Pathophysiology of the trigeminal autonomic cephalalgias

INTRODUCTION — The trigeminal autonomic cephalalgias are a group of primary headache disorders characterized by unilateral trigeminal distribution pain that occurs in association with prominent ipsilateral cranial autonomic features [1,2]. The trigeminal autonomic cephalalgias include cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA), and hemicrania continua [3].

This topic will review the pathophysiology of the trigeminal autonomic cephalalgias.

Clinical aspects of these disorders are discussed separately.

●(See "Cluster headache: Epidemiology, clinical features, and diagnosis" and "Cluster headache: Treatment and prognosis".)

●(See "Paroxysmal hemicrania: Clinical features and diagnosis" and "Paroxysmal hemicrania: Treatment and prognosis".)

●(See "Short-lasting unilateral neuralgiform headache attacks: Clinical features and diagnosis" and "Short-lasting unilateral neuralgiform headache attacks: Treatment and prognosis".)

●(See "Hemicrania continua".)

PATHOPHYSIOLOGIC MODELS — The pathogenesis of the trigeminal autonomic cephalalgias – cluster headache, paroxysmal hemicrania, short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT), and hemicrania continua – is complex and remains incompletely understood. Any pathophysiologic construct for trigeminal autonomic cephalalgias must account for the three major features that are common to the syndromes:

●Trigeminal distribution pain

●Ipsilateral cranial autonomic features

●Cyclical variation of attacks

In addition, the underlying pathophysiology should account for the differentiation of the syndromes, including the episodic (cyclical) pattern of attacks seen in cluster headache [4].

The excruciatingly severe unilateral pain is likely to be mediated by activation of the first (ophthalmic or V1) division of the trigeminal nerve, while the autonomic symptoms, such as lacrimation, are due to activation of the cranial parasympathetic outflow from cranial nerve VII [5]. The sympathetic paralysis (miosis and ptosis) may be caused by a (neurapraxic) injury of postganglionic fibers in most patients [6,7].

Trigeminal autonomic reflex — The trigeminal autonomic reflex encapsulates the notion that stimulation of trigeminal afferents can result in cranial autonomic outflow.

●The pain-producing innervation of the cranium projects through branches of the trigeminal and upper cervical nerves to the trigeminocervical complex in the caudal brainstem and upper cervical spinal cord. From there, nociceptive pathways project to higher centers. This reflex may be supported by a direct peripheral connection between the sphenopalatine ganglion (SPG) and trigeminal ganglion [8].

●The ipsilateral autonomic features of the trigeminal autonomic cephalalgias suggest cranial parasympathetic activation (lacrimation, rhinorrhea, nasal congestion, and eyelid edema) and sympathetic hypofunction (ptosis and miosis). These cranial autonomic symptoms are thought to result, in part, from activation of the trigeminal autonomic reflex [1,9,10].

There is considerable experimental animal literature showing that stimulation of trigeminal afferents can result in cranial autonomic outflow [9]. Some degree of cranial autonomic symptomatology is a normal physiologic response to cranial nociceptive input [11,12]. In addition, electrical stimulation in the brainstem at the level of the superior salivatory nucleus, which is the origin of cells for the cranial parasympathetic autonomic vasodilator pathway, results in both neuronal trigeminovascular and cranial autonomic responses [10].

The SPG is an extracranial parasympathetic ganglion located in the pterygopalatine fossa that may be a potential treatment target. Post-ganglionic parasympathetic fibers from the SPG innervate facial structures and the cerebral and meningeal blood vessels; they also mediate the trigeminal-autonomic reflex. The theoretical construct is that high frequency stimulation leads to a depolarization within the ganglion, which effectively blocks the peripheral parasympathetic innervation of the eye and nose [13]. In clinical trials, SPG stimulation relieved pain of cluster headache attacks in approximately two-thirds of patients [13,14].

Painful activation of the trigeminovascular system leads to neuropeptide release. In patients with cluster headache, alterations have been found in the levels of calcitonin gene-related peptide (CGRP), pituitary adenylate cyclase-activating peptide (PACAP), and nitric oxide synthase [15]. Monoclonal antibodies against CGRP may be useful for episodic and chronic cluster headache [16-18].

Cranial autonomic symptoms are also recognized in other forms of head pain, including experimental head pain with capsaicin injection [19] and other headache syndromes such as migraine [20,21]. The main distinction between the trigeminal autonomic cephalalgias and other headache syndromes is, next to the shortness of attacks, the degree of cranial autonomic activation and its often prominent lateralization [22,23]. The cranial autonomic symptoms may be prominent in the trigeminal autonomic cephalalgias due to a central disinhibition of the trigeminal-autonomic reflex.

In chronic cluster headache, the headache and autonomic symptoms may be generated entirely through central mechanisms, as an activation of the trigeminal autonomic reflex is not necessary (any more) to display the full clinical picture [24].

Hypothalamic activation — The posterior hypothalamic region plays an important role in the pathophysiology of the trigeminal autonomic cephalalgias [25]. Several characteristic cluster headache features imply involvement of a biologic clock in the origin of the illness, namely the suprachiasmatic nucleus of the hypothalamus [26-28]. These include the relapsing-remitting course [29], seasonal variation [29,30], and the clockwise regularity of single attacks [31].

Hypothalamic involvement is suggested by lowered levels of plasma testosterone in some males with cluster headache during bouts [32]. Further support was provided by the finding of a reduced response to thyrotropin-releasing hormone [33] and by a range of other circadian irregularities in patients with cluster headache. As an example, melatonin is a marker of the circadian system, and one study found that patients with cluster headache during cluster periods demonstrated a blunted nocturnal peak in melatonin level and a complete loss of a circadian rhythm [34].

The following observations from experimental animal and clinical neuroimaging studies also support the role of the hypothalamus in pain modulation:

●There are direct hypothalamic-trigeminal connections [35,36]

●The hypothalamus is involved in anti-nociceptive and autonomic responses [37-39]

●The hypothalamus is activated during acute cluster headache when intracranial pain structures are activated [40]

●The hypothalamic neuropeptides orexin A and B can elicit pro-nociceptive and anti-nociceptive effects in the trigeminal system [41]

●Activation of the trigeminal-autonomic reflex by a painful stimulus causes activation of the anterior hypothalamus, locus coeruleus, and ventral posterior medial nucleus of the thalamus [42]

Anatomic correlates — Functional imaging data suggest that primary headache syndromes can be distinguished on a neuroanatomic basis by areas of activation specific to the clinical presentation [43-45]. Positron emission tomography (PET) studies in cluster headache [46,47], paroxysmal hemicrania [48], and hemicrania continua [49] and functional magnetic resonance imaging studies in SUNCT syndrome [50-52] have demonstrated that all of these headache syndromes share an activation of the region of the posterior hypothalamic gray. Other studies using deep brain stimulation refer to this region as the midbrain tegmentum [53]. The terminology is interchangeable and the distinction unimportant without human anatomical data.

For hemicrania continua, which shares some symptoms of migraine and cluster headache, PET imaging has shown significantly increased activity in the posterior hypothalamus (involved with trigeminal autonomic cephalalgias generation), in the dorsal rostral pons, and the ipsilateral ventrolateral midbrain (involved with migraine generation) [49]. This activity may be successfully blocked with indomethacin. In addition, hypothalamic activation does not accompany experimental trigeminal distribution head pain [54,55]. These findings have led to the successful introduction of a therapeutic target for cluster headache and the other trigeminal autonomic cephalalgias using deep brain stimulation of the posterior hypothalamic gray matter [25].

Of note, anatomically distinct regions of the hypothalamus have been implicated in migraine attack generation [56-58]. (See "Pathophysiology, clinical manifestations, and diagnosis of migraine in adults", section on 'Pathophysiology'.)

Temporal correlates — The hypothalamic involvement in the pain process appears to occur in a phase-dependent permissive or triggering manner rather than simply as a response to pain mediated by the trigeminal nociceptive pathways [9,59]. Compared with healthy controls, patients with cluster headache exhibited functional connectivity changes between the hypothalamus and medial frontal gyrus and occipital cuneus [60]. Moreover, changes were observed in functional connectivity in the medial frontal gyrus, precuneus, and cerebellum, and in dorsal and frontal attention networks between in-bout and out-of-bout status [13]. More work in this area is needed.

In contrast with hypothalamic activation in trigeminal autonomic cephalalgias, most studies in episodic and chronic migraine attacks have not observed ictal hypothalamic activation [61-65], although there are exceptions [66]. Hypothalamic involvement in migraine appears to occur shortly before but not during the attack [56,57,67].

Vascular theory — The vascular theory holds that the clinical symptoms of cluster headache are caused by neurogenic inflammation of the walls of the cavernous sinus, which is the only peripheral anatomic location where a single pathology could involve trigeminal C-fibers and sympathetic fibers [68]. This inflammation is postulated to obliterate venous outflow and thus injure the traversing sympathetic fibers of the intracranial internal carotid artery and its branches [19,68], thus explaining the unilateral pain and ipsilateral damage of sympathetic outflow.

The vascular theory has been largely abandoned by the recognition that the neurovascular phenomena related to the trigeminal autonomic reflex and some central impulse generator or "oscillator" – thought to be in the hypothalamic region – seem to be more important.

OUTSTANDING ISSUES — There are several issues that remain unresolved in the understanding of the pathophysiology of the trigeminal autonomic cephalalgias.

●What is the nature of the hypothalamic abnormality?

●Why do cluster headache, hemicrania continua, paroxysmal hemicrania, and short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) have such different phenotypes and treatment responses if the defining abnormality of the trigeminal autonomic cephalalgias is hypothalamic derangement?

The hypothalamus is a complex structure with various nuclei and widespread projections to numerous central structures. It is possible that the specific substructures, neurons or biochemical pathways involved in these primary headache syndromes vary, thereby explaining both the different phenotypes and treatment responses.

Further studies are needed to seek the anatomic or functional basis of these variations. Advances in the pathophysiologic understanding of the trigeminal autonomic cephalalgias are likely to lead to better treatments for these devastatingly painful syndromes.

SUMMARY

●Clinico-pathophysiologic constructs – Understanding of the trigeminal autonomic cephalalgias must account for the core clinical features common to the syndromes including the trigeminal distribution pain, the ipsilateral cranial autonomic features, and the cyclical variation of attacks. (See 'Pathophysiologic models' above.)

●Trigeminal autonomic reflex – Stimulation of trigeminal afferents projecting to nociceptive pathways such as the sphenopalatine ganglion and trigeminal ganglion may result in pain and cranial autonomic symptoms through central disinhibition and neuropeptide release. (See 'Trigeminal autonomic reflex' above.)

●Hypothalamic activation – The most widely accepted theory is that the trigeminal autonomic cephalalgias are due to a functional abnormality in the hypothalamus leading to hypothalamic activation with secondary activation of the trigeminal autonomic reflex, probably via a trigeminal-hypothalamic pathway. (See 'Trigeminal autonomic reflex' above and 'Hypothalamic activation' above.)

●Vascular theory – The vascular theory, largely abandoned, holds that the autonomic symptoms of cluster headache are caused by neurogenic inflammation of the walls of the cavernous sinus. (See 'Vascular theory' above.)