Pathogenesis of autonomic crises

Vegetative crises are observed in a wide variety of diseases, both mental and somatic. This suggests that both biological and psychogenic mechanisms are involved in the pathogenesis of crises. Undoubtedly, in real life we are dealing with a constellation of various factors, with a greater or lesser specific weight of each of them. However, for didactic purposes, it seems appropriate to consider them separately, highlighting various aspects of the biological and mental.

Biological factors of pathogenesis of vegetative crises

Violation of vegetative regulation as a factor in the pathogenesis of vegetative crises

Clinical practice and special studies convincingly show that vegetative crises often occur against the background of sympathicotonia. Most authors attribute the decisive role in the occurrence of crises to the preceding increase in sympathetic tone. Special studies have established that significant deviations of vegetative tone towards sympathicotonia are characteristic of emotional disorders (fear, anxiety). As clinical and physiological studies have shown, the activity of systems both at the anatomical-functional level (sympathetic - parasympathetic) and at the functional-biological (ergo- and trophotropic) is organized synergistically and the nature of vegetative manifestations on the periphery can be determined only by the predominance of one of them. According to the theory of H. Selbach (1976), the relationship between the two systems corresponds to the principle of "swinging equilibrium", i.e. an increase in tone in one system induces its increase in the other. In this case, the initially increased tone in one system entails a more significant deviation in another, which brings the constantly existing fluctuations of vegetative homeostasis into the zone of increased lability. It is assumed that it is not so much the intensity of fluctuations that is pathogenic, but the variability of physiological functions, their spontaneous changes. Clinical and experimental studies of patients with vegetative crises have discovered this lability in almost all systems: disturbances in the oscillatory structure of the heart rhythm, a high frequency of heart rhythm disturbances, changes in the daily temperature rhythm and a distorted reactivity of the vegetative systems in the sleep-wake cycle. This determines the instability of the system, increases vulnerability to external disturbing effects and disrupts natural adaptive processes.

In such conditions, exogenous or endogenous stimuli can lead to a critical phase, which occurs when all systems are synchronized, which manifests itself as a vegetative crisis. It has been experimentally shown that the degree of behavioral and physiological activation is determined by the number of physiological systems participating in the paroxysm. These data are in good agreement with clinical observations. Thus, the maximum expression of the affective component (fear of death) is mainly observed in a full-blown crisis, i.e. with the participation of many vegetative systems, and only in these crises is an objective indicator of vegetative activation stably recorded - a significant increase in pulse rate.

At the same time, the concept of activation cannot be strictly associated only with the emotions of anxiety and fear. It is known that physiological activation also accompanies other emotional-affective states, such as anger, irritation, aggression, disgust or pathological forms of behavior. Taking into account the various clinical variants of vegetative crises (crises with aggression, irritation, "conversion crises", etc.), it is appropriate to assume that there is a common radical of vegetative regulation disorders, which can be a common link in the pathogenesis of vegetative crises in different nosological forms.

Recently, concepts have emerged suggesting that in the occurrence of some crises, it is not so much sympathicotonia that plays a significant role, but rather the insufficiency of the parasympathetic system. The following facts served as the basis for this assumption:

1. frequent occurrence of crises during periods of relaxation;
2. a decrease in pulse rate recorded in some patients using monitoring immediately before the development of a crisis;
3. a sharp increase in heart rate (from 66 to 100 or more per minute);
4. lack of effect of beta-blockers in preventing a crisis provoked by the introduction of sodium lactate;
5. some decrease in the content of adrenaline and norepinephrine in urine in the pre-crisis period.

It is possible that different mechanisms of autonomic dysregulation are responsible for the development of crises in patients of different clinical groups.

The role of peripheral adrenergic mechanisms in the pathogenesis of vegetative crises

The most expressive manifestations of vegetative crises are symptoms of hyperactivity of the sympathetic nervous system, which can have a dual origin: either increased activity of the sympathetic nerves, or increased sensitivity of peripheral receptor formations (postsynaptic a- and beta-adrenergic receptors).

However, studies in recent years have not confirmed this hypothesis. Thus, in patients with vegetative crises, no higher levels of norepinephrine and adrenaline or their metabolites were found compared to the levels in healthy subjects. Moreover, a detailed study revealed reduced sensitivity of adrenoreceptors in patients with vegetative crises. Given these facts, one can only assume that peripheral adrenergic structures participate in the pathogenesis of crises, but the mechanisms of their participation remain unclear.

The role of central mechanisms in the pathogenesis of vegetative crises

Full-blown vegetative crises with pronounced anxiety or fear of a vital nature can be considered as a variant of a paroxysm of anxiety, fear with vegetative accompaniment. The subsequent anxious expectation of an attack, the formation of secondary emotional and psychopathological syndromes lead to an adequate consideration of the pathogenesis of vegetative crises through the analysis of cerebral mechanisms involved in the implementation of normal and pathological anxiety.

Experimental data show that disturbances of the central noradrenergic systems play a significant role in anxiety mechanisms. Animal experiments have shown that the large noradrenergic nucleus of the brainstem - locus coeruleus (LC) - is directly related to anxious behavior.

Anatomically, the LC is connected via ascending noradrenergic pathways with the structures of the limbic-reticular complex (hippocampus, septum, amygdala, frontal cortex), and via descending pathways with the formations of the peripheral sympathetic nervous system.

This central location with diffuse ascending and descending projections throughout the brain makes the LC noradrenergic system a global mechanism potentially involved in alertness, arousal, and anxiety functions.

Deepening our understanding of the neurochemical mechanisms underlying VC is associated with studying the properties of drugs whose mechanism of action is due to activation or inhibition of LC. Thus, administration of yohimbine (an LC activity stimulator) to patients increased the frequency of crises and the patients' report of anxiety, which was accompanied by a greater release of 3-methoxy-4-hydroxyphenylglycol (MOPG), the main metabolite of cerebral norepinephrine, than in healthy subjects. At the same time, administration of clonidine (a drug that reduces noradrenergic activity) to patients with autonomic crises led to a decrease in the plasma MOPG content to a greater extent than in healthy subjects. These data indicate increased sensitivity to both agonists and antagonists of the central noradrenergic systems, which confirms a violation of noradrenergic regulation in patients with autonomic crises.

Clinical observations of recent decades have convincingly shown that there is a dissociation in the antiparoxysmal effect of typical benzodiazepines and antidepressants: while benzodiazepines are particularly effective directly during a crisis, the effect of antidepressants develops much more slowly and consists mainly in preventing the recurrence of crises. These data have allowed us to assume the participation of different neurochemical systems in the implementation of a crisis and its repeated initiations.

A special analysis of the long-term action of tricyclic antidepressants (TA) showed that their anti-crisis action is accompanied by a decrease in the functional activity of postsynaptic beta-adrenoreceptors, a decrease in the activity of LC neurons and a decrease in norepinephrine metabolism. These assumptions are confirmed by biochemical studies: thus, with prolonged exposure to TA, the MOFG in the cerebrospinal fluid and in plasma decreases, which correlates with a decrease in the clinical manifestations of the disease.

In recent years, along with noradrenergic mechanisms, the role of serotonergic mechanisms in the occurrence of vegetative crises has also been discussed, which is due to:

1. the inhibitory effect of serotonergic neurons on the neuronal activity of those brain structures that are directly associated with anxiety (LC, amygdala, hippocampus);
2. the influence of TA on serotonin metabolism;
3. the high efficacy of zimeldine, a selective serotonin reuptake blocker, in the treatment of agoraphobia crises.

Taking into account the presented data, the question arises about the possibility of the participation of different neurochemical mechanisms in the pathogenesis of vegetative crises, which is possibly associated with the biological heterogeneity of crises.

Discussing the central mechanisms of the pathogenesis of vegetative crises and emphasizing the important role of noradrenergic stem formations, one cannot help but dwell on the significance of other structures of the limbic-reticular complex, in particular the parahippocampal region. The authors of clinical and experimental works of recent years, studying cerebral blood flow in patients with vegetative crises using positron emission tomography, found that in the intercrisis period, patients have an asymmetric increase in cerebral blood flow, blood filling and oxygen utilization in the right parahippocampal region.

Specific facts indicating the involvement of deep temporal formations in the pathogenesis of vegetative crises are in good agreement with recent reports on the high efficiency of anticonvulsants in the treatment of vegetative crises. Antelepsin (clonazepam) has been shown to have a good anti-crisis effect. A model of the pathogenesis of vegetative crises has been formulated, in which parahippocampal pathology determines pathological sensitivity to anxiety states, and the "trigger" situation is the increased activity of noradrenergic projections to the hippocampal region (in particular, from the LC), which in turn implements the development of a vegetative crisis through the septoamygdaloid complex.

Biochemical factors in the pathogenesis of vegetative-vascular crises

Traditionally, the occurrence of vegetative crises is associated with the activation of the sympathetic nervous system, the humoral mediators of which are adrenaline and noradrenaline. In this regard, the study of these substances both at the time of the crisis and in the intercrisis period is of particular interest. When studying the content of catecholamines in the intercrisis period, no significant and stable increase was found in them compared to the control group. Moreover, according to OGCameron et al. (1987), in patients with vegetative crises under natural conditions, the content of adrenaline and noradrenaline in the urine even decreases slightly. A number of studies have revealed a slight increase in the content of adrenaline in the blood plasma immediately before the provocation of the crisis. As for the moment of the crisis, no unambiguous increase in either adrenaline or noradrenaline in the blood plasma was found in both spontaneous and provoked vegetative crises.

Among other biochemical indicators, a stable biochemical pattern reflecting respiratory alkalosis (increase in HCO3, pH, decrease in PCO2> calcium and phosphorus levels) can be noted, which is detected in the intercrisis period and at the time of the crisis. In addition, during crises (both spontaneous and provoked), the level of prolactin, somatotropic hormone and cortisol increases.

Thus, the biochemical pattern of vegetative crises consists of a slight increase in the level of prolactin, somatotropic hormone and cortisol, as well as a complex of biochemical shifts reflecting respiratory alkalosis.

Studies of lactate-induced crises have revealed a number of factors that may play a significant role in understanding the pathogenesis of crises. The following has been established:

1. lactate infusion itself can cause significant physiological changes - an increase in heart rate, systolic blood pressure, lactate and pyruvate levels in the blood, an increase in HCO3 and prolactin levels, as well as a decrease in PCO2 and phosphorus concentrations in both healthy and sick people;
2. the onset of the crisis coincides with rapid and significant physiological changes following the introduction of lactate;
3. There is a significant difference in the rate of increase of lactate levels in the blood: in patients this indicator is significantly higher than in healthy people.

Several hypotheses are used to explain the mechanism of action of lactate in provoking vegetative crises: stimulation of noradrenergic centers in the brain; hypersensitivity of central chemoreceptors; the role of cognitive-psychological factors.

Among the possible mechanisms of the crisogenic effect of lactate, the role of carbon dioxide (CO2) is widely discussed today. Inhalations of 5% and 35% CO2 are an alternative way to provoke vegetative crises in sensitive patients. At the same time, hyperventilation, which reduces the CO2 content in the blood and causes hypocapnia, is directly related to vegetative crises, i.e. two procedures that cause opposite shifts in CO2 in the body lead to an identical clinical picture. How is this contradiction resolved and how is it related to the mechanisms of the crisogenic effect of lactate?

It is known that an elevated level of cerebral CO2 is a strong LC stimulator, while the administered lactate, the content of which in the blood of patients increases faster than in healthy people, is metabolized to CO2, contributing to a rapid increase in CO2 in the brain, which can occur despite the general decrease in PCO2 in the blood due to hyperventilation. It is assumed that an increase in cerebral CO2 is a common mechanism of the crisis-inducing effect both with CO2 inhalation and with lactate administration.

The role of hyperventilation in autonomic crises is more difficult to understand. In a study of 701 patients with chronic hyperventilation, autonomic crises were observed in only half of them. Hyperventilation may contribute to the onset of VC in some patients; it is unlikely to be the principal cause of an attack in most patients.

A well-known attempt to combine the facts concerning the biochemical mechanisms of the pathogenesis of vegetative crisis was the hypothesis of D. B. Carr, D. V. Sheehan (1984), who suggested that the primary defect is located in the central chemoreceptor zones of the brainstem. In their opinion, patients have an increased sensitivity of these zones to sharp changes in pH that occur with an increase in the lactate-pyruvate ratio. With hyperventilation, developing hypocapnia leads to systemic alkalosis, which is accompanied by a narrowing of the brain and heart vessels and, accordingly, an increase in the lactate-pyruvate ratio and a drop in intraneuronal pH in the medullary chemoreceptors. With the introduction of sodium lactate, on the one hand, there is a sharp alkalization of the environment due to sodium ions, i.e., systemic alkalosis and corresponding changes in the brain occur; on the other hand, a sharp increase in lactate in the blood and cerebrospinal fluid leads to a rapid passive rise in the lactate-pyruvate ratio in the chemoregulatory zones of the brainstem. Both ischemia and a passive rise in the lactate-pyruvate ratio reduce intracellular pH in medullary chemoreceptors with subsequent clinical manifestations of vegetative crisis. This hypothesis also helps explain the mechanism of action of CO2 inhalations, since animal experiments have shown that pH on the brain surface decreases within a few minutes after the start of 5 % CO2 inhalations.

Thus, it is likely that in the presence of initial alkalosis, any influences (sodium lactate administration, CO2 inhalation, hyperventilation, intrapsychic stress with catecholamine release) increase lactate levels more intensively than in healthy individuals; perhaps this in turn causes a sharp change in pH on the surface of the brain and, as a consequence, anxiety and its vegetative manifestations arise.

Psychological factors in the pathogenesis of vegetative crises

A vegetative crisis can occur in almost any person, but this requires extreme physical or emotional overload (natural disasters, catastrophes and other life-threatening situations); as a rule, such crises occur once. What factors determine the occurrence of a vegetative crisis in ordinary life situations and what leads to their recurrence? Along with biological factors, psychological factors play a significant, and possibly leading, role.

As clinical practice shows, crises can occur in harmonious personalities with individual traits of sensitivity, anxiety, demonstrativeness, and a tendency to subdepressive states. More often, they occur in those patients in whom these traits reach the degree of accentuation. The types of corresponding personality accentuations and their characteristics are as follows.

Anxious and fearful personalities

The anamnesis of these patients since childhood shows fear of death, loneliness, darkness, animals, etc. They often have a fear of separation from their home, parents, perhaps on this basis a fear of school, teachers, pioneer camps, etc. is formed. For adult patients of this group, increased suspiciousness, constant anxiety, fear for their own health, the health of loved ones (children, parents), hypertrophied responsibility for the assigned task are characteristic. Often, excessive sensitivity is diffuse: both pleasant and unpleasant events can be exciting; situations can be real or abstract (movies, books, etc.).

In some patients, the leading features are anxious suspiciousness and timidity. In others, sensitive accentuation comes first.

Dysthymic personalities

Dysthymic personalities are subdepressive in their more severe manifestations. Such patients tend to have a pessimistic assessment of events, focus on the sad sides of life, and often blame themselves for all negative situations. They easily develop reactive-depressive reactions; sometimes sharp mood swings can be observed.

Hysterical personalities

They are characterized by pronounced egocentrism, increased demands on others, pretentiousness, a tendency to dramatize ordinary situations, and demonstrative behavior. Often, vivid demonstrativeness is masked by external hyperconformity. The anamnesis of these patients often reveals somatic, vegetative, and functional-neurological reactions in difficult life situations. As a rule, patients do not correlate these symptoms with the emotional tension of the situation. Clinically, these reactions can manifest themselves as short-term amaurosis, aphonia, difficulty breathing and swallowing due to a constant feeling of a "lump in the throat", periodic weakness or numbness, more often of the left hand, unsteadiness of gait, acute pain in different parts of the body, etc. In clinical practice, however, it is rarely possible to observe pure variants of personality accentuations. As a rule, clinicians encounter more or less mixed variants, such as: anxious-phobic, anxious-sensitive, anxious-depressive, hysterical-anxious, sensory-hypochondriacal, etc. Often it is possible to trace a hereditary predisposition to the manifestation of certain personality accentuations. Specially conducted studies have shown that close relatives of patients with vegetative-vascular crises often have anxious-phobic, dysthymic, anxious-depressive character traits, often (especially in men) they are masked by chronic alcoholism, which, according to many authors, is a certain way of relieving anxiety. Almost all researchers note an extremely high representation of alcoholism in relatives of patients with vegetative crises.

The identified personality traits of patients, on the one hand, are determined by hereditary factors, but they can often arise or worsen under the influence of unfavorable situations in childhood - childhood psychogenia.

Conventionally, it is possible to distinguish four types of childhood psychogenic situations that play a pathogenic role in the formation of personality traits.

1. Dramatic situations in childhood. These circumstances arise, as a rule, in those families where one or both parents suffer from alcoholism, which gives rise to violent conflicts in the family, often with dramatic situations (threats of murder, fights, the need to leave the house for safety, and often at night, etc.). It is assumed that in these cases there is a possibility of fixing fear by the imprinting type, which in adulthood, under appropriate conditions, can suddenly manifest, accompanied by vivid vegetative symptoms, i.e. cause the appearance of the first vegetative crisis.
2. Emotional deprivation is possible in families where the interests of the parents are strictly related to work or other circumstances outside the family, while the child grows up in conditions of emotional isolation in a formally preserved family. However, this is more common in single-parent families, where a single mother, due to personal characteristics or the situation, does not form an emotional attachment to the child or care for him is limited to formal control over his studies, additional classes (music, foreign language, etc.). In such conditions, we are talking about the so-called insensitive control. Patients who grew up in such a family constantly experience an increased need for emotional contacts, and their tolerance to stress is significantly reduced.
3. Overanxious or hyperprotective behavior. In these families, excessive anxiety as a trait of the parent or parents determines the child's upbringing. This is excessive concern for his health, studies, anxiety in every uncertain situation, constant expectation of danger, misfortune, etc. All this often forms excessive personal anxiety in the patient as a variant of learned behavior. Undoubtedly, in these cases, a hereditary predisposition to an anxious stereotype is transmitted.
4. Constant conflict situation in the family. A conflict situation arising for various reasons (psychological incompatibility of parents, difficult material and living conditions, etc.) creates constant emotional instability in the family. In these conditions, the child, emotionally involved in the conflict, cannot effectively influence it, he is convinced of the futility of his efforts, he develops a feeling of helplessness. It is believed that in such cases, so-called learned helplessness can develop. In later life, in certain difficult situations, the patient, based on past experience, makes a prediction that the situation is insoluble and helplessness arises, which also reduces stress tolerance.

Analysis of children's family situations is extremely important for every patient with vegetative crises, since it significantly complements our understanding of the mechanisms of crisis formation.

Moving on to the analysis of actual psychogenies, i.e. those psychotraumatic situations that immediately precede the emergence of crises, it is necessary to immediately distinguish between 2 classes of psychogenies - stresses and conflicts. The relationships between these factors are ambiguous. Thus, an intrapsychic conflict is always stress for the patient, but not every stress is caused by a conflict.

Stress as a factor causing crises is currently being widely studied. It has been established that both negative and positive events can lead to a stress-inducing effect. The most pathogenic in terms of overall morbidity are severe losses - the death of a spouse, the death of a child, divorce, etc., but a large number of different events that occur in a relatively short period of time (expressed in units of psychosocial stress) can have the same pathogenic effect as severe loss.

It was found that before the onset of vegetative crises, the overall frequency of life events increases significantly, and these are mainly events that cause distress. It is characteristic that a major loss is less associated with the onset of VC, but significantly affects the development of secondary depression. For the onset of a vegetative crisis, threatening situations are of greater importance - a real threat of loss, divorce, child's illness, iatrogenesis, etc., or an imaginary threat. In the latter case, the patient's personality traits are of particular importance. Some authors believe that these traits play a leading role due to increased anxiety, a constant premonition of danger, and, in addition, increased stress due to a subjective feeling of inability to cope with it (learned helplessness). At the same time, a high level of psychosocial stress reduces the effectiveness of defense mechanisms to overcome stress.

Thus, the intensity of stress, its specific characteristics in combination with personality traits play an important role in the occurrence of vegetative-vascular crises.

In the presence of a conflict, an external stressor event may cause the culmination of the conflict, which in turn may lead to the manifestation of a vegetative crisis. Among the typical conflicts, it is necessary to note the conflict between the intensity of impulses (including sexual ones) and social norms, aggression and social demands, the need for close emotional connections and the inability to form them, etc. In these cases, the ongoing conflict is the soil that, when exposed to additional non-specific stress, may lead to the manifestation of the disease in the form of a vegetative crisis.

When discussing the psychological factors of the emergence of a vegetative crisis, one cannot ignore cognitive mechanisms. There are experimental data explaining the emotional-affective component of the crisis as secondary in relation to the primary peripheral changes:

1. It turned out that the presence of a physician can prevent the fear that usually arises during pharmacological modeling of a crisis;
2. using repeated lactate infusions in the presence of a physician, it was possible to carry out effective desensitizing treatment of patients with crises;
3. Data from individual authors indicate that by using only psychotherapy without the use of medications, it is possible to block the occurrence of lactate-induced crises.

When highlighting the cognitive factors involved in the formation of a vegetative crisis, it is necessary to emphasize the main ones: memory of past experience; expectation and premonition of a dangerous situation; assessment of the external situation and bodily sensations; a feeling of helplessness, uncertainty, threat and loss of control over the situation.

Combining the psychological and physiological components of the pathogenesis of vegetative crisis, we can propose several models of their occurrence.

1. Stress → anxiety → autonomic activation → crisis.
2. Stress → anxiety → hyperventilation → autonomic activation → crisis.
3. The situation of the culmination of intrapsychic conflict → anxiety → vegetative activation → crisis.
4. The situation of revival of early (childhood) fear patterns → vegetative activation → crisis.

In all four models, the development of vegetative activation into a vegetative crisis occurs with the participation of cognitive factors.

However, questions of the relationship, primacy and secondary nature of psychological and physiological components in the formation of crises require further research.

Thus, it is necessary to emphasize that individuals with certain personality traits, genetically determined and/or conditioned by psychogenic influences of childhood, may develop vegetative crises at a high level of psychosocial stress or at the culmination (exacerbation) of an intropychic conflict.

The primary nature of physiological changes and the secondary nature of their perception by the individual with the formation of an emotional-affective component or whether the primary factor is affect, which is accompanied by vivid vegetative symptoms, determining the clinical picture of a vegetative crisis, remain debatable.

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