Clinical manifestations and development of migraines

Migraine as a complex neurovascular disease

Migraine is a complex neurovascular disease of the brain [8, 12]. Within a year, approximately 15% of the population is affected[12, 17, 26]. After dental caries and tension-type headaches, migraine is the third most common human disease [24]. More than 50 years ago, long-term Scandinavian studies in children and adolescents pointed out the great importance of headaches [3]. Since then, a significant increase in headaches has been noted in epidemiological studies. On the one hand, this has to do with precise modern diagnostics. While earlier living environments kept the sensitivity to the genetic susceptibility to headaches stable and clinical disease progressions did not occur with the severity and frequency known today, modern lifestyles with high demands on the functions of the nervous system can lead to increased clinical manifestations of headache disorders. The need for treatments is increasing.

Migraine is the second most debilitating disease worldwide and is even the first in young women [8, 24]. Severe migraine attacks are ranked by the World Health Organization among the most disabling diseases, comparable to dementia, paraplegia and active psychosis.

The disease imposes an enormous clinical and economic burden on individuals and society. Migraine is a chronic condition that can last for many decades of life. In some patients it can progress progressively. This means that the frequency of migraine attacks as well as their intensity and duration can increase. At the same time, accompanying symptoms such as nausea, vomiting and hypersensitivity to noise and light can also be increased. The result is that episodic migraine attacks can turn into a chronic form.

Chronic migraine affects approximately 1-2% of the population [8, 12, 26]. That's around 1.66 million people in Germany. About 2.5% of people with episodic migraine develop chronic migraine. The affected patients have 15 or more headache days per month. The prevalence of migraines peaks in adulthood between the ages of 25 and 55. Those affected are most affected by migraine attacks between the ages of 40 and 50. These people are more likely to be unable to work or retire early. Clinical observations show that the pain-maintaining psychological comorbidity of migraine patients has become significantly more complex and severe in recent years. This applies to both depressive illnesses and anxiety disorders. The risk of depression, anxiety disorders and suicide is 3-7 times higher among those affected than among healthy people. The risk of circulatory diseases, heart attacks and strokes is around 1.5-2 times higher than in healthy people. This particularly affects young women under 45 years of age.

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 reason for short-term incapacity to work. According to projections, incapacity to work due to migraines alone costs 3.1 billion euros annually in Germany, calculated on the basis of 32 million days lost.

Migraine is diagnosed according to the diagnostic criteria of the 3rd edition of the International Headache Classification ICHD-3 [17] (see table). Today there are 48 main types of migraine. The main subgroups are migraine without aura, migraine with aura, chronic migraine, migraine complications, probable migraine and the episodic syndromes that may accompany migraine. Accurate knowledge of the International Headache Classification is the basis for keeping up with the progress in today's diagnosis and treatment of migraines.

Table 1: ICHD-3 criteria for different types 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 fulfilled by another ICHD-3 diagnosis.

The headache attacks last 4-72 hours (untreated).
The headache has at least two of the following four characteristics: unilateral location, pulsating quality, moderate or severe pain intensity, aggravated by or avoidance of routine physical activities.
During the headache, at least one of the following features occurs: 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 appear one after the other, each individual aura symptom lasts 5-60min, at least one aura symptom is unilateral, at least one aura symptom is positive, the aura becomes accompanied by a headache or follows within 60 min.

Chronic migraines

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

Occurs 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 any of the following criteria:
Criteria for migraine without aura, criteria for migraine with aura, or the patient believes it is a migraine at onset and the symptoms are relieved by a triptan or an ergot derivative.

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The phases of migraines

Interictal phase

The phases of migraine are differentiated in Fig. 1 [8, 17]. Due to their genetic makeup with special risk genes [15], migraine patients show a special neuropsychological profile between the headache phases. Reactivity to sensory, cognitive and affective stimuli is increased. Those affected perceive more intensely and do not habituate to repetitive stimuli, or only to a small extent. The readiness to perceive is increased. The filtering of stimuli and the averting of the permanent stimulation impulse are reduced. The sensory, affective and cognitive stimulation caused by internal and external stimuli permanently causes increased activation of the nervous system. Thinking, creativity and impulsivity can be intensified as a result. On the other hand, there is a particular constant stress caused by fears and ruminations.

Prodromal phase, trigger factors

It is still widely believed that migraine attacks are caused by specific trigger factors. So-called trigger lists are known from earlier decades, which list numerous suspected trigger factors. However, there is no clear evidence of their effect. According to current assumptions, it is assumed that the effects of possible trigger factors already represent part of the prodromal symptoms in the migraine complex [19, 25]. The perception of stress is a result of the increased irritability and irritability before the migraine attack. At other times, corresponding processes cannot trigger migraine attacks in those affected. The hunger for certain foods such as chocolate or high-calorie foods is an expression of a protective mechanism in the event of an energy deficit and hypothalamic hyperexcitability as part of the migraine attack [4, 9]. The reaction is therefore not the cause of the migraine, but rather a consequence of the ongoing attack.

Due to this permanent activity of the central nervous system, an energy deficit in the nerve cells can occur after a certain phase of increased work demands on the brain [16]. This leads to a protective reaction of the nervous system with activation of cravings to absorb energy in the form of carbohydrates and yawning to absorb oxygen. During this phase of irritability, prodromal symptoms of migraine include fatigue, sleepiness, yawning, increased sensory sensitivity with allodynia, hyperpathy, irritability, and osmophobia. The cognitive and affective performance of the nervous system becomes irritated, the autonomic control becomes increasingly disturbed and edema, nausea, diarrhea and other autonomic symptoms occur.

Aura phase

This is followed by the next phase, the aura phase, which is accompanied by focal neurological symptoms. The symptoms show a gradual migration and spread continuously over a period of 5 to 60 minutes [8, 17]. In individual cases, they can last for hours or days and, in individual cases, turn into a migraine attack. Most commonly, visual disturbances are noted in the form of fortification spectra with zigzag lines in the visual field that gradually spread homonymously. With the migraine app [13], an aura simulation can be carried out and those affected can understand the course of a typical aura (see Fig. 2). This can support the diagnosis and confirmation of the diagnosis. The migraine aura represents the encyclopedia of neurology. Accordingly, a variety of symptoms can occur. These include sensory, motor, affective and neuropsychological disorders. Particularly complex aura symptoms 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 migraenosus, the headache phase can continue beyond this. The headache is characterized by one-sided pulsating, throbbing pain of very severe intensity. The pain increases with physical activities such as running, bending or climbing stairs. As a rule, patients often become 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. For precise classification, the minimum characteristics described above are specific and sensitive.

Postdromal phase

The headache phase continues into the postdromal phase in around 30% of those affected [8, 17]. Here, patients experience fatigue, asthenia, increased irritability, reduction in thinking processes and other cognitive functions for up to 48 hours. The migraine then enters the interictal phase again. The neuropsychological peculiarities that already occurred before the migraine attack apply here, based on the special genetic makeup that leads to the characteristic neurovascular reactivity of the nervous system of migraine patients.

Migraine is not just a pain disorder, characterized by the headache phase. Rather, it affects the entire creative life span of those affected [8, 12, 24, 26]. It usually occurs in the first two decades of life and affects the sixth and seventh decades of life with the characteristics described during the interictal phase and the period during the headache attacks.

Chronic lifelong peculiarity of the nervous system

The clinical features of migraine are complex and show extensive variability between patients [8, 12, 24, 26]. The frequency, characteristics, duration and severity of the symptoms vary greatly within and between individuals. Symptoms can also change over time. The course of migraines can fluctuate due to hormonal changes. Particularly severe attacks can occur in women during the menstrual window. During pregnancy, however, migraine attacks are less severe in many women. In the postpartum period and while breastfeeding, they can be put under even greater strain.

Migraine is a chronic, lifelong peculiarity of the nervous system that increases the risk of migraine attacks due to inherent risk genes [3, 15, 17, 24]. In most patients, the attacks occur episodically. The term “chronic migraine” refers to conditions in which patients suffer migraine attacks on 15 or more days per month and this form has persisted for over three months. Of the 15 days with a headache, there must be at least eight days on which the headache has the characteristics of a migraine. Migraine is inherently a chronic disease that occurs in episodes. The term “chronic migraine” refers to migraine attacks that occur at a very high frequency. In 2-5% of those affected, 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 those affected take acute medication on 10 or more days per month, the frequency of headaches can paradoxically increase. The result is more headache days per month and an increased need to take additional acute medication. Eventually, the frequency of migraine days per month increases to 15 or more days. In individual cases, permanent headaches can also result. Typically, those affected then experience a basic headache, which is episodically superimposed by pain attacks. Further risk factors for the transition from episodic migraine to chronic migraine are a high attack frequency, insufficient acute treatment of migraine, severe attacks, long attacks, ineffective preventive therapy, obesity, anxiety, depression and a general increased sensitivity to stimuli. If treated successfully, chronic migraines can also relapse into episodic migraines.

Comorbidities

Migraines can be associated with numerous comorbidities. This can further complicate migraine-related disability and increase the complexity of clinical symptoms and treatment approaches [8, 17, 24]. The focus is on mental and cardiovascular diseases. In the area of mental illnesses, the focus is on depression, anxiety, stress disorders, substance abuse, chronic fatigue syndrome, fibromyalgia, hyperventilation syndrome and musculoskeletal pain disorders. Neurovascular diseases include stroke, myocardial infarction, dissections, epilepsy, attention deficit hyperactivity disorder, chronic pain disorders, irritable bowel syndrome, arthritis and restless leg syndrome.

Pathophysiology

Based on genome-wide association studies (GWAS), it is concluded that 40-60% of clinical symptoms of migraine are caused by 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, among others. In genome-wide association studies, 38 risk genes for migraine with 44 gene variants were uncovered [8, 15]. The discovered risk genes are involved in glutaminergic neurotransmission, synapse development, synapse plasticity, metabolism and pain processing.

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

In recent years, neurophysiological, functional and structural imaging as well as pharmacological studies have developed a comprehensive picture of the pathomechanisms of migraine [1, 20]. Functional imaging studies using PET, SPECT, and functional MRI studies during migraine aura have revealed ongoing blood flow changes. Initially, a brief hyperperfusion is observed, which is followed by a subsequent, prolonged hypoperfusion. These changes occur in areas of the brain that are correlated 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 the processes arise from a neuronal energy deficit due to a lack of energy supply to the nerve cells or from increased energy consumption [1, 4, 8, 9, 16]. The result is a decompensation of the metabolic processes in the nerve membranes.

According to experimental data, spreading depression can activate trigeminal nociceptive pathways. As a result, headaches can be triggered. The consequence is the activation of pial and dural macrophages as well as dendritic cells [22]. Glymphatic pathways are closed and numerous nociceptive mediators are released [23]. As a result, peripheral trigeminovascular neurons in the trigeminal ganglion and trigeminovascular 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 migraines

Stimulation of the trigeminal ganglion causes a release of calcitonin gene-related peptide (CGRP) and substance P [7]. CGRP is released into the cranial circulation and can be blocked by triptans. CGRP activates nociceptive mechanisms in the dura, trigeminal ganglion, cervical trigeminal nucleus complex, thalamus, and periaquaductal gray [7]. During severe, prolonged migraine attacks, the release of CGRP in the cranial circulation can be observed. The clinical symptoms as well as 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 that specifically target the CGRP as a ligand (eptinezumab, fremanezumab and galcanezumab) or the CGRP receptor (erenumab) are now available in healthcare for the preventive treatment of episodic and chronic migraine [6, 10]. They inhibit the effect of CGRP in migraines (Fig. 3). They have been shown to be effective and tolerable in controlled studies. The effectiveness occurs within weeks and lasts for years.

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

During the migraine attack, the release of neuropeptides causes peripheral and central trigeminovascular sensitization. Algogenic proinflammatory mediators such as CGRP, nitric oxide and prostaglandins increase the sensitivity of neurovascular structures [5, 21]. These respond to mechanical stimulation, to which they are usually not sensitive. The result is a spontaneous activation of nociceptive neurons, an expansion of receptive fields as well as local allodynia and hyperpathy in areas of the head and outside the head. In addition, muscle reflexes are also activated. Physical activation such as coughing, straining or motor activities can increase the intensity of pain. Allodynia of pericranial and cranial structures in the head and shoulder and neck area causes increased pain sensitivity and muscular sensitivity of the head and shoulder and neck area. Thalamic sensitization causes increased physical sensitivity and sensory hyperexcitability with avoidance of sensory stimuli. In patients with chronic migraine, corresponding mechanisms can be permanently present.

The migraine brain between attacks

Even between attacks, the nervous system of migraine sufferers shows clear structural and functional differences to healthy controls [11, 21]. The volume of gray matter in pain processing areas is reduced, the volume of gray matter in the somatosensory cortex is increased. White matter lesions may be increased and white matter integrity may be reduced. These changes can be caused by the repeated nociceptive activation and ischemia of the affected brain areas or by the repeated migraine attacks. At the same time, visual, auditory, somatosensory and motor-evoked responses are increased through nociceptive processes in the rostral pons. The result is a dysfunctional habituation to sensory stimulus processing. Pain processes can therefore be stabilized and modulated less effectively. Elevated glutamate levels in the visual cortex of migraine patients indicate constant cortical hyperexcitability.

outlook

In recent years, fascinating advances have been made in understanding the process and pathomechanisms of migraine. Today, migraine can be precisely diagnosed using the ICHD-3 criteria [17] and differentiated from other types of headache using differential diagnosis. On this basis, specific pathomechanisms could be discovered and elucidated [8]. This has led to the development of highly effective treatment measures with very effective and precise interventions in the disease process [6, 7]. Many affected people can therefore receive effective help today. However, there are patients who cannot yet be satisfactorily helped by the available preventative therapies and attack therapies. However, the current research pipeline gives hope: it is well filled with potential new targets, drugs and other future therapy options.

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