleep apnea was intermediate in 45.2% of the patients with hypertension-induced headache, but was lower in the majority of others. There was a high tendency for moderate-to-severe depression in the participants; however, the Beck Depression Inventory scores were significantly higher in medication-overuse headache patients. CONCLUSION: Proper treatment of headache in middle-aged and older adults requires the recognition of secondary causes, comorbid diseases, and drug induced or medication overuse headaches. Special attention should be paid to depression and obstructive sleep apnea in such patients suffering from headache disorders.

Cranial autonomic symptoms in episodic and chronic migraine: a cross sectional study in Iran.

BACKGROUND: Cranial autonomic symptoms are common in migraine, with eye redness and tearing being the most common ones. Their identification can help to avoid misdiagnosis, predict the disease course, and select the appropriate treatment. METHODS: This was a cross-sectional study of 904 patients who presented with migraine to a headache referral clinic. The participants filled out a questionnaire about their headache characteristics, as well as the presence of cranial autonomic symptoms. A total of 904 patients, 698 women (77.2%) and 206 men (22.8%), were included in the study, with a mean (SD) age of 38.05 (11.76) years. RESULTS: About 70% of subjects with chronic migraine and 56.2% of those with episodic migraine reported one or more cranial autonomic symptoms. The two most commonly reported autonomic symptoms were eye redness (36.06%) and tearing (21.02%). Chronic migraine (43.4% vs. 29.5%), unilateral headache (56.8% vs. 48.7%), and blurred vision (20% vs. 14.7%) were significantly more frequent in migraineurs with cranial autonomic symptoms. Headache intensity and frequency in subjects with cranial autonomic symptoms were significantly higher than in those without cranial autonomic symptoms. CONCLUSION: We found higher percentages of cranial autonomic symptoms in patients with unilateral headaches, frequent and severe attacks and blurred vision. A diagnosis of cranial autonomic symptoms accompanying migraine may predict more severe disease and the possibility of evolution into chronic migraine.

Estimating quality of life in a headache referral population based on Migraine disability assessment scale and headache impact test.

Background: Headache is among the most common disabling neurologic disorders. We measured quality of life in chronic migraine (CM) and episodic migraine (EM), stratified by medication overuse headache (MOH) and presence of aura. Methods: In this observational study, conducted from January 2016 to December 2018, adult patients referred to the tertiary headache clinic of Sina Hospital in Tehran, Iran, who met International Classification of Headache Disorders, 3rd Edition-beta (ICHD-3 ß) criteria for migraine were classified to EM and CM subtyped based on presence of aura and MOH. Validated Farsi versions of Migraine Disability Assessment Scale (MIDAS) and 6-item Headache Impact Test (HIT-6) questionnaires were used. Results: A total of 2454 patients (1907 women) were enrolled from which 1261 (51.4%) patients had EM and 1193 (48.6%) had CM, while 908 subjects (37.0%) had MOH, of whom 890 (98.0%) had CM. Median scores of MIDAS and HIT-6 were significantly higher in patients with CM compared to EM sufferers. Chronic migraineurs with MOH had a significantly higher median score of MIDAS and HIT-6 compared to patients with non-MOH CM. Also, there was a moderate positive correlation between MIDAS (disability) and HIT-6 scores (impact on patients' life) and a moderate correlation between HIT-6 and pain severity. Conclusion: The results of this study confirm that CM and MOH are associated with a higher headache-related disability and impact on life compared to EM. Therefore, treatment goals in prevention of MOH and migraine transformation warrant higher quality of life in patients with migraine.