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Migraine Is not Just a Headache: Rethink Beyond the Pain

Migraine is a heritable neurological disease with mild to severe headaches, nausea, photophobia, and phonophobia. Genetic, environmental, and neurologic factors contribute to migraine attacks. Advances in migraine treatment, including gepants targeting CGRP pathways, offer new hope for management.

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𝐒𝐇𝐈𝐁𝐀𝐒𝐈𝐒 𝐑𝐀𝐓𝐇

2/20/20258 min read

Decoding Migraine:

From Genetic Roots to Revolutionary Treatments

Migraine is a heritable neurological disease of adverse prognosis, and the main presentation is episodic mild to moderate headache. These migraine headaches are usually unilateral and are affected by symptoms such as nausea and the tendency to photosensitivity (photophobia) and phonophobia. This word "migraine" is from Greek word hemikrania, which is further adopted into Latin as hemigranea and then into French as migraine.

Migraine is the most common reason of disability and has a negative impact on daily life and occupational performance. These attacks may continue for hours to days, mild to severe. Within the variety of migraine subtypes, the most common is migraine with aura (accounting for ~75% of cases).

Migraineotypes are subdivided into different clusters according to clinical features. Migraine without aura is the most prevalent form, with headache episodes ranging from 4 to 72 hours. Pain is classic, contralateral, throbbing and pain is made worse by activity. This form of migraine is usually accompanied by nausea, photophobia and hyperacusis. Migraine with aura is another transient neurological dysfunction detected both before and/or during headache phase. These dysfunctions can include visual, sensory, and language abnormalities.

Chronic migraine is characterized by headache for 15 or more days/month for at least 3 months in which pain is accompanied by distinctive severe headache (speciﬁc migraine) on at least 8 days of those months. Possible migraine is defined as symptomatic migraine attack which, at least, partially, but not completely, lies within the range of criteria for possible migraine. Paraesthesia and food dysphagia in many forms [eg including prickly heat in (cutaneous), in the "(kingdom of brownian motion)" in cerebral and Willoughby's ring phobia in (grating) are fairly frequent presentations in paediatric patients that can be reliably predicted from associations between family characteristics and food assuming a "lactic" form when exposed to upped concentrations of associated physiological particulate matter in the environment, which can be quite alarming given the presumed allergen in iodized flour particles that triggers severe illness and hospital admissions in adults but not children.

Migraine has, on the one side, some cases, led to a serious complication requiring medical care. Status migrainosus is a disabling migraine episode for more than one day, lasting longer than 72 h. Isolated unilateral aura without infarction is characterized as experiencing aura symptoms for more than one week in the absence of evidence on imaging studies of brain infarction. Migrainous infarction is used to describe migraine attack with ischmic brain damage. A complication, migraine aura-induced seizure, occurs when a subject with migraine aura induces a seizure.

Migraine is a neurologic disorder caused by genetic, environmental and neurologic mechanisms. According to the available evidence, migraine is considered as a result of brain dysfunction, and functional activities of nerve, neurochemicals, and cerebral circulation are implicated. Genetic studies have revealed that people with family history of migraine are 3 times more likely to have a migraine attack than people without family history of it.

Mendelian disorders that present with migraine-like symptoms have been associated with migraine. The autosomal recessive severe hereditary migraine inheritance form familial hemiplegic migraine (FHM) is linked to mutations in ion channel genes and neuronal excitability genes spanning CACNA1A, ATP1A2, and SCN1A. Other illness [MITAD (Mitochondrial Encephalopathy, Lactic Acidosis and Stroke-like Episodes) and CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) can have the features of migraine-like aura. These syndromes exemplify the genetic complexity of migraine pathophysiology.

It is known that migraine attacks are often heralded by a range of environmental and lifestyle triggers. Reports also show that 76% of the patients with migraine reported at least one trigger. Stress is a major onset trigger for migraine in more than 80% of affected individuals. Hormonal (in particular, menstrual, pregnancy and ovulatory) changes are the main reason for headaches in 65% of the female patients affected by headaches.

Dietary triggers (eg, interruption of fast, intake of alcohol (particularly of wine), food intake, e.g., chocolate and aged cheese) may lead to attacks. Therefore, both excessive and deficient sleep also known to induce migraine attacks. Sensory input such as bright lights, strong smells and sound may actually make symptoms worse. Alteration in the weather, such as barometric pressure change, thermoregulation and humidity variabilities, has been reported to be associated with increased migraine counts. Further, physical activity, vigorous activity and sexual activity have been reported to be an antecedent.

Detailed data regarding migraine phenotypes, complications, genetic modifiers and causative agents are of paramount importance to enable the optimal management and therapies. Currently lifestyle modification and preventive measures can be utilized to reduce incidence of migraine, although such research, as well as research on identifying novel therapeutic agents and ones tailored to specific agents, is also underway to improve migraine treatment.

Andrea West and the Discovery of Gepants

Andrea West states that in 2021, she first learnt about a novel migraine medication class which had the promise of ending the decades of suffering which she had endured for the majority of her life. In 2021, a scientist was on the radio and speaking about gepants which were a class of drugs that were designed to prevent migraines from occurring by targeting the calcitonin gene related peptide CGRP pathway. When atogepant was approved last year in the United Kingdom she directly contacted her general practitioner and on receiving gepants West promptly consulted her physician. Andrea West had been suffering migraines for an amount of seventy years. She had endured migraines for 70 years however since she started gepant she has not experienced a single migraine attack to which she is ecstatic. ' it is reproductive work that is remarkable and as a genuine form of change to my life ' she reveals. Historically migraine sufferers had had very limited relief options.

Historical Approaches to Migraine Treatment

Ancient Egyptian physicians resorted to the task of placing clay crocodiles onto the patients heads whilst seventeenth century surgeons performed trepanation, which meant drilling holes in the patients skulls in order to release the supposed cause of migraine - thinking it to be an existing and system. The twentieth century saw a significant improvement in the medicinal treatments available however still a significant amount of migraine sufferers remained unresponsive to these forms of therapy.

The Impact of Gepants on Migraine Management

Recent advances has seen migraine recognized as a curable and manageable condition. Recent advances have been measured by the approval of medicine such as gepant have seen the perspective of migraines change. Diana Krause a nervous pharmacologist at the University of California, Irvine noted that these recent medicinal inventions have seen migraines transform into an ailment which can be effectively managed.

Research has deepened the understanding of migraines, which are complex events that originate in/on the brain and have a range of symptoms including severe headaches with a sensitivity to bright lights and the installation of auras which are conflicting and have the effect of cognitive impairments and fatigue and Richard Lipton, a neurologist at The Albert Einstein College of Medicine in New York describes this symptom set as extremely diverse and painful in terms of its severity and disability isn't solely attributed to the intensity of the pain. "We have treatments to address these symptoms", he adds.

Ongoing Research in Migraine Pathophysiology

Investigations are ongoing in order to determine the signal defects that are responsible for enabling a brain to go into a hyperactive state which leads to attacks of full blown migraines. Understanding the predisposition to migraines is an essential area of research being investigated and Arne May, a neurologist at the University Medical Center Hamburg-Eppendorf in Germany, is in favour of developing novel research frameworks in order to fully comprehend how the brain organises the chain of functional events which lead to migraines. During the 1990s migraines were often characterised as psychological issues or vascular disorders leading to blood vessel dilation. Mis characterisation by medical practitioners resulted in general stigma with patients frequently being referred to psychiatrists or psychologists. Krause noted that the field partially recovered from these preconceptions that were encountered previously. Brain imaging studies from a similar time period revealed that specific structures of the brain became hyped up during the phase of a migraine showing migraine as a biological ill rather than purely psychological or purely vascular disorder during that time.

Phases of Migraine Attacks

Premonitory Phase – Occurs hours to days before an attack, exhibiting symptoms such as nausea, food cravings, fatigue, and yawning.
Attack Phase – Characterized by intense headache pain and other debilitating symptoms.
Postdrome Phase – Following an attack, individuals experience depression and constant fatigue.
Inter-ictal Phase – The phase between migraine attacks, which may also result in persistent symptoms.

This phenomenon is noticeable in individuals who are holistically isolated from others. Dom Horton is a genetic nut music publishing editor in the United Kingdom who does not experience headaches but presents with constant dizziness and mental labeling. Fiona Gartside, a veterinary surgeon in Scotland, suffers from intensive headaches accompanied by sensitivity to light and sound and, in one rare instance, suffered from fainting.

How Gepants Work in Migraine Treatment

The development of Gepants, including atogepant has been pivotal in the treatment of migraine. These Gepants work by antagonizing CGRP receptors preventing CGRP induced neurogenic inflammation and vasodilation whilst not causing vasoconstriction. This mechanism will provide a therapeutic alternative to those who cannot use traditional treatments like triptans. Clinical Trials have shown efficacy of atogepant at reducing the number of migraine days, with a safety profile comparable to that of placebo. Common Adverse effects such as nausea and fatigue are observed. Notably, atogepant must not be associated with significant liver toxicity problems, a problem previously encountered with earlier formulations of CGRP receptor antagonists. Despite the success of currently available CGRP-targeting therapies, some patients are nonetheless suffering from headache pain without adequate relief from symptoms e.g. West who experienced large amounts of relief. Gartside reports that whilst atogepant has reduced some of her symptom, managing migraines is currently very complex with balance required between the use of preventive medication, avoidance of irritants and coping with residual headache symptoms. Migraine responses have yielded mixed results, which points to the need for a further elucidation of the pathophysiology of this disease.

The Role of the Hypothalamus in Migraines

Recent research has implicated the hypothalamus as the central target in the development of migraine, previous research has demonstrated by functional imaging a hypothalamic increase in connectivity to multiple brain regions prior to an attack occurring which indicates that the hypothalamus is involved in initiating the subsequent migraine cascade leading to the development of the premonitory signs such as fatigue and food cravings. This altered connectivity could thereby disrupt homeostatic functions causing premonitory symptoms. Researchers posit that a dysregulated hypothalamus is thought to lead to a hyperexcitable brain state in the brain, along with a lowering of the threshold to initiate a migraine. The precise sequence of events and which brain regions are involved in the process remains a topic of active research. Understanding these neural pathways could allow researchers to target treatments that will lead to effective management of migraine episodes rather than just symptom alleviation to looking at the root causes of the ability to initiate some of these blood vessels to dilate leading to pain of migraines.

Conclusion: Advances in Migraine Treatment

In summary, advancements in understanding the biological underpinnings of migraines have led to the development of targeted therapies like gepants. While these treatments have significantly improved the quality of life for many sufferers, ongoing research aims to unravel the complex neural networks involved in migraines to develop more comprehensive and effective interventions.

References

Nature 638, 600-602 (2025)

doi: https://doi.org/10.1038/d41586-025-00456-x

Migraine Headache - StatPearls - NCBI Bookshelf

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