One of the special characteristics of cluster headache is the frequent occurrence of attacks with periods of remission in between. Because of this time-bound occurrence, it was obvious altered circadian or circannual rhythms as the cause of the genesis of this headache disorder. Such altered chronobiological activities could be responsible for the disruption of vascular and autonomic balance . The termination of the cluster period could also be reconciled with this pathophysiological assumption. After the desynchronization of the chronobiological functions has subsided, equilibrium is reestablished and the remission phase begins.

This interpretation is supported by the fact that a very rigid time pattern at the beginning , while at the end of an active cluster phase there is irregular behavior of the cluster attacks. In this context, it is also of interest that several authors the influence of the season on the progression of cluster headaches. There are seasonal accumulations of active cluster periods in the months of March, April and May as well as in the months of September, October and November . However, this time preference can vary from person to person. position of the sun also been linked to the occurrence of cluster periods. For example, in North America an increased occurrence of cluster periods observed during the highest and lowest solar positions Scandinavian countries also show an increased occurrence of cluster periods in January and August, while reduced cluster activity is recorded in April and November. However, here too there is an individual connection to the temporal pattern. This bond can be explained by external chronobiologically effective trigger activities , such as environmental influences in the sense of daily activity, stress, workload, psychosocial conditions, etc.

The special chronobiological activity of cluster headache attacks is also reflected in the occurrence of cluster attacks at very specific times, which . The occurrence with waking up after a sleep phase two hours apart or the repeated occurrence at certain times during the night the importance of chronobiological changes in the genesis of cluster headache.

Based on these observations, an attempt was made to uncover the biological basis of the chronobiological changes in cluster headache patients. It is known from chronobiological studies that

  • Melatonin

is of particular importance for the control of circadian rhythms. there was no significant change in melatonin concentration between different months in cluster headache patients who were systematically examined over several months . However, compared to healthy controls, a reduced mean melatonin concentration revealed in cluster headache patients over the entire observation period of one year. But the circadian variation within the group of patients suffering from cluster headaches shows changes . This shows a reduction in the maximum increase during the night at the time of an active cluster period. The time of the maximum increase in the nocturnal melatonin concentration can also be either early or late. In principle, this behavior could be explained solely by pain-induced stress . However, other stressful conditions are not able to cause similar changes in the melatonin balance.

The causes of altered melatonin metabolism are of particular importance as they could potentially be the key to the genesis of cluster headache. The chronobiological behavior of melatonin concentration is modulated by an endogenous zeitgeber . This endogenous timer can be influenced by internal and external conditions These include, in particular, daylight and sleep patterns . Melatonin is metabolized from serotonin. changes in the metabolic conditions for serotonin found over the course of the year.

Circadian changes are also known for nor-epinephrine . It is particularly important that nor-epinephrine has maximum concentrations in the morning. The reasons for this increased concentration in the morning may be the positional dependence of the nor-epinephrine levels after getting up and the connection with sleep. However, changes caused by primary endogenous rhythms are also known.

Hormonal changes

Hormones play a prominent role in the timing of body functions. This is particularly clear in the area of ​​reproductive functions . For this reason, hormonal changes were also analyzed in connection with the temporal occurrence of cluster attacks. It was shown that the morning peaks in cortisol concentrations in cluster headache patients occur either early or late This shift can also be found during lithium treatment. Cortisol production is increased throughout the day in cluster headache patients . This behavior occurs not only during the active cluster phase but also during the remission phase. The changes in cortisol are therefore not primarily stress-related peculiarities, but are probably primary changes in the area of ​​the hypothalamus -pituitary-adrenocortical axis . Evidence for such disorders also comes from reduced elevation of cortisol and ACTH after insulin-induced hypoglycemia during the cluster attack and during the remission phase.

There is also evidence of altered daily variations in prolactin levels . Reduced prolactin levels are evident over the course of the day , both during the active cluster period and in the remission phase. When the D2 antagonist metoclopramide is administered, a reduced increase in prolactin can be demonstrated in cluster headache patients. A possible explanation is a reduced sensitivity of the lactotroph cells in the pituitary gland. A similarly reduced increase in prolactin can be observed after administration of morphine. In connection with the reduced responses of cortisol and ACTH to insulin provocation, it can be assumed that cluster headache patients a reduced response to a wide variety of external or internal stressors .

The analysis of possible changes in the area of ​​sex hormones received particular attention. Several studies have reduced concentrations of testosterone , reduced production throughout the day, and shifts in maximum concentrations throughout the day. There is currently no explanation for these changes; they may be seen as a reaction to the increased plasma cortisol levels . A regular behavior has been described for progesterone and estrogen activity in cluster headache patients.

When challenged with the dopamine antagonist metoclopramide, a pronounced increase in growth hormone be induced in cluster headache patients. This increase does not occur when L-dopa is administered. A corresponding reaction does not occur in other painful diseases, so that this excessive increase in growth hormone after metoclopramide administration can be interpreted specific reaction

immune system

Due to the connection between stress, pain and the immune system, immunological parameters were also analyzed in cluster headache patients. increase in the number of monocytes and a reduction in the number of lymphocytes can be observed during the cluster period compared to the remission phase Due to the possible connection between stress reactions and the active cluster phase, other pain disorders analyzed for immunological changes. As expected, patients with back pain , as in patients with an active cluster period, also showed an increased number of monocytes and a reduced number of T lymphocytes and T helper cells. Based on this behavior, it can be assumed that these are secondary parameters of the pain-induced stress situation . no evidence of altered concentrations of circulating immune complexes, immune globulins, anticardiolipin antibodies or altered behavior of the complement system in patients with cluster headaches . There is also no reliable evidence of altered behavior of histocompatibility antigens in cluster headache patients.

The concentration of lymphocytic b-endorphin significantly reduced both in the active cluster period and during the remission phase . This evidence of disruption of the endogenous opioid systems, which are modulated by serotonin, dopamine and g-aminobutyric acid, may also be associated lesion of the immune system

Blood flow studies

Changes in hemodynamic parameters can be directly observed during an acute cluster headache attack. Conjunctival injection, redness of the skin and nasal congestion occur. Some patients feel chilly, others have facial sweating. For this reason, hemodynamic parameters have already been analyzed in detail in previous studies.

During a cluster headache attack, increased ocular pulsation with increased ocular blood flow be observed. These changes are found in both eyes , both on the symptomatic and asymptomatic sides. However, the increase in ocular blood flow is greater on the affected side . These changes can be interpreted in terms of ocular vasodilation . in the attack-free period , reduced ocular blood flow and reduced intraocular pressure are evident . These changes can be observed in both eyes and can be explained by either vasoconstriction or increased vascular resistance.

, no changes in regional cerebral blood flow been reliably determined to date When using the xenon 133 method to examine regional cerebral blood flow, some patients show a slight increase, others see a slight decrease, and still others show no change. Even with the help of the SPECT method, no consistent changes could be observed during spontaneous or alcohol- or nitroglycerin-induced cluster attacks.

blood flow velocity be obtained using transcranial Doppler sonography When using such examination procedures, it is noticeable that a bilateral reduction in flow velocity in the middle cerebral artery can be observed both during spontaneous pain attacks and during nitroglycerin-induced cluster attacks. This reduction in blood flow velocity is more pronounced on the affected side . When the regional cerebral blood flow was simultaneously determined in these patients, it was observed that the mean cerebral blood flow was not changed despite the reduced blood flow velocity.

From these findings it can be concluded that the middle cerebral artery exhibits vasodilation an increase in blood flow velocity in the middle cerebral artery is also evident during the cluster period outside the attack . This finding can be explained vasoconstriction Interestingly, it can be demonstrated that even after administration of nitroglycerin, the reduction in blood flow velocity in the middle cerebral artery is more pronounced on the affected side than on the unaffected side.

A further indication of a change in the hemodynamic parameters was a reduced vasoreactivity for CO 2 in the anterior cerebral artery . However, this reduced vasoreactivity is only found on the side affected by the cluster attack . The CO 2 reactivity in the other vessels is not changed. During the remission period, there is also real CO 2 reactivity in all vessels.

Overall, the studies of hemodynamic parameters of intra- and extracerebral vessels indicate that the changes in blood flow are not a primary source of cluster headache, but rather a secondary consequence of the headache disorder.