Neuropharmacology & Neurotherapeutics
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May. 14, 2026
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Migraine: pathogenesis and pathophysiology
- Updated 01.27.2026
- Released 01.19.2021
- Expires For CME 01.27.2029
Migraine: pathogenesis and pathophysiology
Introduction
Overview
Migraine is prevalent and is one of the leading causes of disability worldwide. The International Classification of Headache Disorders defines “migraine with aura” as recurrent attacks, lasting minutes, of unilateral fully reversible central nervous system symptoms usually followed by headache and associated migraine symptoms. “Migraine without aura” is defined as recurrent headache attacks lasting 4 to 72 hours with typical characteristics (eg, unilateral, pulsating, etc.). To effectively address this condition and help the millions suffering worldwide, we must first understand the pathophysiology of migraine and how it is associated with the hypothalamus, cortical spreading depression, and the trigeminal cervical complex. In recent years, our understanding of migraine pathophysiology has advanced through human experimental migraine models and functional neuroimaging, leading us to put away old theories like the vascular theory and further evaluate the involvement of the hypothalamus, cortical spreading depression, and the trigeminal cervical complex in various migraine phases (premonitory, aura, headache, postdrome, and interictal phase). In this article, we review the pathogenesis and pathophysiology of migraines.
Key points
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• The hypothalamus is a key contributor to multiple migraine phases, including the premonitory phase, headache phase, postdrome phase, interictal period, and chronic migraine. | |
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• Cortical spreading depression is an approximately 3 mm/min neural depolarization that spreads across the cortex leading to a release of neurotransmitters and regional changes in blood flow, likely corresponding to the conscious experience of “aura”. | |
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• Cortical spreading depression involves changes in ion concentrations from various triggers that leads to a loss of membrane potential (associated with the buildup of glutamate) resulting in a current that releases vasoactive substances like nitric oxide, therefore increasing regional blood flow to meet the increased metabolic demand. | |
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• A key process in understanding migraine headache is the trigeminal network; input from the meningeal vessels (via pituitary adenylate cyclase-activating polypeptide and calcitonin gene-related peptide) pass through the trigeminal ganglion and eventually synapse onto thalamic neurons, contributing to migraine pain and impairment. | |
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• Increased pain states lead to increased activation of the trigeminal pain network resulting in peripheral sensitization, central sensitization, decreased threshold, and alterations in connectivity, together creating chronic migraine. | |
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• Migraine attack initiation and pain perception involves activation of the trigeminovascular system, with both neuronal and vascular mechanisms contributing. |
Pathophysiology by migraine phases
Premonitory. The premonitory phase involves nonpainful symptoms that occur days to hours prior to the headache phase. The premonitory phase, or prodrome, is defined as the 48 hours leading up to headache based on imaging changes observed during this time frame, and some studies have used this definition to study this phase with functional neuroimaging (25). Meta-analyses have shown that about two thirds of patients will experience at least one premonitory symptom, and 72% of patients were able to correctly predict the onset of migraine headache based on their premonitory symptoms (16; 14). Common symptoms include fatigue (49%), neck stiffness (46%), mood changes (37%), concentration difficulties (30%), nausea (29%), photophobia (29%), phonophobia (26%), yawning (22%), feeling depressed (19%), irritability (16%), and food craving (16%) (51; 16; 14). Children can display changes in mood or behavior, fatigue, pallor, and dark circles (43). Premonitory symptoms have been a research interest due to their early onset and lack of headache, offering the opportunity to study attack initiation before pain onset and to initiate early therapeutic intervention.
The most likely source of these symptoms is the hypothalamus, which plays a role as a central facilitator of pain and is involved in a number of premonitory symptoms, including mood, appetite, thirst, energy, yawning, and polyuria (43). Functional imaging has shown hypothalamic involvement during the premonitory phase and greater connectivity between the hypothalamus and pain and autonomic areas between headaches (38; 43; 30). Positron emission tomography has also shown hypothalamic activation during both spontaneous migraine headache and the premonitory phase (38). Network mapping data support that hypothalamic activity is associated not only with inducing a migraine but also with maintaining migraine chronicity through atrophy of brain regions, including the insula and hypothalamus, not unlike other chronic pain states (07).
Hypothalamic neurotransmitters have been implicated in the premonitory phase; neuropeptide Y and dopamine (secreted through the hypothalamus) are likely involved in mediating some of these premonitory symptoms (25). Dopaminergic stimulation has been associated with vomiting, nausea, and yawning, and dopamine antagonists have demonstrated the ability to abort migraine attacks while still in the premonitory phase (43; 25). The presence of dopaminergic premonitory symptoms supports dopaminergic dysfunction in migraine, with premonitory activation of the hypothalamus, substantia nigra, and ventral tegmental area as shown in imaging studies (38; 26; 25). More research is needed to uncover the roles of neuropeptide Y and dopamine, along with other hypothalamic hormones and neurotransmitters (orexins, somatostatin, cholecystokinin) in mediating premonitory symptoms.
The locus coeruleus and raphe nucleus have also shown selective activation during the premonitory phase. As these regions are responsible for modulating sensory stimuli (eg, light and sound), they may contribute to sensory sensitivities, such as phonophobia, photophobia, and osmophobia, during the premonitory phase (13). In addition to the brainstem, sensory sensitivities may also arise from altered thalamocortical connections (25). Limbic premonitory symptoms, such as mood and cognitive changes, have been postulated to arise in the insula, amygdala, and cingulate cortex (38; 26; 25). Neck stiffness has been theorized to arise from the convergence of trigeminal and cervical sensory afferents in the trigeminal cervical complex in the brainstem (25).
Aura. Aura is defined by the International Classification of Headache Disorders, Third Edition (ICHD-3) as “recurrent attacks, lasting minutes, of unilateral fully reversible visual, sensory or other central nervous system symptoms that usually develop gradually and are usually followed by headache and associated migraine symptoms”. These can occur from many brain areas and are divided into the following types: visual, sensory, speech and/or language, motor, brainstem, and retinal (ICHD). Visual aura is the most common (90%), and motor aura is rare but can last longer (14). Per ICHD-3, each individual aura typically lasts between 5 and 60 minutes, and motor symptoms may last up to 72 hours. Auras may occur before the headache, simultaneously with the headache, or without headache and can be persistent (25). The prevalence of aura in migraine patients ranges from 20% to 40% in population studies (09).
Auras have been studied for much longer than many migraine phases. An early study by Dr. Hubert Airy in 1870 examined his own visual auras and how they changed over time (37). Gordon Holmes and Aristides Leão independently discovered a wave of spreading depolarization at approximately 3 mm/min, which is now known as cortical spreading depression (35; 36; 34; 47). Later researchers combined these two pieces and hypothesized that migraine scotomas were the conscious experience of spreading depolarization, a hypothesis still considered true today (37).
Cortical spreading depression can be triggered in animal models by multiple modalities, including electrical stimulation, mechanical stimulation, potassium, endothelin, or ouabain (11; 10). This trigger causes a depolarization with a shift of ions (increase in extracellular potassium, decrease in extracellular sodium, changes in chloride, protons, magnesium, and zinc) and a large release of neurotransmitters (eg, glutamate and dopamine) (11; 10). This ion shift causes neuronal dysfunction, resulting in a regional increase in blood flow (hyperemia) followed by a relative decrease in blood flow (oligemia), facilitated by glutamate. Glutamate builds up, resulting in a loss of membrane potential and a subsequent current shift, and releases vasoactive substances like nitric oxide. These substances are responsible for the increase in blood flow (hyperemia) to meet the increase in energy requirements. Those with visual auras have cortical spreading depression-caused vascular changes starting in the occipital pole, then propagating outwardly, generally stopping by the central sulcus (33; 02; 43). Vascular changes caused by cortical spreading depression have been visualized using fMRI (utilizing BOLD signal changes), PET, flow studies, and MRI with arterial spin labeling (11; 09; 10; 08; 43). Hyperemia is followed by a period of oligemia with a gradual shift back to baseline blood flow (11; 09; 10; 43). The prolonged phase of oligemia generally does not reach a threshold for ischemia, but it has been reported to increase the ischemic area of a stroke when superimposed.
The cortical spreading depression activation of the headache phase of migraine is still under investigation. It has been previously suggested that cortical spreading depression can activate neurons in the trigeminovascular system via two distinct pathways: one involving molecule-activated meningeal nociceptors (pain pathway), and the other being an inhibitory pathway originating in the primary sensory cortex (20). Therefore, it would be possible for cortical spreading depressions to either activate or inhibit the trigeminal pain pathway depending on the anatomical location (20). In contrast, migraine without aura is more common than migraine with aura, and there is no real evidence of cortical spreading depression mechanisms in patients with migraine without aura (25). Functional neuroimaging has demonstrated that attack initiation in patients with migraine with and without aura is similar and involves the hypothalamus up to 48 hours preceding headache, suggesting that cortical spreading depression likely does not directly generate migraine pain in most patients, but its modulatory role remains under investigation (09; 42; 25). Despite advances in our understanding of the aura phase, it remains unclear whether and how migraine and aura mechanisms are related in migraine pathophysiology.
Headache. Migraine headache pain is multifactorial and involves genetic predisposition, prior experiences, and pain mediators, among many others (43). A pure vascular model of migraine is largely considered outdated, as vasoconstriction is not required for pain abortion, and a more neuronal theory has been suggested by functional imaging studies. Migraine attack initiation has been proposed to occur centrally as functional imaging studies have shown activation of central regions, including the brainstem, in both spontaneous and triggered migraines, with these changes occurring before pain onset (27; 25). Vascular changes occur in migraine pathophysiology (28), but their significance remains to be elucidated. Vascular changes in migraine have been hypothesized by some to occur as an epiphenomenon to neural activation (28). In contrast, neurosurgical findings have shown that stimulating or mechanically distending the intracranial arteries can elicit migraine-like pain, suggesting that the intracranial vessels contribute to migraine pathogenesis (12). Therefore, both neuronal and vascular mechanisms are felt to play a role in migraine attack initiation and pain perception.
Migraine pain is closely associated with activation of the trigeminal sensory pathways. Trigeminal activation starts with peripheral afferents, composed of unmyelinated C fibers and myelinated A-delta fibers, that innervate peripheral structures of the head and neck via the trigeminal nerve (V1 and V2 more so than V3), C1, and C2 (25). Peripheral trigeminal ganglion afferents innervate the meninges and large cerebral arteries as well as the skin and eyes. These peripheral afferents also innervate the trigeminal nucleus caudalis, or the caudal part of the spinal trigeminal nucleus. These peripheral trigeminal ganglion afferents converge with upper cervical afferents (innervating skin and muscles of the neck) to create the trigeminal cervical complex within the brainstem (25).
Trigeminal activation via inflammatory mediators and vasoactive peptides, including substance P, neurokinin A, pituitary adenylate cyclase-activating polypeptide (PACAP), and calcitonin gene-related peptide (CGRP), plays a key role in migraine pain and processing (20; 30). Ascending projections from the trigeminal cervical complex transmit signals to the hypothalamus and multiple brainstem nuclei, including the locus coeruleus, rostral ventromedial medulla, nucleus raphe magnus, superior salivatory nucleus, and periaqueductal gray (13; 25). Ascending fibers from the trigeminal cervical complex also transmit signals to various cortical processing areas via the thalamus. Second-order nociceptive neurons from the trigeminal cervical complex connect to the thalamus, specifically the medial nucleus of the posterior thalamus and ventroposteromedial thalamus. From there, bidirectional connections are made to numerous cortical and autonomic systems, such as the hypothalamus, somatosensory cortex, and limbic structures, including the insula, hippocampus, and amygdala (13; 43). This complex pain matrix correlates with our knowledge of migraine impairments, including cognitive, emotional, and autonomic, among others.
The hypothalamus is not only implicated in the premonitory phase but also in the headache phase. The hypothalamus has many connections to pain systems, including the spinal trigeminal nuclei (39). There are specific cells within the hypothalamus that have been shown to inhibit pain signals from the trigeminal cervical complex, an effect blocked by the selective dopamine antagonist eticlopride (39). In one study, Schulte and colleagues followed a patient with migraines for an entire month with daily functional imaging (46). They found increased hypothalamic activity in response to trigeminal nociceptive input in the 24 hours leading up to an attack, as well as increased functional connectivity between the hypothalamus and the spinal trigeminal nuclei during the premonitory and pain phases (39; 46). Imaging studies suggest that the anterior hypothalamus is associated with the premonitory phase and chronic migraine, whereas the posterior hypothalamus is involved with the headache phase (46).
Postdrome. The postdrome is a common, but the least studied, phase of migraine and is colloquially known as the “migraine hangover.” The postdrome follows the resolution of the headache phase and includes symptoms, such as fatigue, nausea, neck stiffness, difficulty concentrating, irritability, and light sensitivity (43). These symptoms can last an entire day following the attack (average duration 25.2 hours). Up to 94% of patients report at least one of these symptoms, with the predominant symptom being fatigue (04; 43). Functional imaging during the postdrome phase has shown widespread reduction in brain function and has also found alterations in the same neural networks as the premonitory phase (48). The similarities in migraine symptoms during the prodrome and postdrome, and particularly the persistence of cognitive, sensory, and homeostatic changes, has led to a theory that these symptoms represent a continuum of migraine symptomatology rather than distinct phases (25; 48; 14).
Studies have also found a reduction in blood flow during migraine episodes, including the postdrome phase, which may be contributing to the symptoms. A couple of theories have been brought forward to explain this effect. The reduction in blood flow may be caused by activation of brainstem nuclei (eg, locus coeruleus) during and after pain stimuli processing, causing activation of alpha-2 adrenoceptors and, therefore, leading to vasoconstriction (04; 43; 30). Cortical spreading depression, as described above for migraine aura, could also be implicated in the postdrome. The CGRP is involved in brain circulation and nociception (along with many other functions) and may be a key aspect in cortical spreading depression and, therefore, the postdrome phase (13; 43).
Interictal period. Another aspect of migraine that has drawn recent attention is the interictal period, or the period between migraine attacks. During this period, some migraine patients are symptom-free, but others may experience migraine related symptoms, such as photophobia and cognitive changes (25). Imaging studies during the interictal period have suggested widespread dysfunction affecting regions known to play a role in migraine pathophysiology, including the hypothalamus, insula, locus coeruleus, amygdala, brainstem, and thalamocortical pathways (25). It is thought that there may be intrinsic sensory dysregulation and impaired sensory habituation in the brains of patients with migraine, which could contribute to interictal sensitization and the manifestation of other symptoms during the interictal period (25). Functional imaging has shown abnormal activity and connectivity in regions important for cognition, such as the dorsolateral prefrontal and parietal cortices, associated with slower response times in attention-shifting tasks (17).
Chronic migraine. Chronic migraine is included as a diagnosis in ICHD-3, rather than a complication of migraine in ICHD-2. Chronic migraine is defined by ICHD-3 as “headache occurring on 15 or more days/month for more than 3 months, which, on at least 8 days/month, has the features of migraine headache.” It is associated with a large burden of disability, frequent headaches, and medication overuse. The trigeminal pain system can shift to what’s known as “chronic migraine” through a variety of factors, including impaired modulation, peripheral sensitization, central sensitization, decreased threshold, and alterations in connectivity (43). First, it is believed that the descending modulatory pain pathways are mainly regulated by the periaqueductal gray, the locus coeruleus, and the rostral ventromedial medulla. Dysregulation can amplify preexisting pain signals, leading to an increased pain state. Increased pain states, therefore, have increased activation of the beginning of the pain matrix, the afferent trigeminal ganglion neurons, called peripheral sensitization (43; 49). Increased first-order afferent activation causes increased sensitivity of second-order trigeminal nucleus caudalis neurons and, therefore, increased third-order thalamic neuron sensitivity, deemed central sensitization (43; 49). Increased first-order afferent activation increases the sensitivity of second-order trigeminal nucleus caudalis neurons and, therefore, the sensitivity of third-order thalamic neurons, a phenomenon termed “central sensitization” (43; 49). During an acute migraine, the threshold for nociceptive inputs to the trigeminal nucleus caudalis decreases while the receptive field for nociception increases, leading to acute migraine activation. In the chronic form, there is altered resting state connectivity (for example, in the amygdala and insula) as well as persistent interictal changes (43). Network mapping research also found a possible feedback loop with hyperactivity of the visual cortex and associated gray matter atrophy/volume loss, causing a decreased threshold for cortical spreading depression and, therefore, an increased chance of repeated attacks and chronification of migraine (07).
Neuropeptides. As our understanding of migraine mechanism has advanced over time through various clinical studies, research efforts have increasingly focused on two neuropeptides: GCRP and PACAP.
After substance P, CGRP was the second neuropeptide identified in the trigeminovascular system. CGRP is a more potent vasodilator than substance P and is expressed in several key regions implicated in migraine pathophysiology, including perivascular trigeminal sensory afferents, cerebral vascular walls, and the trigeminal ganglion (25). Intravenous infusion of CGRP has been shown to induce migraine-like attacks without aura in patients (23). Moreover, in migraine patients, CGRP administration has been demonstrated to provoke non-headache symptoms of migraine attacks, including photophobia, phonophobia, and nausea (31). CGRP exerts its effects in migraine through vasodilation, activation of peripheral meningeal nociceptors, and mast-cell degranulation, which further activates nociceptors in the meninges and vasculature, thereby potentiating pain (13; 25). As the role of CGRP has been elucidated, eight FDA-approved CGRP therapies for migraine have been developed, including monoclonal antibodies targeting the CGRP molecule or receptor and small-molecule CGRP receptor antagonists. However, some studies have suggested that only about 40% to 60% of migraine patients experienced significant improvement with these medications, suggesting that other elements play a role in migraine pathophysiology beyond CGRP, such as PACAP (40; 45; 31).
PACAP, particularly its predominant isoform PACAP-38, is another neuropeptide established in migraine pathophysiology. PACAP is expressed in the sphenopalatine ganglion and trigeminal ganglia (25). Like CGRP, intravenous infusions of PACAP-38 in patients with a history of migraine can provoke migraine-like attacks as well as other non-headache symptoms, including photophobia, but have also been reported to trigger premonitory symptoms in some (22). PACAP levels are centrally increased in the blood during migraine headaches (and cluster headaches) (25). PACAP binds to several receptors, eg, PAC1 [HY3.1] expressed in the trigeminovascular nociceptive system, and activates mast cell degranulation and vasodilation, leading to dural C-fiber activation (25). A study by Al-Karagholi and colleagues evaluated migraine patients pretreated with epitnezumab (a CGRP monoclonal antibody against the CGRP ligand) versus placebo, followed by infusion with PACAP-38. The results showed that eptinezumab did not prevent PACAP-38-induced migraine attacks, suggesting that PACAP may work independently of CGRP in driving migraine attacks (01). This makes PACAP an attractive target for patients who do not respond to anti-CGRP therapies. However, a phase 2, randomized, double-blind, placebo-controlled trial for a selective PAC1 receptor antagonist failed to demonstrate benefit over placebo for migraine prevention (03). At the time of this publication, there are no PACAP-targeted therapies approved or commercially available; they are currently in clinical development.
Triggers. A common theme of many migraine triggers is metabolic derangements, including changes in hormones (emotional stress, menstruation), sleep, weather, diet, physical activity, and alcohol intake (49; 30). These can create an unbalanced energy equation, leading to oxidative stress. White matter hyperintensities due to increased oxidative stress can be found in migraine patients and are associated with changes in oxidative biomarker levels (30). It is postulated that the body uses cortical spreading depression and/or activation of the trigeminovascular system to balance the energy equation and maintain homeostasis (21).
A “high-risk area” hypothesis has been proposed suggesting that migraine attacks arise from three primary factors – depressive or unstable mood, unrestful sleep, and sympathetic-parasympathetic imbalance with parasympathetic prevalence – through disruption of homeostasis via hypothalamic connections (44). These three factors can create a low brain energy state, containing “high-risk areas” in which migraine attacks can arise in susceptible individuals.
Hormones. Hormones, particularly hormone fluctuations in women, have been shown to influence migraine pathophysiology, with estrogen playing a larger role than other hormones. Estrogen acts on pain pathways by modulating the μ-opioid system and neurotransmitters, including serotonin, GABA, and norepinephrine (50). Estrogen also plays a role in CGRP release and influences migraine attacks in women. Estrogen fluctuations are thought to regulate CGRP receptor synthesis, expression, and release within the trigeminovascular system (15). Animal studies have shown a significant increase in CGRP-induced dural vasodilation following estradiol pretreatment (32). Interictal CGRP levels are significantly higher in females than in males, and postmenopausal females show decreased estradiol levels that correlate with reduced plasma CGRP concentrations (15). Additionally, females with menstrual-related migraine or migraine without aura can experience significant improvement in migraine during pregnancy due to steady estrogen levels that mitigate migraine triggers. After childbirth, bottle-feeding mothers typically experience earlier recurrence of migraines due to hormone fluctuations: decreased prolactin levels and elevated estrogen levels that fluctuate. In contrast, breastfeeding mothers experience improvement in migraine symptoms during the lactation period due to prolactin-induced suppression of estrogen production. The strong relationship between estrogen and CGRP supports higher prevalence of migraine in females.
Right-to-left shunt. Another active area of migraine pathophysiology research is the connection between migraine and right-to-left shunting. It is still being determined whether there is a causal relationship or simply an increased coexistence (24). Conditions include intracardiac shunting, such as a patent foramen ovale or an atrial septal defect, as well as extracardiac shunting, such as a pulmonary arteriovenous malformation (41). With regards to migraine prevention, patent foramen ovale closure trials have shown mixed results, and the consensus for routine patent foramen ovale closure as a treatment for migraine is not recommended at this time (29).
Predominating theories about pathogenesis include: hypoxemia with an associated increase in hemoglobin and cardiac output (which can initiate cortical spreading depression), an increase in trigger chemicals (like serotonin) that avoid pulmonary capillary filtration, and microemboli/microthrombi that are shunted to the brain from the venous circulation causing tiny infarctions (and therefore low blood flow and/or cortical spreading depression) (41). Migraine patients with right-to-left shunts may be responsible for a large proportion of those with migraine who have clinical or subclinical brain infarction (41).
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- References especially recommended by the author or editor for general reading.
Contributors
All contributors' financial relationships have been reviewed and mitigated to ensure that this and every other article is free from commercial bias.
Authors
-
Eric Dunn DO
Dr. Dunn of Cleveland Clinic has no relevant financial relationships to disclose.
See Profile -
MaryAnn Mays MD
Dr. Mays of Cleveland Clinic received consulting fees from Axsom, Aspeya, Dynamed, Lundbeck, Oakley Health, and Pfizer; she received a research grant from Lundbeck and also served as a research safety monitor for Cooltech, Inc.
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Editor
-
Hsiangkuo Yuan MD PhD FAHS
Dr. Yuan of Jefferson Health-Thomas Jefferson University Hospitals received a consultant honorarium from Abbvie, Cerenovous, Pfizer, and Salvia.
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Former Authors
- Aravindhan Veerapandiyan MD
- Hannah Smashey Lewis MD
- Stephen D Silberstein MD
- Hannah Smashey Lewis MD and Aravindhan Veerapandiyan MD
Patient Profile
- Age range of presentation
-
- 1 month to 65+ years
- Sex preponderance
-
- Female > male (Wöber-Bingöl 2013; Burch et al 2015; Burch et al 2019; GBD 2016 Headache Collaborators 2016; GBD 2019 Diseases and Injuries Collaborators 2020)
- Heredity
-
- Heredity may be a factor
- Polygenic
- Rare monogenic forms (eg, familial hemiplegic migraine; autosomal dominant)
- Population groups selectively affected
-
- American Indians and Alaska Natives
- Whites
- Blacks/African-Americans
- Hispanics
ICD & OMIM codes
- ICD-10
-
- Migraine: G43
- ICD-11
-
- Migraine: 8A80
- OMIM
-
- Migraine, familial hemiplegic, 1: #141500
- Migraine, familial hemiplegic, 2: #602481
- Migraine, familial hemiplegic, 3: #609634
- Migraine with or without aura, susceptibility to, 6: %607516
- Migraine with or without aura, susceptibility to, 1: %157300
- Migraine with or without aura, susceptibility to, 2: %300125
- Migraine with or without aura, susceptibility to, 3: %607498
- Migraine with or without aura, susceptibility to, 4: %607501
- Migraine with or without aura, susceptibility to, 5: %607508
- Migraine with or without aura, susceptibility to, 7: %609179
- Migraine with or without aura, susceptibility to, 8: %609570
- Migraine with or without aura, susceptibility to, 9: %609670
- Migraine with or without aura, susceptibility to, 10: %610208
- Migraine with or without aura, susceptibility to, 11: %610209
- Migraine with or without aura, susceptibility to, 12: %611706
- Migraine with or without aura, susceptibility to, 13: %613656
- Vasculopathy, retinal, with cerebral leukodystrophy: #192315
- Retinal dystrophy, optic nerve edema, splenomegaly, anhidrosis, and migraine headache syndrome; ROSAH: #614979
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