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Migraine is defined as a primary and debilitating neurological condition in which the predominant symptom is episodic and recurrent headache, which usually leads to consultation of a neurologist.
The main clinical features of migraine, in addition to headaches, which are often one-sided and pulsating, are nausea and / or vomiting, photophobia and phonophobia.
It is assumed that migraine affects about 12% of the population. The latest epidemiological studies show that about 16.6% of people over the age of 18 have migraines or other intense headaches throughout their lives. Of these, 11.7% were diagnosed with migraine, and the remaining 4.5% were diagnosed with probable migraine, providing a total prevalence of up to 16%.
The WHO, through its global ranking of diseases in 2016, identifies migraine as the second most debilitating disease in the world. A day of migraine is considered to be equivalent in value to a day of disability caused by blindness or paraplegia.
In the first years of life, the prevalence of this pathology is equal between the sexes. These data change radically with the onset of puberty, increasing the frequency in women by 3 times. The figures for the male population are stable. This means that in women of childbearing age there is a frequency of up to 25%, while in adult males it is 8%. This trend is equalling between the two sexes after the fifth decade.
Another proof that shows that women suffer more often from the disease is the presence of so-called “menstrual headaches”. Some patients report improvement in symptoms in the second and third months of pregnancy. Others say that the use of contraceptives or hormone replacement therapy can change the frequency and intensity of a migraine crisis. Today, given the information we have accumulated about the enzyme diaminoxidase (DAO) and the effects of its deficiency, we know what is the cause of this phenomenon.
A migraine-type headache can also be of vascular origin, known as Horton’s headache, cluster headache or “histaminic cephalgia”. It has been shown that the mechanism of development of histamine dysphalgia is more sudden than in migraine, since the release of endogenous histamine is present.
Cluster headache, or histaminic cephalgia, is characterized by attacks of severe, usually one-sided pain, which can be orbital, supra/temporary or a combination thereof. The episode lasts between 15 and 180 minutes and can have a frequency of between two and eight episodes per day. Very intense pain can be accompanied by a feeling of laceration, nasal congestion, watery rhinorrhea, sweating of the forehead and face, myosis and / or swelling of the eyelids, as well as anxiety and agitation.
During the most severe attacks, the intensity of pain is unbearable. In general, patients may not be able to move normally or find a suitable resting position.
Seizures can occur in a series of days or weeks. They can last for months, separated by periods of remission that can last for years. Some patients may have an annual recurrent attack. Only 10% of patients suffer from chronic cluster headaches, that is. no periods of remission.
The age of onset is usually 20-40 years. For unknown reasons, men have more frequent episodes than women in the proportion of 3 to 1.
In migraine, prophylactic treatment is essential, especially for patients who have a large number of seizures, as well as for those who have a high intensity or duration. The fact is that migraine significantly reduces the quality of life and affects the family, social and work relationships of patients.
In 50% of patients, the migraine attack lasts more than 24 hours. 20-40% of patients experience more than one attack of migraine per month with a maximum prevalence among the age group 25-55 years (the most productive part of the population).
As a result, migraines have a major economic impact. It is estimated that migraines produce 112 million days lost per year, worldwide. Productivity in the United States fell by $5-17 billion a year because of this. In addition, since the crisis has a maximum duration of 72 hours, patients usually do not have compensation from public health systems.
On the other hand, 50% of migraine patients resorted to self-medication, and half of the attempts to relieve symptoms failed.
Histamine is a biogenic amine, widely distributed in the body. It is involved in various processes of the body, including digestive processes, vascular regulation, allergic reactions and inflammatory processes.
Histamine can be found in many products in the daily diet, which have been shown to activate migraine episodes in sensitive people.
The relationship between food and migraine/headache is widely mentioned in the literature.
In fact, for decades, experts have considered diet (or certain foods) as one of the causes of some headaches and migraines. According to various sources, the percentage of patients with migraines who associate the onset of pain with the consumption of certain foods ranges from 12% to 60%. However, many other patients with migraines do not associate the onset of an episode with food, given that between the symptoms it can appear up to 3 days after eating the food.
The most cited foods that are considered to cause migraines or cluster headaches are chocolate, cheese, citrus fruits, alcohol (especially wine and beer), meat products, dried fruits, coffee and some supplements.
Many of these foods are potentially rich in biologically active amines: histamine, tyramine and others.
High levels of histamine, excessive exogenous intake or its inadequate degradation provoke accumulation in plasma. Excess of this substance is associated with digestive, cutaneous and neurological diseases, especially migraine.
The role of histamine as an activator of migraine or cluster headache has been confirmed by dose response studies with oral histamine in humans. In addition, the European Food Safety Authority, in its scientific opinion on the risk of nutritional amines in food, published in 2014, states that dietary histamine is involved in the pathogenesis of migraine in sensitive people with enzymatic deficiency. activity of diamine oxidase (DAO).
Among the many types and classifications of headaches, the International Society for the Study of Headaches (IHS) Classification Committee includes the “histamine-induced headaches” and considers how this condition can be caused by acute histamine exposure.
A key point of histamine metabolism are the different ways of decay. The main enzyme responsible for the absorption of histamine is diamine oxidase (DAO), which is distributed in various tissues of the body. A transient or permanent decrease in DAO activity results in the accumulation of histamine. As a result, the risk of migraine symptoms increases.
There is no diagnostic method based on additional tests (resonances, analysis, etc.) to be used for diagnosing migraine. Recently, however, it has been shown that measurement of DAO activity can be a major biological and genetic marker for migraine and other headaches.
Until recently, the diagnosis was mainly clinical, based on criteria established by the International Headache Research Society (IHS), which are accepted by all neurological societies in the world. IHS classifies the disease into two main subgroups – migraine without aura and migraine with aura.
Migraine without aura
It is a recurrent idiopathic condition that lasts from 4 hours to a maximum of 3 days. Often it is characterized by a one-sided and pulsating headache, but it can sometimes affect the entire skull.
Usually it is of moderate or severe intensity, and usually the patient suffers from damage to the capacotence of moving the skull, which significantly prevents even the simplest physical activities. It is often associated with other symptoms that allow to diagnose the condition. Additional symptoms may include nausea, vomiting, photophobia, phonophobia, and sometimes osmophobia.
Diagnostic criteria for migraine without aura:
Migraine with aura
Usually in this disease are combined positive and negative symptoms of a reversible type, as well as visual phenomena. In some patients, transient changes in speech may occur.
These phenomena develop gradually over a period of about five minutes, and the duration of the episode does not exceed one hour. They can be self-limited without symptoms, but more often during the episode there is a headache, which is clinically defined as a migraine. At other times, the pain does not manifest itself completely.
Diagnostic criteria for migraine with aura
Diagnostic criteria for cluster headache or “histaminic cephalgia” according to IHS:
Treatment of the crisis is necessary due to the intensity and debilitating effects of pain in most patients. The goal is to find the effectiveness of the treatment with minimal side effects, in order for the patient to restore his normal functional state, with a lower risk of recurrence in the coming hours. Most of the symptoms that accompany the pain are susceptible to adjuvant treatment, with the exception of migraine with aura.
Treatment should be prompt and administered as soon as the patient identifies the type of pain and migraine. Early treatment and the optimal dose increase effectiveness and reduce the risk of recurrence. Once the crisis occurs, the pharmacological response is clearly smaller and even zero.
Symptomatic treatment of a seizure is usually carried out with nonsteroidal analgesics and anti-inflammatories, specific drugs (usually composed of ergots and triptans) and adjuvants (antiemetics, sedatives and neuroleptics).
Repeated use of drugs can lead to a situation of abuse of painkillers, which can turn the headache into a chronic problem and lead to a loss of pharmacological effectiveness. We now know that this phenomenon is partly due to the possible inhibitory effect of drugs on the activity of Diamino Oxidase (DAO).
Standard pharmacological treatment used until a few years ago for migraines and other headaches provides a number of disadvantages:
Histamine and the nervous system
The link between the hypothalamus and migraine has been known for years. It is believed that the various activation mechanisms of migraine can activate the symptoms of this part of the brain. It is believed that migraine triggers excite the hypothalamus, limbic areas and cortical regions.
There are brain structures that have areas where the blood-brain barrier can be circumvented, in particular – around the third and fourth ventricles, which are richly vascularized and exposed to large amounts of substances circulating in the blood, such as histamine and other biogenic amines.
Localization of histamine and its relationship with migraine and headache
Histamine is difficult to penetrate through the bloodstream into the structures of the brain, and, but when it accumulates, it causes a crisis of migraine and other vascular headaches.
Epidermal cells, as well as the cerebrovascular endothelium can produce histamine. As for systemic metabolism, histamine is produced by oxidation. The enzyme responsible for this process is diamino oxidase (DAO). Small amounts of this enzyme have been found in the brains of mammals.
Histamine has an imidazole and ethylamine ring as its main structure, which is shared with the neurotransmitters dopamine, norepinephrine and serotonin. It is synthesized by various hematopoietic and neuroepithelial cells, having a wide range of functions inside and outside the nervous system.
It is estimated that there are about 64,000 neurons capable of synthesizing histamine, located in the posterior basal regions of the hypothalamus and in the tubero-mammary nuclei.
Recent studies have shown that the activity of central histamine plays an important role in the onset of changes in sleep rhythm, changes in meal times and emotional responses.
H1 receptors
This type of histaminergic receptors are spread throughout the body, including the brain. Their central activation is associated with responses and depolarization functions such as awakening and sleep cycles and cognitive functions. Localization studies with follow-up indicators show that most of these receptors are not associated with neurons, but with vessels and glial cells.
The role of histamine may be related to signaling functions to provide a greater flow of glucose from the blood to increase neuronal activity. The vasodilating effect of histamine and its effect at the onset of headaches has been known for years.
When the H1 receptors in the endothelium of the intracranial arteries are stimulated, the synthesis of nitric oxide (NO) is activated and vasodilation occurs. This leads to the formulation of the nitric oxide hypothesis as an activation factor. The first phenomenon is vasodilation mediated by H1 receptors located in brain vessels. However, studies with drugs that block H1 and H2 receptors have not shown effectiveness in the treatment of migraine. This can be explained by the fact that the blockade of histamine receptors affects a process that has already been started and that cannot be controlled in this way.
H2 receptors
These are postsynaptic receptors that create excitatory inputs or mediate the excitatory actions of neurons. They have a 40% similarity with H1 receptors, but their effects on the nervous system are less known, in part due to the increased difficulty of crossing the blood-brain barrier of potential antagonists.
Experimental studies show that short exposures to H2 agonists can increase the activity of various types of neurons over a long period of time. This increase in neuronal responses can be observed in cortical neurons in response to sensory stimuli, the appearance of which is associated with thalamic inflows.
The most often used drug with an H2 antagonist effect is cimetidine. Its use is to reduce the secretion of gastric acid.
H3 receptors
Histamine has a high affinity for these receptors. Unlike the activation effects of H1 and H2, H3 has an inhibitory function on histaminergic neurons. They are located in presynaptic sites and have a low structural similarity with H1 and H2 receptors. They are associated with various brain functions, such as modulation of wakefulness-sleep processes, cognitive processes, homeostatic regulation and inflammation.
There are several isoforms of different activity, which clearly shows the polymorphism of the existing H3 receptor in humans. Replacing the amino acid 280 (alanine) with valine, known as H3R, is considered a risk factor for migraines. This option can lead to an increase in histamine due to inactivity of auto-receptors.
Receptorii H4
This receptor is about 35% similar to H3 and is localized mainly in peripheral tissues and mast cells. In recent years, such receptors have been located in the cortical and subcortical areas of the structures of the brain.
Its exact role is not known, but the activation of this receptor leads to hyperpolarization of neurons in the somatosensory cortex in rats. This process of cortical hyperexcitability, including that of the somatosensory cortex, appears to be a major process in migraine etiopathogenesis.
The similarity found between H3 and H4 led to a difficult interpretation of their functions. The potential effect of cortical activation is reduced by the antagonistic effect of H3 receptors. In a recent study, intraventricular administration of an H4 receptor agonist induced an anti-nociceptive response. Using an antagonist reverses this action.
The enzyme diaminoxidase (DAO) is one of the two enzymes responsible for histamine metabolism. The process causes oxidative deamination, which is why this enzyme is also called histaminase. It is preserved in the plasma vesicles of epithelial cells and is secondaryly secreted into the bloodstream by various stimuli.
Therefore, DAO is considered to be the enzyme responsible for histamine metabolism, which is found in the extracellular space. In mammals, DAO is found in the intestines, ascending colon, placenta and kidneys.
Some studies have shown an increase in DAO activity during a migraine crisis, which can be interpreted as a protective mechanism for removing excess histamine.
In addition to these specific situations, various mutations have been studied that cause a decrease in DAO activity in patients with various pathologies associated with increased plasma histamine levels. A recent medical publication demonstrates that people who carry mutations rs10156191 and rs2052129 in the gene that encodes DAO and causes a decrease in its activity have a higher risk of suffering from migraines.
On the other hand, 87% of patients diagnosed with migraine are reported as deficient in DAO activity. When treated with exogenous enzyme DAO, their symptoms improve.
Given these data, the deficiency of the activity of the DAO enzyme should be treated as a trigger for migraine. In vitro measurement of DAO activity and/or genetic analysis of DAO genotypes make it possible to determine the risk of migraine and apply appropriate treatment with dietary supplements and dietary changes. Supplements with exogenous enzymatic DAO are the new option in dietary treatment and in the prevention of migraine. Since it is a food with special medical purposes and is a protein of animal origin, the risk of side effects with this treatment is minimal or non-existent.
In patients with cluster headache or histaminic headache, determining DAO activity may be a good biomarker for diagnosis. Usually, the enzymatic activity during a seizure is higher, so it is a good idea to measure in advance, as well as regularly monitor the concentration of circulating histamine. Examination of DAO genotypes can also contribute to a good diagnosis.
As for nutrition, it is necessary to reconsider, in particular, those foods that, without having a high concentration of histamine, support endogenous release, since repeated consumption can cause the accumulation of histamine in a non-metabolic way.
Sources
Maintz et al. Intolerance to histamine and histamine. Am J Clin Nutr 2007; 85: 1185-1196.
Jarisch et al. Histamine intolerance. Histamin und Seekrankheit edn, 2. Stuttgart, Germany: Georg Thieme Verlag KG, 2004.
Izquierdo-Casas et al. Low levels of diamine oxidase serum (DAO) in migraine patients. J Physiol Biochem 2018; 74 (1): 93-99.
Garcia-Martin et al. Variants of diamine oxidase rs10156191 and rs2052129 are associated with the risk of migraine. Headache 2015; 55 (2): 276-86.
A. Duel et al. The low-histamine diet supplemented with the exogenous enzyme diamine oxidase is useful for treating migraine in patients with DAO deficiency. Ann Nutr Metab 2018; 73 (suppl. 2); 1-93
Izquierdo-Casas et al. The diamine oxidase (DAO) supplement reduces headaches in patients with episodic migraine with DAO deficiency: A randomized double-blind trial. Clin Nutr. 2018 Feb 15. Pii: S0261-5614 (18) 30014-1
Maintz et al. Association of polymorphisms with a single nucleotide in the diamine oxidase gene with serum activities of diamine oxidase. Allergy 2001; 66: 893-902.
Steinbrecher and Jarisch 2005, histamine and headaches. 28: 85-91 Allergy
Music et al., 2013, Serum activity of diamine oxidase as a diagnostic test for histamine intolerance. Wien Klin Wochenschr 125: 239-43
Manzotti et al., 2015, Serum activity of diamine oxidase in patients with histamine intolerance. International Journal of Immunopathology and Pharmacology
Maintz et al., 2006, evidence for a reduced degradation capacity of histamine in a subgroup of patients with atopic eczema. J Allergy Clin Immunol, 117.1106-12.
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