One of the distinctive characteristics of cluster headaches is the frequent occurrence of attacks with intervening periods of remission. Because of this temporally bounded pattern, it seemed plausible altered circadian or circannual rhythms as a cause 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 chronobiological functions subsides, equilibrium is restored and the remission phase begins.
This interpretation is supported by the fact that very rigid temporal pattern of cluster attacks is usually observed at the beginning of an active cluster period at the end of an active cluster phase, attacks irregular . In this context, it is also interesting to note that several authors the influence of the season Seasonal peaks in active cluster periods are observed in March, April, and May, as well as in September, October, and November . However, this temporal preference can vary from person to person. The sun has also been linked to the occurrence of cluster periods. For example, an increased incidence of cluster periods observed North America during the highest and lowest points of the sun's position Scandinavian countries, there is an increased incidence of cluster periods in January and August, while reduced cluster activity is recorded in April and November. However, here too, the temporal pattern individually dependent This dependency 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 unique chronobiological activity of cluster headache attacks is also evident in the still poorly understood occurrence of cluster attacks at very specific times occurrence upon waking after a sleep phase at two-hour intervals, or their consistently fixed nocturnal occurrence at specific times, demonstrates the importance of chronobiological changes in the genesis of cluster headaches.
Based on these observations, attempts were made to uncover the biological basis of chronobiological changes in cluster headache patients. Chronobiological studies have shown that the
- Melatonin
, no significant change in melatonin concentration between months was observed in cluster headache patients systematically examined over several months. Nevertheless, a reduced mean melatonin concentration was found in cluster headache patients compared to healthy controls over the entire one-year observation period Circadian variation within the group of patients suffering from cluster headaches also shows changes , the maximum nocturnal rise during an active cluster period is timing of the maximum nocturnal melatonin concentration increase can also be either earlier or later. In principle, this behavior could be explained solely by pain-induced stress . However, other stress factors are not capable of causing similar changes in melatonin levels.
The causes of altered melatonin metabolism are of particular importance, as they may hold the key to the pathogenesis of cluster headaches. The chronobiological behavior of melatonin concentration is modulated by an endogenous zeitgeber . This endogenous zeitgeber can by internal and external conditions , including, in particular, daylight and sleep patterns . Melatonin is metabolized from serotonin. Interestingly, altered metabolic conditions for serotonin observed throughout the year
Circadian variations are also known for norepinephrine . Of particular importance is the fact that norepinephrine reaches its maximum concentrations in the morning. Reasons for this elevated morning concentration may include the positional dependence of norepinephrine levels after waking and its relationship to sleep. However, variations due to primary endogenous rhythms are also known.
Hormonal changes
Hormones play a crucial role in the temporal regulation of bodily functions. This is particularly evident in the area of reproductive functions . For this reason, hormonal changes have also been analyzed in relation to the timing of cluster attacks. It has been shown that the morning peaks in cortisol concentration in cluster headache patients either earlier or later . This shift can also be observed during lithium treatment. Cortisol production is elevated day in cluster headache patients . This pattern is evident not only during the active cluster phase but also during the remission phase. Thus, the changes in cortisol are not primarily stress-related but likely primary alterations in the hypothalamic -pituitary-adrenal (HPA) axis . Further evidence for such disturbances arises from a reduced increase in cortisol and ACTH following insulin-induced hypoglycemia during both cluster attacks and the remission phase.
There is also evidence of altered diurnal variations in prolactin levels Reduced prolactin levels are observed throughout 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 decreased sensitivity of the lactotrophic cells in the pituitary gland. A similarly reduced increase in prolactin can be observed after morphine administration. In connection with the reduced responses of cortisol and ACTH to insulin provocation, it can be assumed that cluster headache patients a diminished response to a wide variety of external or internal stressors .
Particular attention has been paid to the analysis of potential changes in sex hormones . Several studies have described decreased testosterone concentrations , reduced production throughout the day, and shifts in peak concentrations reaction to elevated plasma cortisol levels . Normal patterns have been observed for progesterone and estrogen activity in cluster headache patients.
Provocation with the dopamine antagonist metoclopramide can induce a pronounced increase in growth hormone . This increase is not observed with L-Dopa. A corresponding reaction is not seen in other painful conditions, so 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. It was found that, compared to the remission phase, an increase in monocyte count and a reduction in lymphocyte count can be observed during the cluster period. Because of the potential link between stress responses and the active cluster phase, other pain disorders were also analyzed for immunological changes. As expected, patients with back pain , like those with an active cluster period, showed increased number of monocytes and a reduced number of T lymphocytes and T helper cells. Based on this pattern, it can be assumed that these are secondary parameters of the pain-induced stress situation No evidence of altered concentrations of circulating immune complexes, immunoglobulins, anticardiolipin antibodies, or altered complement system activity was found in patients with cluster headaches . There is also no conclusive evidence of altered histocompatibility antigen activity in cluster headache patients.
The concentration of lymphocytic β-endorphin significantly reduced both during the active cluster period and during the remission phase . This indication of a disruption in the endogenous opioid systems, which are modulated by serotonin, dopamine, and gamma-aminobutyric acid, can also be linked immune system lesion
Blood flow studies
Changes in hemodynamic parameters can be directly observed during an acute cluster headache attack. These include conjunctival injection, skin reddening, and nasal congestion. Some patients experience chills, while others exhibit facial sweating. For this reason, hemodynamic parameters have been extensively analyzed in previous studies.
During a cluster headache attack, increased ocular pulsation with elevated ocular blood flow be observed. These changes are found in both eyes , on both the symptomatic and asymptomatic sides. However, the increase in ocular blood flow is more pronounced on the affected side be interpreted as ocular vasodilation attack-free period decreased ocular blood flow and reduced intraocular pressure are observed . These changes can be seen in both eyes and can be explained by either vasoconstriction or increased vascular resistance.
In contrast to intraocular blood flow changes, no changes in regional cerebral blood flow been definitively established to date. When using the xenon 133 method to examine regional cerebral blood flow, some patients show a slight increase, others a slight decrease, and still others no change. Similarly, SPECT imaging has not revealed any consistent changes during spontaneous or alcohol- or nitroglycerin-induced cluster attacks.
While the above-mentioned examinations of regional cerebral blood flow provide information about the volume of blood flow, transcranial Doppler sonography can be used to obtain information about blood flow velocity . Using such examination methods, 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 . Simultaneous measurement of regional cerebral blood flow in these patients revealed that the mean cerebral blood flow remains unchanged despite the reduced blood flow velocity.
These findings suggest that the middle cerebral artery (MCA) vasodilation , with the vasodilation being more pronounced on the side ipsilateral to the attack. Similar to the analysis of intraocular hemodynamic parameters, an increase in blood flow velocity in the MCA outside of the attack . This finding can be explained by vasoconstriction . Interestingly, it can be demonstrated that even after administration of nitroglycerin, the reduction in blood flow velocity in the MCA is more pronounced on the affected side than on the unaffected side.
As further evidence of altered hemodynamic parameters, reduced vasoreactivity for CO₂ was detected in the anterior cerebral artery only found on the side affected by the cluster attack . CO₂ CO₂ reactivity was observed in all vessels during the remission period
Overall, the investigations of hemodynamic parameters of intra- and extracerebral vessels indicate that changes in blood flow are not a primary source