Migraine as a complex neurovascular disease

Migraine is a complex neurovascular disorder of the brain [8, 12]. Approximately 15% of the population is affected within a year [12, 17, 26]. After dental caries and tension-type headaches, migraine ranks third among the most common human diseases [24]. More than 50 years ago, Scandinavian long-term studies in children and adolescents highlighted the significant impact of headaches [3]. Since then, epidemiological studies have shown a marked increase in headaches. This is partly due to precise modern diagnostics. While earlier lifestyles kept the genetic predisposition to headaches stable, and clinical disease courses did not occur with the severity and frequency known today, modern lifestyles with high demands on the nervous system can increasingly lead to the clinical manifestation of headache disorders. The need for treatment is increasing.

Migraine is the second most disabling disease worldwide, and the first most disabling disease among young women [8, 24]. Severe migraine attacks are ranked by the World Health Organization as one of the most disabling diseases, comparable to dementia, spinal cord injury, and active psychosis.

Migraine places an enormous clinical and economic burden on individuals and society. It is a chronic condition that can persist for many decades. In some patients, it can progress, meaning that the frequency, intensity, and duration of migraine attacks can increase. Simultaneously, accompanying symptoms such as nausea, vomiting, and sensitivity to noise and light can also intensify. As a result, episodic migraine attacks can develop into a chronic condition.

Chronic migraine affects approximately 1-2% of the population [8, 12, 26]. This equates to around 1.66 million people in Germany. About 2.5% of individuals with episodic migraine develop chronic migraine. These patients experience 15 or more headache days per month. The prevalence of migraine peaks in adulthood between the ages of 25 and 55. Those most affected by migraine attacks are between the ages of 40 and 50. In this age group, the likelihood of work disability or early retirement is increased. Clinical observations show that the pain-maintaining psychological comorbidity of migraine patients has become significantly more complex and severe in recent years. This includes both depressive and anxiety disorders. The risk of depression, anxiety disorders, and suicide is 3-7 times higher in affected individuals than in healthy individuals. The risk of cardiovascular disease, heart attacks, and stroke is approximately 1.5 to 2 times higher than in healthy individuals. This particularly affects young women under 45.

It is estimated that the German population loses 32 million working days a year due to migraines. Migraines and chronic headaches are the second most common cause of short-term sick leave. Projections indicate that sick leave due to migraines alone costs €3.1 billion annually in Germany, calculated based on these 32 million lost days.

Migraine is diagnosed according to the diagnostic criteria of the 3rd edition of the International Classification of Headache Disorders (ICHD-3) [17] (see table). Currently, 48 main forms of migraine are distinguished. The most important subgroups are migraine without aura, migraine with aura, chronic migraine, migraine complications, probable migraine, and episodic syndromes that may accompany migraine. A thorough understanding of the International Classification of Headache Disorders is essential to keeping pace with advances in current migraine diagnostics and treatment.

Table 1: ICHD-3 criteria for different forms of migraine [17]
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Migraine without aura

At least five migraine attacks that meet the following three criteria and are not better met by another ICHD-3 diagnosis.

  • The headache attacks last 4-72 hours (untreated).
  • The headache exhibits at least two of the following four characteristics: unilateral location, pulsating quality, moderate or severe pain intensity, aggravation by or avoidance of routine physical activities.
  • At least one of the following symptoms occurs during the headache: nausea and/or vomiting, photophobia and phonophobia.

Migraine with aura

At least two attacks that meet the following two criteria and that cannot be better explained by another ICHD-3 diagnosis.

  • One or more of the following fully reversible aura symptoms: visual, sensory, linguistic, motor, brainstem, retinal.
  • At least three of the following six characteristics: at least one aura symptom spreads gradually over ≥5 minutes, two or more aura symptoms occur consecutively, each individual aura symptom lasts 5-60 minutes, at least one aura symptom is unilateral, at least one aura symptom is positive, the aura is accompanied by a headache or follows within 60 minutes.

Chronic migraine

Headache (migraine-like or tension-type) that meets the following two criteria on ≥15 days/month for >3 months and cannot be better explained by another ICHD-3 diagnosis.

  • Occurrence in a patient who has already had at least five attacks that meet the criteria for migraine without aura or at least two attacks that meet the criteria for migraine with aura.
  • Headache occurring on ≥8 days/month for >3 months and meeting one of the following criteria:
  • Criteria for migraine without aura, criteria for migraine with aura, or the patient believes that it is a migraine at onset and that the symptoms are relieved by a triptan or an ergot derivative.

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The phases of migraine

Interictal phase

Figure 1 differentiates the phases of migraine [8, 17]. Due to their genetic makeup with specific risk genes [15], migraine patients exhibit a particular neuropsychological profile between headache phases. Their reactivity to sensory, cognitive, and affective stimuli is increased. Affected individuals perceive more intensely and do not habituate, or only minimally, to repetitive stimuli. Their perceptual readiness is heightened. The filtering of stimuli and the deflection of the constant stimulus impulse are reduced. The sensory, affective, and cognitive stimulation from internal and external stimuli thus leads to a permanently heightened activation of the nervous system. Thinking, creativity, and impulsivity can therefore be intensified. On the other hand, there is a particular, persistent burden of anxiety and rumination.

Prodromal phase, trigger factors

The assumption that migraine attacks are caused by specific trigger factors is still widespread. So-called trigger lists from previous decades exist, enumerating numerous suspected trigger factors. However, clear evidence for their effect is lacking. Current understanding suggests that the effects of potential trigger factors are already part of the prodromal symptoms within the migraine complex [19, 25]. For example, the perception of stress is a consequence of increased irritability and excitability before a migraine attack. At other times, such processes cannot trigger migraine attacks in affected individuals. Cravings for certain foods, such as chocolate or high-calorie foods, are an expression of a protective mechanism in response to energy deficit and hypothalamic hyperexcitability as part of a migraine attack [4, 9]. This reaction is therefore not the cause of the migraine, but rather a consequence of the ongoing attack.

Due to this constant activity of the central nervous system, an energy deficit in nerve cells can occur after a certain period of increased brain activity [16]. This leads to a protective reaction of the nervous system, activating cravings for energy in the form of carbohydrates and yawning to increase oxygen intake. During this phase of irritability, prodromal symptoms of migraine include fatigue, drowsiness, yawning, increased sensory sensitivity with allodynia, hyperpathia, irritability, and osmophobia. The cognitive and affective functions of the nervous system are disrupted, autonomic control becomes increasingly impaired, and edema, nausea, diarrhea, and other autonomic symptoms occur.

Aura phase

The next phase, the aura phase, follows, accompanied by focal neurological symptoms. These symptoms exhibit a gradual migration and spread continuously over a period of 5 to 60 minutes [8, 17]. In some cases, they can persist for hours or days and, in rare instances, even progress to a migraine infarction. Most commonly, visual disturbances are observed in the form of fortification spectra with zigzag lines in the visual field, which spread gradually and homonymously. The migraine app [13] allows for aura simulation, enabling affected individuals to trace the course of a typical aura (see Fig. 2). The migraine aura represents the encyclopedia of neurology. Accordingly, a wide variety of symptoms can occur, including sensory, motor, affective, and neuropsychological disturbances. A particularly complex aura symptomatology can occur in migraine with brainstem aura [17].

Headache phase

The headache phase follows within up to 60 minutes [17]. This typically lasts 4–72 hours. In the context of status migrainosus, the headache phase can persist even longer. The headache is characterized by unilateral, throbbing, pulsating pain of very severe intensity. The pain is exacerbated by physical activities such as walking, bending over, or climbing stairs. Patients are often bedridden due to the severity of the pain. Accompanying symptoms may include nausea, vomiting, and photophobia and phonophobia. The headache phase can be characterized by a variety of other symptoms. The minimum criteria described above are specific and sensitive for precise classification.

Postdromal phase

The headache phase transitions into the postdromal phase in approximately 30% of affected individuals [8, 17]. During this phase, patients experience fatigue, asthenia, increased irritability, and a reduction in thinking and other cognitive functions for up to 48 hours. Subsequently, the migraine returns to the interictal phase. Here, the neuropsychological characteristics that were already present before the migraine attack persist, based on the specific genetic makeup that leads to the characteristic neurovascular reactivity of the nervous system in migraine patients.

Migraine is not merely a pain disorder characterized by the headache phase. Rather, it affects the entire creative lifespan of those affected [8, 12, 24, 26]. It typically occurs in the first two decades of life and continues to be a burden until the sixth and seventh decades, with the described characteristics during the interictal phase and the duration of headache attacks.

A chronic, lifelong peculiarity of the nervous system

The clinical features of migraine are complex and exhibit considerable variability between patients [8, 12, 24, 26]. The frequency, characteristics, duration, and severity of symptoms vary greatly both within and between individuals. Symptoms can also change over the course of a person's life. The course of migraine can fluctuate due to hormonal changes. Women may experience particularly severe attacks during their menstrual cycle. In contrast, migraine attacks are often less severe during pregnancy. However, they can be particularly burdensome during the postpartum period and while breastfeeding.

Migraine is a chronic, lifelong condition of the nervous system that increases the risk of migraine attacks due to pre-existing risk genes [3, 15, 17, 24]. In most patients, attacks occur episodically. The term "chronic migraine" refers to cases in which patients experience migraine attacks on 15 or more days per month, and this pattern has persisted for more than three months. Of these 15 headache days, at least eight must be days on which the headaches meet the criteria for migraine. Migraine is inherently a chronic condition that occurs in episodes. The term "chronic migraine" refers to migraine attacks that occur with a very high frequency. In 2-5% of affected individuals, the transition from episodic migraine to chronic migraine can occur [8].

This transition can occur spontaneously. However, it often occurs in connection with the overuse of acute medications to treat migraine attacks [14]. If affected individuals take acute medications on 10 or more days per month, the headache frequency can paradoxically increase. This results in more headache days per month and an increased need to take further acute medications. Eventually, the frequency of migraine days per month increases to 15 or more days. In some cases, persistent headaches can also result. Typically, affected individuals then experience a baseline headache that is episodically overlaid by pain attacks. Other risk factors for the transition from episodic migraine to chronic migraine include a high attack frequency, inadequate acute treatment of migraine, severe attacks, long attacks, ineffective preventive therapy, obesity, anxiety, depression, and a generally increased sensitivity to stimuli. With successful treatment, chronic migraine can also remit to episodic migraine.

Comorbidities

Migraine can be associated with numerous comorbidities. This can further exacerbate migraine-related disability and increase the complexity of clinical symptoms and treatment approaches [8, 17, 24]. Mental health and cardiovascular disorders are particularly prominent. Mental health disorders include depression, anxiety, stress-related disorders, substance abuse, chronic fatigue syndrome, fibromyalgia, hyperventilation syndrome, and musculoskeletal pain disorders. Neurovascular disorders include stroke, myocardial infarction, dissections, epilepsy, attention deficit hyperactivity disorder (ADHD), chronic pain disorders, irritable bowel syndrome (IBS), arthritis, and restless legs syndrome.

Pathophysiology

Based on genome-wide association studies (GWAS), it is concluded that 40–60% of the clinical symptoms of migraine are due to genetic factors [8, 15]. Extensive endogenous and exogenous factors can be responsible for the other characteristics of migraine. These include behavior, age, diet, hormones, sleep, stress, and others. Genome-wide association studies have identified 38 risk genes for migraine with 44 gene variants [8, 15]. The identified risk genes are involved in glutamatergic neurotransmission, synaptic development, synaptic plasticity, metabolism, and pain processing.

Specific forms of migraine can also be monogenic. Four different variants are currently described [8]: cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestation (RVCL-S), familial advanced sleep phase syndrome (FASPS), and familial hemiplegic migraine (FHM). The corresponding mutations have been specifically identified in genetic studies.

In recent years, neurophysiological, functional, and structural imaging studies, as well as pharmacological studies, have provided a comprehensive picture of the pathomechanisms of migraine [1, 20]. Functional imaging studies using PET, SPECT, and functional MRI during migraine aura have revealed continuous changes in blood flow. Initially, a brief hyperperfusion is observed, followed by a longer period of hypoperfusion. These changes occur in brain regions that correlate with clinical aura symptoms, particularly in the visual cortex.

Clinical and experimental findings indicate that migraine aura is caused by a so-called spreading depression [27]. During this phase, nerve cells in the affected brain region exhibit extensive depolarization with massive reflux of potassium ions and numerous other neurotransmitters. These include glutamate, sodium, and calcium ions, as well as neuronal swelling. Studies indicate that these processes arise from a neuronal energy deficit due to insufficient energy supply to the nerve cells or from increased energy consumption [1, 4, 8, 9, 16]. The consequence is a decompensation of metabolic processes in the nerve membranes.

According to experimental data, spreading depression can activate trigeminal nociceptive pathways. This can trigger headaches. The consequence is the activation of pial and dural macrophages as well as dendritic cells [22]. Glymphatic pathways are occluded and numerous nociceptive mediators are released [23]. As a result, peripheral trigeminal neurons in the trigeminal ganglion and trigeminal neurons in the spinal trigeminal nucleus and upper cervical spinal cord are activated. Numerous endogenous factors such as hormones and gene variants, as well as exogenous factors such as lifestyle, diet, and medications, can alter the brain's sensitivity to spreading depression [8, 27].

CGRP and migraine

Stimulation of the trigeminal ganglion leads to the release of calcitonin gene-related peptide (CGRP) and substance P [7]. CGRP is released into the cranial bloodstream and can be blocked by triptans. CGRP activates nociceptive mechanisms in the dura mater, trigeminal ganglion, cervical trigeminal nucleus complex, thalamus, and periaquaductal gray [7]. In severe, prolonged migraine attacks, the release of CGRP into the cranial circulation can be observed. Both the clinical symptoms and the release of CGRP can be blocked by triptans [18]. CGRP infusions can provoke an attack in migraine patients [2]. This is not the case in healthy controls. Monoclonal antibodies specifically targeting CGRP as a ligand (eptinezumab, fremanezumab, and galcanezumab) or the CGRP receptor (erenumab) are now available for the preventive treatment of episodic and chronic migraine [6, 10]. They inhibit the effects of CGRP in the migraine process (Fig. 3). They have been shown to be effective and well-tolerated in controlled trials. Efficacy develops within weeks and lasts for years.

Fig. Mechanisms of action of CGRP monoclonal antibodies in migraine prevention

 During a migraine attack, the release of neuropeptides causes peripheral and central trigeminal vascular sensitization. Algogenic pro-inflammatory mediators such as CGRP, nitric oxide, and prostaglandins increase the sensitivity of neurovascular structures [5, 21]. These structures respond to mechanical stimulation to which they are not normally sensitive. This results in spontaneous activation of nociceptive neurons, expansion of receptive fields, and local allodynia and hyperpathia in and around the head. Muscle reflexes are also activated. Physical activation such as coughing, straining, or other motor activities can increase pain intensity. Allodynia of pericranial and cranial structures in the head and shoulder-neck region leads to increased pain sensitivity and muscular sensitivity in this area. Thalamic sensitization causes heightened bodily sensitivity and sensory hyperexcitability, with avoidance of sensory stimuli. In patients with chronic migraine, corresponding mechanisms may be permanently present.

The migraine brain between attacks

Even between attacks, the nervous system of migraine sufferers exhibits significant structural and functional differences compared to healthy controls [11, 21]. The volume of gray matter in pain-processing areas is reduced, while the volume of gray matter in the somatosensory cortex is increased. White matter lesions may be more prevalent, and white matter integrity may be reduced. These changes may be caused by repeated nociceptive activation and ischemia of the affected brain areas or by repeated migraine attacks. Simultaneously, visual, auditory, somatosensory, and motor-evoked responses are increased by nociceptive processes in the rostral pons. This results in dysfunctional habituation to sensory processing, making pain processes less effectively stabilized and modulated. Elevated glutamate levels in the visual cortex of migraine patients indicate persistent cortical hyperexcitability.

outlook

In recent years, fascinating progress has been made in understanding the course and pathomechanisms of migraine. Migraine can now be precisely diagnosed using the ICHD-3 criteria [17] and differentiated from other headache disorders. Based on this, specific pathomechanisms have been discovered and elucidated [8]. This has led to the development of highly effective treatments with very effective and precise interventions in the disease process [6, 7]. Many sufferers can therefore now be effectively helped. Nevertheless, there are patients for whom the available preventive and attack therapies are not yet providing satisfactory relief. However, the current research pipeline offers hope: it is well-stocked with potential new targets, medications, and further future treatment options.

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