Long-awaited breakthrough in the fight against migraine: antibodies can prevent attacks of the disease

Migraine in its various forms and manifestations is extremely common. The disease is characterized primarily by headache attacks and other symptoms of varying intensity and duration, often having a severe impact on a person's daily life.

In recent years, the mechanisms of development of migraine attacks have been clarified, which made it possible to develop new approaches to treatment and, most importantly, prevention of attacks. What is meant here is a group of innovative drugs, so-called antibodies, which block the substances and structures responsible for the development of migraine attacks.

These new medicines have successfully passed all stages of clinical trials and have proved to be very effective.

What the disease is and how it manifests itself

Migraine is one of the most common neurological disorders. It affects 6-8% of the male population and 12-17% of all women.

Typical cases of migraine requiring treatment are attack-similar headaches. They can feel like throbbing or "hammering". They are typically localized on one side. The intensity can range from moderate to severe and usually intensifies with movement and physical activity. They are frequently accompanied by nausea, vomiting, and high sensitivity to light, sound, and other stimuli. The pain may last from a few hours to several days. Such episodes are called migraine attacks.

Triggers (provoking factors)

The causes of migraine are not yet fully understood. There are so-called triggers, i.e. factors that provoke the development of attacks. Patients are not always able to recognize them easily. Often the cause is a combination of several factors.

The most common attack triggers are:

•  stress;
•  hormone fluctuations (menstruation);
•  disruption of sleep-wake rhythm;
•  insufficient fluid intake;
•  skipping meals;
•  certain medications;
•  possibly certain foods.

Causes of migraine

The causes of the disorder and the complex processes occurring in the brain during an attack have not yet been fully investigated. It is assumed that there is a hereditary predisposition: certain genetic mechanisms are responsible for metabolic disorders of certain nerve cells. Due to this, a specific pain mechanism develops in response to external stimuli. This is why attacks occur, for example, when there is a lack of sleep or stress.

Forms and manifestations

The International Headache Society (IHS) has developed a classification of migraine forms.

Without aura - the most frequent variant. It is typified by headaches of varying intensity and duration, often with nausea, vomiting and/or sensitivity to light and noise.

In some cases, this type of disease occurs in connection with the beginning of menstruation and may accompany two to three consecutive cycles.

The variant with aura is much less common.

By the term “aura” doctors mean visual disturbances and other neurological symptoms, which in most cases precede the phase of headaches or can occur simultaneously with them. Sometimes only the aura occurs, not accompanied by headache (in the past, the French expression "migraine sans migraine" was used for such cases).

Symptoms of aura appear, as a rule, only on one side, develop gradually and last from a few minutes to an hour, then disappear completely.

The most typical of them (occurring separately or in combination), are:

•   visual disturbances (light flashes or flickering in front of the eyes, curved lines, visual field loss);
•   speech disorders (aphasia);
•   sensory disturbances (numbness or "goosebumps", for example, in the hand);
•   paresis (incomplete paralysis);
•   dizziness.

Often the symptoms of the aura phase are similar to a stroke. But unlike a stroke, they begin imperceptibly and gradually intensify, are transient and have no consequences.

Like migraines without aura, this form can occur in correlation with the menstrual cycle. Its specific types are truncal, retinal, abdominal, hemiplegic, vestibular and some other rare syndromes.

What underlies migraine attacks

The development of an attack is a complex process involving brain activation. Nerve cells in a certain situation start producing special signaling substances, the so-called neurotransmitters, in excessive quantities, which starts a chain reaction causing microinflammation and other changes in small vessels. At the same time, the brain nerve cells first get highly activated, then deactivated, which disturbs their electrolyte balance and results in the development of throbbing pain.

This substance plays an important role in neurons of the central and peripheral nervous system. In addition, it is also a potential vasodilator (i.e. it dilates blood vessels) and has physiological importance in neuroimmunology, gastrointestinal tract and in the wound healing process. Migraine attacks are accompanied by an increased release of CGRP, which leads to swelling and inflammation of vessels in the dura mater and the development of attack symptoms.

About diagnostic methods

Doctors diagnose migraines in the presence of typical symptoms and normal physical examination findings (including a neurological examination).

There is no special examination or procedure, or any specific method to confirm the diagnosis.

Some examination findings are the warning signs that the headache may be caused by a serious condition. Such signs include:

• Headache that peaks in a few seconds or less (with a thunderclap).
• Headaches that started after the age of 50.
• Headaches that increase in intensity or frequency over several weeks, or more.
• Pain syndrome in people who have had cancer or have a weakened immune system (due to illness or medication).
• Persistent problems that indicate brain disease, such as sensory or visual disturbances, weakness, lack of coordination, dizziness, or confusion.
• Severe headache accompanied by fever, stiff neck and/or confusion.
• Definite change in the existing headache pattern.

If the attack has occurred recently, or has certain warning signs, a brain MRI is often performed, sometimes also a spinal tap, to rule out other conditions.

When people with pre-existing migraine episodes have headaches that resemble the previous episodes, tests are rarely performed. However, if the pattern is different, especially in the presence of warning signs, a physical examination and various studies are often required.

Conventional therapies and ways of prevention

Jan-Peter Jansen, head of the Berlin Pain Therapy Centre, describes the situation that existed until recently:

Until now, migraine treatment options have been very limited.

Painkillers and anti-nausea medications are used to relieve or reduce symptoms during an attack.

These medications are aimed at inflammation and pain. Triptans additionally constrict blood vessels and reduce nausea, but do not affect the aura.

In terms of prevention, it is primarily recommended to avoid trigger factors, as well as to use various relaxation techniques, certain herbal preparations, some special drugs, and adapt the lifestyle.

Novel antibody-based methods of attack management and prevention

The situation with the treatment and prevention of attacks of the disease has changed dramatically in recent years, when antibody-based drugs were developed. They represent an extremely promising method of drug treatment of migraine.

The "target point" of new forms of treatment is the very mechanism of attack development. The drugs are called CGRP blockers. When administered, they are fixed on the protein itself or its receptors. This prevents the swelling of blood vessels and stops the entire cascade of the pain mechanism before the attack begins. For patients with severe forms of the disease, this means a completely different quality of life.

Thus, antibodies specially developed for the prevention of chronic migraine episodes interfere directly with the CGRP - system.

Available targeted drugs and specifics of their administration

New targeted methods for the prevention and treatment of migraine attacks with antibodies offer great promise in this field. Currently, there are 4 monoclonal antibodies approved for use in Europe.

Erenumab, an antibody that attacks CGRP - receptors.

In contrast, fremanezumab, galcanezumab and eptinezumab block the CGRP molecules themselves.

These agents are administered subcutaneously (erenumab, galcanezumab, fremanezumab) or intravenously (eptinezumab).

There is also the monoclonal antibody substance atogepant available in tablets.

Monoclonal antibodies are highly specific and better tolerated than other prophylaxis methods. Due to their long half-life, they should be administered once a month or every 3 months.

The effect of such drugs begins almost immediately and obviously increases with each administration. In clinical practice, a break in the use of antibodies is recommended 6-9 months after the start of the course. The purpose of this is to find out whether further prophylaxis is required. The results of long-term clinical studies have shown that the prophylactic effect does not decrease over time.

Importantly, the new substances also enable patients to make greater use of non-drug preventive options and contribute to meaningful improvements in the quality of life.

Which patients have the indications for antibodies as a method of prevention?

For patients with episodic symptoms, the medication is prescribed if at least five of the four approved pharmacological groups such as beta-blockers (metoprolol or propranolol), flunarizine, topiramate, valproic acid or amitriptyline have been ineffective, are not tolerated or if there are contraindications or risk factors. In the case of chronic variant, an additional argument in favor of the use of innovative methods is the lack of response to therapy with OnabotulinumtoxinA.

Are there any contraindications?

Monoclonal antibodies against the CGRP or CGRP receptor should not be used during pregnancy and breastfeeding. In addition, they are not recommended for those who, in addition to migraine, have such chronic conditions as coronary heart disease, peripheral arterial occlusive disease, a history of ischaemic stroke and subarachnoid haemorrhage. Restrictions also apply to patients with inflammatory bowel disease, chronic pulmonary obliterative disease, pulmonary hypertension, Raynaud's disease, wound healing disorders, or transplant recipients.

References:

1. Atogepant kann Migräne wirksam vorbeugen. DAZ Onlne. STUTTGART - 14.07.2022, 12:15 UHR
2. Migräneprophylaxe: Neue Antikörper – wann und wie einsetzen? Diener, Hans-Christoph; Holle-Lee, Dagny; Nägel, Steffen; Gaul, Charly. Dtsch Arztebl 2020; 117(27-28): [10]; DOI: 10.3238/PersNeuro.2020.07.08.02
3. S1-Leitlinie Therapie der Migräneattacke und Prophylaxe der Migräne der Deutschen Gesellschaft für Neurologie. In: AWMF online (Stand 2008)
4. A. May: Diagnostik und moderne Therapie der Migräne. In: Dtsch. Ärztebl. 103(17), 2003, s. A 1157–A 1166