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8. Some Observations About the Origin of the Pain in Cluster Headache
8.1 Introduction
Given the clinical presentation and neuroscientific evidence, it is undisputed that the hypothalamus plays a central role in cluster headache (CH) pathogenesis [1, 2]. But does an activation of the hypothalamus suffice in generating the perception of pain or are peripheral structures required? This chapter revolves around the question of nociceptive input: where does the pain in CH originate from? This is a question which, as of yet, has no conclusive answer [2–5]. However, looking at previous research and clinical observations, we might be able to make some assumptions and pose some qualified guesses.
In order for an anatomical structure to come into consideration as the origin of the pain, it must have an effect on the trigeminocervical complex (TCC) [6]: an extension of the spinal nucleus of the trigeminal nerve into the adjacent column of grey matter from the brainstem into the upper cervical cord receiving nociceptive intra- and extracranial afferents from the trigeminal nerve and the upper cervical spinal nerves (C1 and C2) converging onto second-order neurons. These neurons project cranially and form a most complex network throughout the brainstem, diencephalic and cortical areas [7, 8]. Signals are relayed to medullary pontine nuclei [9], to hypothalamic nuclei via the trigeminohypothalamic tract [10] and along the quintothalamic tract to areas in the thalamus such as the ventral posterior medial nucleus (VPM) [11]. Higher central structures, such as the somatosensory cortex and insular cortex, take part in the integration and processing of nociception [8, 12]. However, they also convey descending, direct and indirect modulatory signals via several anatomical structures [13], including the hypothalamus [14, 15] and, in turn, through other medullary pontine nuclei.
Also contributing to the rich brainstem network is the connection between the TCC and the superior salivatory nucleus (SSN) as the main parasympathetic nucleus. Efferent parasympathetic fibres project through the greater petrosal branch of the facial nerve and the sphenopalatine ganglion (SPG), where they synapse to secondary neurons, to the lacrimal gland, nasal mucosa and the cranial vasculature [16]. This connection allows for a reflex response to trigeminal stimuli on the cranial vasculature, dura mater and the lacrimal gland (the trigeminal-autonomic reflex) [3]. Other efferent fibres project to the parotid and buccal secretory glands via the otic ganglion [16].
This anatomical construct leads to the question of whether the pain originates from a peripheral structure, in which case it would have to be within the receptive fields of the aforementioned nociceptive afferents, or whether it originates centrally.
Any structure considered must, in addition, fit into a pathophysiological model which provides a satisfactory explanation to some of the main features of the disease, namely the severe pain intensity, the strict unilaterality and mainly retro-orbital location of the pain, the symptoms of parasympathetic activation and sympathetic deficit and the striking circadian and circannual rhythmicity [17]. Furthermore, one would expect excitatory and inhibitory stimulation of the structure to lead to initiation and termination of a CH attack, respectively.
The eye and retro-orbital tissue
Intra- and extracranial vessels including the cavernous sinus and the internal carotid artery
Peripheral nervous tissue such as the trigeminal nerve and trigeminal ganglion, the parasympathetic branch of the facial nerve and the sphenopalatine ganglion and the vagal nerve
Central nervous structures such as brainstem networks and the hypothalamus.
In the following, the above-mentioned structures will be discussed as possible origins of pain. Clinical and pathophysiological aspects regarding the attack generation and oscillating systems are described in other chapters; hence their mention will be kept to a minimum in this chapter.
8.2 The Possible Sites of Pain Origin
8.2.1 The Eye and Retro-Orbital Tissue
The most pronounced symptom in CH is the severe pain located mainly supra- or retro-orbitally. Some patients describe a feeling of having their eye pushed out of its socket [5], which entails the question whether CH could be an ocular disease.
Intraictal intraocular pressure measurements in CH patients show increased pressure bilaterally but predominantly ipsilateral to the symptomatic side [18]. The change in intraocular pressure happens swiftly, which points more towards a changed intraorbital blood volume than a change in aqueous humour, as this is a slower process [18]. However, neither pain nor autonomic symptoms experienced during a CH attack could be elicited by an experimentally induced increase in intraocular pressure (Valsalva manoeuvre) interictally in CH patients within a cluster bout. However, the intraocular pressure increases significantly more on the symptomatic side when the patient is within a bout [19]. As CH still occurs after removal of the orbital bulb [20, 21], it is safe to assume that cluster headache is not an ocular disease. The increased intraorbital pressure could, however, point towards a dysfunction of the orbital vascular bed, either as a vascular disturbance or as an epiphenomenon occurring due to a nervous malfunction [19].
8.2.2 Vascular Structures
Cluster headache, as first described by Horton et al., has long been referred to as a vascular headache [22]. Vasodilation within the trigeminovascular system has been observed during attacks [23, 24], and experimentally induced attacks with vasodilating agents such as nitroglycerin and histamine have been reported [25, 26]. However, as vasodilatation is not necessary for an attack to occur [27] and as vasodilating agents cannot elicit an attack in patients outside of a bout [25], CH is now recognised as a neuro-vascular disease [3].
A multitude of vascular structures have been placed under scrutiny in the search of a peripheral origin of pain in CH. Of the intra- and extracranial vessels investigated, especially the cavernous sinus and the internal carotid artery have been given much attention.
8.2.2.1 Cavernous Sinus
The cavernous sinus is, with its parasellar location and close relation with a myriad of vascular and nervous structures, an intriguing anatomical location when considering the origin of pain in CH. In fact, given its distinct anatomical features the cavernous sinus has been mentioned early in the literature as the possible source of the pain in CH [28–30]. The sinus is a dural cavity receiving venous output from the superior and inferior ophthalmic veins. Various structures traverse the sinus, such as the internal carotid artery densely innervated with sympathetic autonomic fibres, the oculomotor nerve, the trochlear nerve, the ophthalmic and maxillary branch of the trigeminal nerve and the abducens nerve. A malady in this area could affect the ophthalmic division of the trigeminal nerve and thereby explain the location of the headache pain. Moreover, it could explain the sympathetic deficit as an undermining of the sympathetic fibres located along the wall of the internal carotid artery.
In the late 1980s it was postulated that the pain in CH originates as an intracavernous inflammatory process [30]. It had been shown that irritative stimuli on the cavernous sinus amongst other vascular structures could produce pain in or behind the eye. Moreover, studies using orbital phlebography had pointed towards an inflammatory process in the cavernous sinus during CH attacks [29].
It was thought that an inflammation in this area would obliterate venous outflow from the sinus and, in cases with insufficient drainage, thereby causing venous congestion, which was argued to be painful [28]. Furthermore, the inflammation was thought to cause damage to poorly myelinated sympathetic fibres, causing symptoms of sympathetic deficit, which in turn afflicted the duration of the attack. The explanation being that a regeneration of the myelin would cause an attack to cease, whereas a prolonged inflammation could cause a chronification of the disease. Moreover, the tendency of a CH attack to initiate during sleep in a circadian pattern was explained with the increase in venous load due to horizontal positioning [28].
The theory was dismissed [16, 31] after several studies had shown either no signs of inflammation in magnetic resonance imaging (MRI) [32], similar findings with orbital phlebography in patients with other diseases [33, 34] or no differences in frequency of pathology between CH patients and patients with tension-type headache (TTH) or migraine [35].
If the cavernous sinus is the pain origin in CH, it is not because of inflammation [31]. But could it be due to another dysfunction in the area? The characteristic ipsilateral location would still remain enigmatic, considering the anastomoses connecting the bilateral cavernous sinuses. Moreover, how it is possible that none of the other cranial nerves crossing the sinus are affected and causing symptoms?
8.2.2.2 Internal Carotid Artery
Along with the cavernous sinus the internal carotid artery (ICA) has been argued to be a peripheral drive in the CH pain [36]. The ICA arises from the common carotid artery bilaterally as it bifurcates into an external and internal part. A sympathetic nervous plexus, the carotid plexus, surrounds the artery which protrudes cranially.
A case study reported two cases of CH following carotid endarterectomy. It was argued that, in patients with existing hypothalamic dysfunction, damage to the trigeminal nerve roots, along with damage to the sympathetic plexus on the ICA, could present a peripheral trigger mechanism for CH, causing pain, vasodilatation and in turn reflex parasympathetic activation of the trigeminal-autonomic reflex [3, 36].
Secondary cluster-like headache following carotid endarterectomy is rarely reported, however, often enough for it to be listed in the IHS classifications system [17]. Moreover, carotid dissection has been reported to elicit symptoms mimicking CH attacks [37].
It is worth noticing that changes in blood flow through the ICA are an epiphenomenon to nociceptive input on the first trigeminal branch [3].
If one considers the carotid artery as the source of the pain, one implies that damage of the trigeminal C-fibres travelling along the vessel wall into the cranium is responsible. There is no definite answer why this cannot be the case and this theory therefore must stand at the moment. However, the strict side-locked and retro-orbital spatial distribution pain would be difficult to explain.
8.2.3 The Trigeminal Nerve and Ganglion
The pain in CH is mainly distributed within an area innervated by the trigeminal nerve. The pseudounipolar trigeminal nerve provides the sensory innervation of structures such as the frontal dura mater, the meningeal vessels and the most components of the eye. Providing afferent somatosensory information from these structures via the trigeminal ganglion to the TCC in the brainstem, this nerve plays a central role in the speculations about the origin of the CH pain.
Activation of the trigeminovascular system in CH has been demonstrated by means of increased jugular blood levels of calcitonin gene-related peptide (CGRP) within CH attacks [24]. Moreover, triptans, one of the key therapeutics in the acute treatment of CH, exert their effects on the 5-hydroxytryptamine (5-HT) 1B/1D receptors mainly on trigeminal nerve endings and blood vessels, respectively, causing diminished release of neurotransmitter and vasoconstriction. This indicates that the trigeminal nerve could be an important nociceptive component of CH. However, CH has been shown to persist despite complete trigeminal nerve root section in two case reports [27, 38] where continued effects of triptans were reported in one patient. This data must be regarded with caution, as there are no more than these two reports. In addition, though, it has been shown that some newer triptans able to cross the blood-brain barrier might also have an inhibitory effect on neurons within the TCC [7, 39]. Taken together, it seems unlikely that activation of the trigeminal system alone can explain the pain in CH [4].
8.2.4 The Parasympathetic Fibres of the Facial Nerve and the Sphenopalatine Ganglion
Parasympathetic activation and resulting symptoms closely accompany the pain in CH [24]. The parasympathetic fibres of the facial nerve form the efferent component of the trigeminal-autonomic reflex [3], innervating the lacrimal gland, mucosa of the nasopharynx and the meningeal vessels [40]. Activation of the SSN near the TCC results in signals relayed via preganglionic fibres projecting to the sphenopalatine ganglion (SPG) where most fibres synapse onto postganglionic fibres. Sympathetic fibres from the carotid plexus follow the same path but only bypass the SPG without synapsing [41]. Whether trigeminal nociception causes parasympathetic activation in CH or vice versa is still unknown. However, the close relation between the structures is evident through the trigeminal-autonomic reflex and furthermore through an anatomic link between the SPG and the trigeminal ganglion [42]. A hypothesis is that, as a consequence of SPG stimulation, subsequent activation of trigeminal nociceptors relays signals to the TCC which in turn activates the SSN via the trigeminal-autonomic reflex, thus forming a self-reinforcing mechanism [41] which generates and maintains the CH pain.
High frequency stimulation of the SPG with an implanted neurostimulator has shown a significant effect in aborting acute attacks as well as in reducing attack frequency [43, 44]. Moreover, low frequency stimulation of the SPG induced cluster-like attacks in three of six chronic CH patients within 30 min after stimulation, which in turn could be treated with high frequency stimulation [45]. This indicates that neurotransmitters released from parasympathetic fibres may activate or modulate trigeminal nociception. This is supported by the fact that SPG blockade [46] or ablation reduces attack frequency [47] and alleviates pain in CH patients [44].
The role of the SPG in CH is intriguing. Most of the initially listed criteria for a peripheral structure to act as a drive for the pain in CH are fulfilled. However, although rare, CH without autonomic symptoms is well known [48] and does indicate that the parasympathetic activation is more likely an epiphenomenon to trigeminal activation than vice versa.
8.2.5 The Vagal Nerve
The vagal nerve is a mixed nerve with both afferent and efferent components. The majority of the cervical vagus nerve fibres carry sensory afferents which relay their input to the nucleus tractus solitarius (NTS) in the brainstem [49, 50]. From here afferents project to different nuclei related to primary headaches such as the locus coeruleus (LC), the dorsal raphe nucleus (DRN) [51], the paraventricular hypothalamus (PVN) [52] and the trigeminal nucleus [53]. Non-invasive vagus nerve stimulation (nVNS) has been proved effective in CH treatment of acute attacks in episodic CH but not in chronic CH patients [54]. The exact mechanism for the pain-relieving as well as frequency-reducing effects is not known. However, animal studies and human fMRI studies have shown that VNS has an inhibitory effect on areas including the spinal trigeminal nucleus [55, 56]. It has moreover been speculated that VNS has an indirect modulatory mechanism on the trigeminovascular system [53]. For example, through activation of areas such as the PVN and LC which lead to an anti-nociceptive modulation on the trigeminal-autonomic system [57].
8.2.6 Brainstem Networks
Several brainstem nuclei are involved in pain transmission in general and trigeminal nociception [8] and headache [58] in particular. However, whereas the brainstem has been repeatedly been discussed as being pivotal in migraine pathophysiology [58, 59], it has never been shown in neuroimaging to be involved in generating cluster headache attacks [60].
8.2.7 Hypothalamus
Involvement of the hypothalamus in CH has become evident through findings in CH patients such as abnormal structural changes in the inferior posterior hypothalamus with neuronal dysfunction [61, 62] and, more importantly, hypothalamic activation of the ipsilateral inferior hypothalamic grey matter during CH attacks [63]. It has therefore been suggested that the hypothalamus serves as a central generator of CH attacks with a focus in the inferior posterior hypothalamus. The theory has led to trials with deep brain stimulation in CH patients with intractable CH [64–66]. Clinical improvement was found in 60% of the cases; however, the effect of hypothalamic high frequency stimulation is only preventive and occurs after prolonged stimulations of weeks to months [67]. As there is no effect of deep brain stimulation on acute CH attacks [66] and as hypothalamic stimulation have never been reported to have triggered attacks, another mechanism of the hypothalamus than a mere inhibitory or excitatory mechanism [68] is sought. It has been suggested that the hypothalamus provides a permissive state for the trigeminal-autonomic reflex and is to a higher degree implicated in terminating rather than triggering CH attacks [67].
8.3 Conclusion
Stimulation of the hypothalamus does not evoke cluster attacks [64, 68].
Sumatriptan penetrates the blood-brain barrier poorly but has excellent therapeutic efficacy in acute attacks of CH. Likewise, monoclonal CGRP antibodies probably have a site of action outside of the CNS as they do not cross the BBB to a relevant extent under normal conditions [1].
SPG stimulation disrupts the trigeminal-autonomic reflex and offers acute pain relief in CH patients [69].
Peripheral mechanisms alone cannot satisfactorily explain the complete symptomatology of CH [2].
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