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6. Pathophysiological Considerations Regarding Cluster Headache and Trigeminal Autonomic Cephalalgias
6.1 Introduction
When we discuss pathophysiological background regarding cluster headache, scientific progress over the last 20 years has put us in the fortunate situation that we can divide this question into “what drives cluster headache” and “where is the source of the pain.” For decades these (fundamentally different) questions have been mixed as so little was known about the pathophysiology of this dreadful disease. We have learned so much about modulators and generators of cluster headache attacks and—to be frank—know still relatively little of what structure actually generates the nociceptive input. We therefore focus here on central generating factors (the why) and refer to the Chaps. 8 and 9 in this book (the where) [1, 2].
Trigeminal autonomic cephalalgias (TACs) are a group of primary headaches characterized by attacks of short-lasting unilateral head pain associated with ipsilateral craniofacial autonomic manifestations [3]. The group includes cluster headache (CH), the main form, paroxysmal hemicrania (PH), short-lasting unilateral neuralgiform headache attacks, and hemicrania continua [3]; attack duration is the main feature that distinguishes TACs [3].
For decades CH has been seen as a vascular headache [4] according to the vascular theory of migraine and related forms, but the term of neurovascular headache is now used given the wealth of evidence suggesting that migraine and related disorders mainly derive from within the brain [5]. Contemporary trigeminal nerve and craniofacial parasympathetic nerve fiber activation are thought to provoke the pain and the autonomic craniofacial phenomena, respectively [6–8]; this activation has been named trigeminal-parasympathetic or trigeminal-facial reflex [6]. An impressive phenomenon reported by many CH patients is the clockwork regularity of attacks as well as the seasonal recurrence of cluster periods in the episodic form of the disease [9] suggesting that the biological clock located in the hypothalamus is involved in its pathophysiology [10]. Results from a number of neuroendocrinological studies lent support to the hypothalamic hypothesis [11]. The first direct demonstration of hypothalamic involvement came from the seminal neuroimaging studies showing activation of the ipsilateral posterior hypothalamus during CH attacks [12] and structural anomalies (increased neuronal density) in the same brain region [13]. These observations suggested that the cluster generator could be located there [12]. It was then hypothesized that high-frequency deep brain stimulation of that brain area could inhibit neuronal activation of the stimulated area just as has been used in the treatment of Parkinson disease [14]. Efficacy of hypothalamic deep brain stimulation as a treatment for intractable chronic CH [14] as well as for other intractable TACs as short-lasting unilateral neuralgiform headache attacks [15–18] and PH [19] confirmed the crucial role of the hypothalamus in CH and other TACs.
In this chapter the main focus will be pathophysiology of CH because of the scarcity of data on the other TAC forms.
6.2 Genetics
An exhaustive and detailed description of genetics in CH and related disorders is reported in this book [20]. Both twins [21] and epidemiological [22] studies suggest a familial occurrence of CH. For instance, in twins an anticipation between generations has been observed [21].
Notwithstanding some methodological limitations, epidemiological studies all suggested an increased risk for first-degree relatives of patients with CH to develop CH: 14 times (or more) higher than that of the general population [22–26]. For second-degree relatives, the risk is much lower ranging between two and eight times above that of the general population [23–26].
A number of studies have investigated involvement of various genes in CH [for a comprehensive review, see Ref. 20].
The CACNA1A gene on chromosome 19p harboring the familial hemiplegic migraine type 1 mutation was investigated in CH because of the paroxysmal nature of both diseases, but no abnormalities were observed [27]. The hypocretin system has been advocated to be involved in CH because of its involvement in pain and in the regulation of the sleep–wake cycle [26] also affected in CH. A missense single-nucleotide polymorphism in the HCRTR2 gene coding for the hypocretin-2 (orexin-B) receptor was reported in CH [28] but not confirmed in other studies [29–31]. Given the circadian occurrence of painful attacks in CH, some studies investigated genes involved in circadian rhythmicity. Among these, the PER3 gene was studied but no association was found [32]. In one study genes linked to circadian rhythms such as the RBM3 protein binding several genes, including BMAL1 (ARTNL), PER1, and CLOCK, seemed to involved in CH [33], but a larger study did not confirm those findings [31]. It has been shown that plasma level of pituitary adenylate cyclase-activating polypeptide (PACAP) is increased during cluster attacks [34], and a genome-wide analysis study indicated that a variant of the PACAP receptor gene ADCYAP1R1 might play a role in CH [35]. Due to the conflicting results on the topic [36], future studies are needed. In summary, the genetic mutation behind the familial occurrence in CH is likely; the exact nature of this remains to be established.
6.3 From the Trigeminal System to Hypothalamus
Graphic illustrating the anatomical and neurotransmitter components of the cluster headache pathobiology. Only neurotransmitters which are known to be involved in cluster headache are shown. SSN, TCC, and ILN stand under hypothalamic control which communicates with the SCN. A strong trigeminal nociceptive input generates a signal which is transmitted to the thalamus. This signal generates in the periphery (between the trigeminal and the parasympathetic ganglion) but also centrally in a physiological reflex arch with a parasympathetic outflow. It may well be that this parasympathetic reaction (lacrimation, conjunctival injection) is facilitated due to the sympathetic deficit (miosis, ptosis) which is inherent to cluster attacks. For further explanation please see text. ACH acetylcholine, CGRP calitonin gene-related peptide, IML intermediolateral nucleus (sympathetic system), SSN superior salivatory nucleus (parasympathetic system), TCC trigeminocervical complex, SCG superior cervical ganglion, SPG sphenopalatine ganglion, SCN suprachiasmatic nucleus, NPY neuropeptide Y, PACAP pituitary adenylate cyclase-activating peptide, VIP vasoactive intestinal peptide, 5-HT serotonin. *Modified after ref. [8]
6.3.1 Trigeminal System
Activation of the trigeminal system in CH is strongly suggested by the increased serum concentrations of CGRP during a CH attack (Fig. 6.1) [37]. CGRP is contained in neurons of the gasserian ganglion and released from these neurons [38] with at least two targets: it is a potent vasodilator and modulates the activity of nociceptive trigeminal neurons [39]. The peripheral axons of the trigeminal pseudounipolar neurons innervate the dura mater and cranial vessels, while the central projections end onto the trigeminocervical complex in the brainstem. The trigeminocervical complex plays a key role in modulating and transmitting potentially painful stimuli from the face and head to the brain. It contains the trigeminal nucleus caudalis and the C1 and C2 dorsal horns of the spinal cord [40]. Animal models have clarified the interplay between the posterior hypothalamus and the trigeminocervical complex. The two areas of the central nervous system are connected by the trigemino-hypothalamic pathway, and a number of neurotransmitters modulate pain transmission between the posterior hypothalamus and the trigeminal nucleus caudalis [41]. In humans high-frequency deep brain stimulation of the posterior hypothalamic area activates a network of brain areas including the ipsilateral trigeminal system that seems to be interconnected and plays a crucial role in attack generation [42]. Another observation questioning at least the role of the peripheral trigeminal system in CH pathophysiology is the persistence of CH after complete trigeminal nerve root section [43–45]. If these data are confirmed, the fully developed cluster picture could occur without peripheral trigeminal input, and vessels would not play any role in cluster headache generation. However, many of the clinical symptoms in CH could then not be explained. There is no question that further studies are necessary to better understand the role of the trigeminal system in pathophysiology and attack generation of CH and TACs [8].
6.3.2 Parasympathetic System
Autonomic phenomena accompanying CH attacks such as conjunctival injection, lacrimation and rhinorrhea, as well as extracranial [46] and intracranial vasodilation [47, 48] are mediated by activation of parasympathetic fibers which form the parasympathetic branch of the facial nerve, whose cell bodies originate from the superior salivatory nucleus (SSN) (Fig. 6.1). Part of the parasympathetic nerve fibers passes through the sphenopalatine ganglion (SPG) (mediating conjunctival injection, lacrimation, rhinorrhea and extracranial vasodilation) [46, 47], and part passes through the otic and carotid mini ganglia (mediating intracranial vasodilation) [47, 48].
The superior salivatory nucleus (SSN) and the trigeminal nucleus are functionally connected in the brainstem, and their contemporary activation gives rise to the trigeminal-parasympathetic reflex [6]. Nociceptive stimulation of the first division of the trigeminal nerve triggers this reflex [49]. Following this trigeminal activation, the parasympathetic neurons traveling through the SPG provoke the release of neuropeptides such as vasoactive intestinal polypeptide (VIP) [50] and pituitary adenylate cyclase-activating polypeptide (PACAP) which are raised during a CH attack (Fig. 6.1) [34]. PACAP might be a particularly interesting target for future treatments given that PACAP is a neurotransmitter of the trigeminal and the parasympathetic system [51]. The superior salivatory nucleus is, just as the trigeminal nucleus, under modulating control of the hypothalamus. Oculo-facial parasympathetic phenomena in cluster headache attacks could therefore be initiated by hypothalamic input instead of being a result of trigeminal nociceptive input, i.e., a trigeminally induced reflex phenomenon. This could explain why some CH patients report painless attacks with only autonomic phenomena [52]. Following this thought, a number of treatment interventions have been tried to stop the parasympathetic outflow and thus stop the acute attack altogether. Consequently, blockade of sphenopalatine ganglion on the pain side has been shown to be effective in CH prophylaxis in more than 50% of patients, but the recurrence rate is high [53].
In the last years, neuromodulation techniques have enlarged the armamentarium in the treatment of CH.
The efficacy produced by both sphenopalatine ganglion electrical stimulation [54, 55] and chemical inhibition of neurotransmission in the sphenopalatine ganglion by onabotulinum toxin A [56] is further evidence of the relevant role that the parasympathetic pathway has for the generation of a cluster attack [57].
In this respect the observation that CH attacks can occur without autonomic symptoms [58], and the recent finding that triggering autonomic outflow is not sufficient to provoke cluster attacks [59, 60] suggests that isolated parasympathetic activation is not the main cause of trigeminal activation.
6.3.3 Hypothalamic Activation and Stimulation
The term “cluster headache” was introduced to describe the typical seasonal recurring pattern of the disease [61]; in addition the circadian periodicity of pain attacks—more often at night and frequently starting at the same time—strongly suggests that the biological clock has a role in the pathophysiology of the disease [10]. The suprachiasmatic nucleus of the hypothalamus plays an important role in circadian synchronization of many body processes. It receives light stimuli from the retina and entrains the biological clock with the light–dark cycle (Fig. 6.1). The suprachiasmatic nucleus controls melatonin production and secretion whose plasma levels peak during the night with darkness [62]. This peak is markedly blunted in patients with CH [63–65]. This and other neuroendocrinological abnormalities lent support to the hypothesis that the hypothalamic biological clock is deranged in CH [5]. A PET study showed activation in the ipsilateral inferior hypothalamic gray matter during CH attacks [12]; and an increased neuronal density of this structure was identified in a voxel-based morphometry study [13]. Even if hypothalamic activation can occur in other painful conditions [66], the fact that application of a painful stimulus in the receptive field of the first division of the trigeminal nerve is not followed by hypothalamic activation [67] indicates that the observed hypothalamic activation is not a consequence of the pain but has a causative role in the disease. A confirmation of the prominent role of the posterior hypothalamic area in the pathophysiology of CH came from the demonstration that high-frequency deep brain stimulation of that area can improve otherwise intractable chronic CH patients [14].
In animals it has been shown that the posterior hypothalamus is a physiologic modulator of trigeminal nucleus caudalis (TNC) neuronal activity: when injected into the posterior hypothalamus, both orexins (orexin A and B) modulate neuronal activity in the TNC [41], and a disturbance in the hypothalamic orexinergic system has been hypothesized in CH [68]. Posterior hypothalamic orexins can also modulate the duration of neuronal discharge in TNC neurons [41] suggesting that these transmitters are involved in generating the various forms of TACs [68]. A significant reduction of hypocretin (orexin)-1 CSF levels has been found in both episodic and chronic CHs [69] and attributed to a reduced activity of hypothalamic descending antinociceptive pathway, but an alternative theory is that it simply represents a pain-induced phenomenon. The conflicting results of genetic studies do not allow confirming involvement of hypothalamic orexinergic system in CH [28–30]. GABA-A receptors in the posterior hypothalamus are also involved in the modulation of neuronal discharge in the TNC [41]. Involvement of hypothalamic GABA-A receptors in CH is also suggested by the efficacy of both verapamil and topiramate in CH prophylaxis [70] since both drugs inhibit GABA-A receptors in the CNS [71].
Hypothalamic deep brain stimulation takes weeks to months to exert its preventive effect [72, 73] suggesting that a mere inhibition of hypothalamic neurons is a too simplistic hypothesis to explain its mechanism of action. It has been shown that prolonged hypothalamic stimulation increases ipsilateral cold pain threshold in V1 territories [74] indicating that the continuous stimulation could restore the antinociceptive system. The periventricular posterior hypothalamic region [75], very close to that of electrode placement in hypothalamic deep brain stimulation [76], includes the A11 nucleus that contains dopamine cells, dopamine cells co-localized with CGRP, as well as CGRP-only cells [75]. Sensory and pain responses in the trigeminocervical complex (TCC) are strongly inhibited by projection from the A11 nucleus [75]. Hypothalamic stimulation could increase V1 cold pain threshold [74] by activating A11 hypothalamic neurons.
Hypothalamic stimulation could also exert its action by interfering with mechanisms leading to pain chronification. Hypothalamic stimulation induces blood flow changes in some brain areas as anterior cingulate, insula, and frontal lobe [42] involved in pain chronification [77] and long-term potentiation could be the basic mechanism of the changes [78]. An interference of hypothalamic stimulation with pain chronification is indicated by the observations that in some CH patients, long-term hypothalamic stimulation reverted chronic to episodic CH [79]. We note that in patients undergoing hypothalamic continuous stimulation, the parasympathetic system activity is normal [80], and this suggests that the stimulation could improve CH by restoring parasympathetic activity in the superior salivatory nucleus and thus preventing further activation of the trigemino-parasympathetic reflex (Fig. 6.1). It needs to be pointed out that although we start unraveling the enigma of cluster headache attacks and although the scientific consensus now is that CH is a brain disorder and not a vascular or vessel disease, many questions remain. We must understand the pathophysiology completely if we ever want to change the course of the disease and by doing so change the life of our patients to the better.
