Note : The following describes scientific theories about the cause of cluster headaches. They are written in scientific technical language.

Location of cluster headache development

One of the main characteristics of cluster headache is its location behind and around one eye . Cluster headaches can also occur in people who have had an eyeball removed on the same side of the cluster headache. not pain occurs within the eye . For this reason, it is likely that the headache arises in structures around or behind the eye . can also occur in other symptomatic diseases Such defined clinical pictures are, for example, upper cervical meningiomas , parasellar meningiomas , large arteriovenous malformations in a wide variety of ipsilateral brain structures , ethmoidal cysts in the area of ​​the clivus and in the area of ​​the suprasellar cisterns , pituitary adenomas , calcifications in the area of ​​the 3rd ventricle, ipsilateral aneurysms and aneurysms Anterior communicating artery . All of these structures show a relationship to the midline in the area of ​​the cavernous sinus . It is therefore reasonable to assume that the cavernous sinus is the anatomical structure that is particularly relevant to the genesis of cluster headache.

Various technical examinations were carried out during the spontaneous progression When magnetic resonance tomograms were performed during a cluster headache attack, it was shown that the increased in the area of ​​the cavernous sinus . This indicates that an inflammatory change occurs in the cavernous sinus during cluster headache attacks. Furthermore, evidence of inflammatory changes CSF and peripheral blood . When performing phlebography, there was evidence of the presence of venous vasculitis in the area of ​​the cavernous sinus and superior ophthalmic vein during the cluster period. Interestingly, these completely resolve remission phase . From these studies it can be concluded that the venous flow area and the cavernous sinus are of important importance for the development of cluster headache pain.

The parasympathetic supply runs via the deep petrosal nerve and the orbital rami from the sphenopalatine ganglion and other microganglia. The parasympathetic fibers pass through the supraorbital fissure in the area of ​​the cavernous sinus . The sensory fibers for innervating the orbit are provided by the ophthalmic nerve and also partly run through the area of ​​the cavernous sinus . Some of the fibers supply the basilar artery and partly run along with the abducens nerve. The greater superficial petrosal nerve also supplies the internal carotid artery with sensory fibers. The sensory supply to the cavernous sinus comes from fibers of the trigeminal nerve and the facial nerve . The dural veins and the dural sinuses are innervated by nociceptive fibers from the tentorial nerve . The sensory, sympathetic and parasympathetic fibers form a plexus in the area of ​​the cavernous sinus . There are additional mechanoreceptors along the internal carotid artery in the carotid canal.

Due to the anatomical structures and the above-mentioned findings, the development of cluster headache can be localized area of ​​the cavernous sinus When a carotid angiography dilatation of the cavernous sinus or an obstruction of the passage orbital phlebography during the cluster period can be seen in the corresponding area The corresponding changes, in particular the dilatation of the cavernous sinus, appeared ipsilateral to the side of the cluster headache that occurred. vascular dilatations can be observed during attacks in the area of ​​the ophthalmic artery , the anterior cerebral artery , and the middle cerebral artery

Vascular dilation in the region of the ophthalmic artery and the anterior cerebral artery was also between cluster headache attacks . Due to this fact, it remains unclear whether the vascular dilatations directly related to the development of pain . Regardless of the causality, however, the ipsilaterality provides evidence of a connection between phases of dilatation and the occurrence of headaches.

Phlebographic examinations reveal evidence of phlebitis in the area of ​​the superior ophthalmic vein and in the area of ​​the cavernous sinus during a cluster headache period. similar findings also occur in Tolosa-Hunt syndrome , in which granulomatous inflammation in the corresponding structures is assumed. Both diseases can also be treated very effectively anti-inflammatory therapy with corticosteroids It is completely unclear why inflammation of the cavernous sinus and the surrounding veins occurs during a cluster headache period.

Hypothetically , it can be assumed that a frequently described narrowing of the airways in the area of ​​the nose and paranasal sinuses in patients with cluster headache could lead to an obstruction of the ventilation of the ethmoidal cells and a corresponding ipsilateral infection is promoted. The fact that the inflammation subsequently spreads to the ipsilateral cavernous sinus is a possible hypothesis for the genesis of cluster headache. However, there is no evidence of this to date. These considerations are reinforced by the increased occurrence among smokers. Active cluster periods also typically occur in seasons with increased susceptibility to upper respiratory tract infections.

Neuroimaging and morphometric studies

Pathophysiological considerations for the development of cluster headaches must take into account the timing of onset, the temporary frequency of attacks, the location of the headache, and the involvement of sympathetic and parasympathetic activation. Originally, the development of cluster headaches was explained by changes in vessel diameters. On this basis, the effect of vasoconstrictor substances and the triggering by vasodilatory agents such as nitroglycerin and histamine could also be clarified.

Positron emission tomography (PET) can be used to examine changes in regional cerebral blood flow. High-resolution PET examinations enable the detection of even small changes in regional cerebral blood flow at rest and during certain activation processes of the brain. Cluster headache attacks can be experimentally triggered by nitroglycerin. These experimentally triggered attacks do not differ from spontaneous cluster headache attacks in terms of essential pathophysiological parameters. Experimentally triggered cluster headaches, like spontaneous clusters, can be effectively treated with sumatriptan.

The working group of May et al. (1998) described significant activation in the ipsilateral hypothalamus during acute cluster headache compared to the headache-free period in a group of patients with cluster headaches.

  • No brainstem activation was found in cluster headache patients, so a differentiation from possible pathophysiological brainstem processes such as in migraine was assumed.
  • These findings also support the clinical experience that the active ingredients used for cluster headaches are not effective in preventing migraines and vice versa.
  • Conversely, experimental pain stimulation of the forehead with capsaicin did reveal any brainstem activation any hypothalamic activation by experimental pain induction with capsaicin in the forehead area.
  • Based on these findings, it was concluded that hypothalamic activation is a specific process for cluster headache that is associated with pain induction or pain maintenance and does not represent a secondary response of nociceptor activation in the area of ​​the first trigeminal branch.
  • The hypothalamus is said to be placed in a state of increased activability during the acute cluster headache period. Circadian rhythms and sleep-wake cycles are supposed to activate the hypothalamic core areas as “primum movens”.

The concept of primary headache assumes functional changes as the basis of the headache. Structural changes in the brain are not assumed in primary headaches. However, using voxel-based morphometry, a significant structural change in gray matter density was described compared to healthy controls. These changes were found both within the active cluster period and outside the active cluster period. The differences were located bilaterally in the region of the diencephalon adjacent to the third ventricle and rostral to the aqueduct. This area coincides with the area of ​​the inferior posterior hypothalamus . Corresponding findings are not revealed in migraine patients. This led to the assumption that structural changes may be associated with the disease process in cluster headaches, while purely functional mechanisms play a role in migraines.

Due to the imaging findings from PET studies and fMRI studies with voxel-based morphometric analyses, direct vasoconstrictor and dilatory vascular changes have moved out of the primary focus of the pathophysiology of cluster headaches. Functional and structural changes in the midbrain and pons area have been suggested in migraine, while corresponding changes in the hypothalamic gray matter area have been suggested in cluster headaches. In addition to the functional activation mechanisms, structural changes in the density of the gray matter in the hypothalamus area are also discussed.

Deep brain stimulation for the treatment of cluster headaches

Deep brain stimulation for the treatment of cluster headaches

Based on these findings, deep brain stimulation has been proposed for the treatment of cluster headaches. The target area of ​​deep brain stimulation was chosen based on morphometric studies. The first interventions were carried out by the Italian group of Leone et al 2000. However, deep brain stimulation for cluster headache has not left the stage of an experimental therapy and has largely been abandoned due to frustrating long-term results and significant risks of death (implantation-induced lethal intracerebral hemorrhage). In the only placebo-controlled, double-blind study to date, no significant difference between real stimulation and simulated stimulation could be described (Fontaine et al. 2010). As a rule, further medication prevention is necessary despite deep brain stimulation. The intensive long-term care, the medication setting and the spontaneous course are confounded with the therapy results. Insufficient therapy efficiency is individually attributed to incorrect electrode positioning in the context of deep brain stimulation.

It remains to be seen whether the structural changes in the area of ​​the inferior posterior hypothalamus are a correlate of the pain in the sense of a non-specific activation, a consequence of the previous therapy or a cause of the headache. The use of deep brain stimulation for cluster headaches remains experimental, for which we see no place in clinical care. The work by Leone et al 2001 is considered the only example of the therapeutic implementation of imaging findings, but it has not proven to be effective. In our view, the studies do not justify clinical use.

The hypothesized role of the inferior posterior hypothalamus in cluster headache

The hypothesized role of the inferior posterior hypothalamus in cluster headache

The stimulation of the target areas and occasional improvement should not lead to the assumption that these regions are causally crucial for the pathophysiology of cluster headache. The stimulation of neural structures in both the central nervous system and the peripheral nervous system can modulate numerous pain mechanisms and have a non-specific effect on the pain process. This is also supported by the improvement rates in cluster headaches and other pain syndromes when the greater occipital nerve is stimulated or the sphenoid ganglion is stimulated. Ex juvantibus conclusions about the cause of cluster headaches based on stimulation results do not appear to be sufficiently justified at this point in time. The hypothetical role of the inferior posterior hypothalamus in cluster headaches is shown in the figure opposite (abbreviation: GCRP calcitonin gene related peptide, SPG sphenopalatine ganglion, SSN superior salivatory nucleus, VIP vasoactive intestinal polypeptide).

Recent studies analyzed the long-term course of cluster headaches and gray matter changes. Nägel et al 2011 examined 75 cluster patients (22 episodically within the active period, 35 episodically outside the active period and 18 chronic cluster patients) and compared changes in the gray matter of 61 healthy parallelized control subjects using voxel based morphometry (VBM). Patients with recent acute cluster attacks during the active period showed the most pronounced reductions in the gray matter area of ​​the central pain processing system. In chronic cluster headache patients, additional changes were revealed in the area of ​​the anterior cingulate, the amygdala and the area of ​​the secondary somatosensory cortex. Outside the active period, there were no changes in the areas mentioned in patients with episodic cluster headache. There were no changes in the hypothalamus area in either the subgroups or the overall group. These data demonstrate gray matter loss in central pain processing systems, particularly in patients with chronic cluster headache. In contrast, there are no changes in the hypothalamus area. The findings are similar to those of patients with other pain disorders. They support the assumption that the morphological changes are effects of acute pain and not the primary cause. It is possible that the changes are correlates of the chronification processes. This is demonstrated by the particularly pronounced abnormalities in patients with chronic cluster headaches. Changes in the area of ​​the hypothalamus were not discovered, so the importance of the hypothalamus in the development of cluster headache remains controversial (Nägel et al. 2011; Holle and Obermann 2011).

Inflammation in the cavernous sinus

Orbital phlebograms performed in cluster headache patients during active cluster periods revealed evidence of inflammatory processes in the cavernous sinus and superior ophthalmic vein area of ​​unknown origin. Sensory fibers of the ophthalmic nerve, sympathetic fibers that ipsilaterally supply the eyelid, the eye, the face, the orbit and the retro-orbital vessels, and venous vessels that drain the orbit and face are bundled together in a narrow, bony space in the area of ​​the cavernous sinus the internal carotid artery (see illustration). Local inflammatory processes can therefore affect sensory and autonomic nerve fibers as well as venous and arterial vessels. Irritation of the nerve fibers is conceivable both directly by inflammatory neuropeptides and as a result of mechanical compression by inflammatory dilated and swollen vessels. This theory can be used to explain cluster pain and the various accompanying symptoms. The ability of vasodilating substances to provoke cluster attacks during active cluster periods (alcohol, nitroglycerin, histamine, hypoxia) and of vasoconstrictive substances (oxygen, sumatriptan, ergotamine) to quickly terminate them is also compatible with the model.

Anatomical situation in the area of ​​the cavernous sinus and in the orbital funnel

Anatomical situation in the area of ​​the cavernous sinus and in the orbital funnel

It is assumed that during active cluster periods there is a basal inflammatory reaction that worsens in attacks. The above orbital phlebograms, which suggested an inflammatory process, were performed between two attacks during a cluster period. In patients with chronic or episodic cluster headaches, Tc-99m albumin SPECT was performed at 10 minutes, 1 hour, 3 hours, and 6 hours after injection of 600 MBq of Tc-99m human serum albumin (HSA) during an active cluster period. An inhomogeneous activity distribution was found in the healthy control group. In contrast, in the cluster headache patients in the active phase, trace enrichment was found in the region of the cavernous sinus, the sphenoparietal sinus, the ophthalmic vein, the petrosal sinus and the sigmoid sinus (see figure). The side of cluster headache and regional protein leakage corresponded in all cluster headache patients. After effective prophylactic treatment with verapamil or corticosteroids, the tracer enrichment disappeared. An active cluster headache period is therefore associated with regional plasma protein extravasation in venous blood vessels at the base of the brain as a sign of local vascular inflammation. Successful treatment with verapamil or corticosteroids blocks both ipsilateral plasma extravasation and cluster headache attacks. In chronic cluster headaches, this basic inflammatory reaction is present continuously, but in the episodic form it is only periodic. The high and reliable effectiveness of anti-inflammatory corticosteroids for the prophylaxis of cluster headaches is also understandable. The cavernous sinus is crossed by the carotid artery, the optic nerves, the ophthalmic nerves and the facial nerve. All of these nerves are affected during the cluster attack. This theory can be used to explain cluster pain and the various accompanying symptoms. The ability of vasodilating substances to provoke cluster attacks during active cluster periods (alcohol, nitroglycerin, histamine, hypoxia) and of vasoconstrictive substances (oxygen, sumatriptan, ergotamine) to quickly terminate them is also compatible with the model.

Cavernous sinus and cluster headache

Cavernous sinus and cluster headache

The adjacent figure shows diagnostic evidence of unilateral plasma extravasation as an expression of vasculitis in the cavernous sinus in a patient with active cluster period. On the side of the cluster attacks in the right cavernous sinus and superior petrosal sinus, there are clear signs of inflammation in the form of asymmetric leakage of plasma from the veins in the Tc-99m albumin SPECT 10 minutes, 1 hour, 3 hours and 6 hours after injection of 600 MBq Tc -99m human serum albumin (HSA). While initially a symmetry of the venous vascular system can be observed after 10 minutes, a clear asymmetry is found after three hours due to the increasing plasma extravasation. These changes are not found in the remission phase

The origin of the pain during sleep, the patient's sitting upright in bed or standing up and the patient's motor restlessness are also understandable: the venous drainage of the cavernous sinus is worse when lying down than when sitting or standing due to the hydrostatic conditions . It can therefore be assumed that during active cluster periods there is a basic inflammatory reaction that worsens in attacks. It is also understandable why smoking and seasonal changes with increased susceptibility to infections and sinus infections are associated with a higher probability of the occurrence of active cluster periods.

Anti-inflammatory drugs such as cortisone lead to the rapid cessation of active cluster periods. However, they are not suitable for long-term therapy due to long-term side effects. Calcium channel blockers, such as verapamil, prevent the inflammatory effects of plasma extravasation and are suitable for long-term treatment. Nonsteroidal anti-inflammatory drugs such as indomethacin can be particularly effective in special forms of cluster headaches, such as chronic paroxysmal hemicrania, but are usually not sufficient for cluster headaches. This also applies to aspirin, ibuprofen, etc. These medications are ineffective in an acute attack, but many people take them and mistakenly believe that the attacks subside after 2-3 hours are due to these medications. There are also individual case reports on the effectiveness of Marcumar in cluster attacks; this medication probably prevents platelet aggregation in the cavernous sinus from intensifying due to venous vasculitis. The effectiveness of azothioprine in individual case reports could be based on a reduction in the basic inflammatory reaction.

Neural changes

Various electrophysiological techniques have been used to analyze changes in neuronal activity in cluster headache. The analysis in side comparison as well as the analysis during the cluster period in comparison to the remission period are also suitable here. Evidence of a disorder of sensory pathways comes from the use of acoustically evoked brainstem potentials and somatosensory evoked potentials.

The pupillary reactions in cluster headache patients were analyzed in particular detail. Miosis is one of the particularly striking characteristics of cluster headaches . The consensual light reaction faster and more pronounced in cluster headache patients . There is a faster and greater constriction in the light and a slower and reduced dilation in the dark. dysregulation can be on the affected side than in the remission phase. The pupil's response to painful electrical stimuli from the sural nerve reduced on the side affected by cluster headache . It is possible that this reduced pupil dilation is caused by an increased supply of released neuropeptides such as substance P and neurokinin A, which lead to direct pupil constriction. If the infratrochlear nerve unilateral pupil constriction also occurs , which is not caused by cholinergic mechanisms. This response may also be mediated by the release of substance P and neurokinin A. These neuropeptides may be released more strongly during the cluster attack (see above), as the response to stimulation of the infratrochlear nerve significantly lower . These findings indicate that not only sympathetic pathways, but also sensory fibers of the trigeminal nerve can play a significant role in the pathophysiology of cluster headache. Another argument in favor of a change in the sensory properties is that during the headache-free period, an increased sensitivity to pain can be observed in cluster headache patients, which is particularly pronounced on the side affected by the cluster headache. During the remission phase, pain sensitivity returns to normal. In connection with the increased response to stimulation of the infratrochlear nerve, these findings can be interpreted indication of increased excitability of nociceptive neurons of the trigeminal nerve

Further changes in the pupillary reaction also occur with pharmacological stimulation . For example, bilateral instillation of indirect sympathomimetics such as hydroxyamphetamine results in reduced mydriasis on the side affected during the active cluster phase outside of an attack. direct sympathomimetic such as phenylephrine is administered to the eye affected by cluster headache, increased mydriasis is seen . These findings suggest reduced sympathetic function on the symptomatic side . The experimentally induced sweating reaction, for example when heat is applied, is also reduced on the symptomatic side in the affected patients during the active phase in the headache-free period. By administering pilocarpine, however, an increased sweating reaction can be observed on the symptomatic side. These findings can also be interpreted as evidence of a disorder of sympathetic fibers . The reduced activity leads to hypersensitivity of the postsynaptic receptors. , the localization of sympathetic hyperfunction does not necessarily have to be in the periphery , as similar findings can also be observed in central Horner syndrome