Cranial autonomic symptoms (CAS) have been typically associated with the trigeminal autonomic cephalalgias (TAC’s), in which they form part of the diagnostic criteria, and are usually lateralised to the side of the pain [1]. However, it has been increasingly recognised that these symptoms can also occur in migraine and should not deter from the diagnosis [2,3,4,5,6,7,8,9,10,11,12,13]. The laterality of these symptoms in migraine has also been examined, and co-lateralisation with pain akin to the TAC’s has also been demonstrated in some studies, although clearly less commonly than in the TAC’s [4, 6, 11]. This lateralisation may be predictive of triptan treatment response [14,15,16]. Similarly, photophobia and phonophobia are also less commonly lateralised in migraine compared to the TAC’s [17].
In an experimental study, we have previously demonstrated that CAS can precede headache in migraine [18], and indeed can occur or persist following headache resolution [19]. Others have shown similar findings in cluster headache, where CAS can occur early before pain onset [20,21,22], and along with other symptoms may be predictive of an impending bout [23]. Clearly, identification and recognition of these symptoms as part of the broader migraine phenotype is important to allow timely diagnosis and effective headache management, in particular in not infrequent, sometimes challenging diagnostic situations for headache physicians, when patients with cluster headache or another TAC have co-existent migraine, and in those with migraine with short attacks.
In primary headache disorders, pain from the structures of the head and neck is thought to be as a result of trigeminovascular activation; that is the system of nociceptive bipolar nerve fibres originating in the trigeminal ganglion (TG), with the peripheral innervation of dural vessels and large cranial vessels and venous sinuses (causing vascular dilatation), and a central projection to the caudal brainstem or high cervical cord [24, 25]. Cervical dorsal root ganglia also innervate the dura [26, 27]. The central pathway runs through the trigeminocervical complex (TCC), and the neuronal inputs from the peripheral and central afferent pathways converge here, with subsequent projection to higher brain areas including the thalamus and cerebral cortex [28]. Activation of the TCC leads to neuronal activation within the superior salivatory nucleus (SSN) in the pons [29, 30]. An afferent arc in the trigeminal nerve (mainly V1), a reflex parasympathetic connection to the SSN in the pons and an efferent arc in the facial nerve, via the sphenopalatine ganglion (SPG) and greater superficial petrosal nerve, are thought to mediate CAS observed in the TAC’s and migraine, using vasoactive intestinal peptide (VIP) [31] and other neurotransmitters [32]. CAS can be provoked by V1 pain stimulation in healthy volunteers also [33].
Parasympathetically-mediated CAS include lacrimation, conjunctival injection and rhinorrhoea, and sympathetic impairment with ptosis, miosis, sweating and flushing are also well reported. Descending control over the TCC and SSN occurs via the periaqueductal grey (PAG) and hypothalamus, amongst other diencephalic areas, such as the locus coeruleus (LC) [34], and may be a plausible mechanism for top-down activation of the SSN without TCC activation as an explanation for why CAS can present without pain [34].
We were interested in looking into the prevalence of CAS in our clinical cohort of migraineurs, as we suspect that symptoms are more common that often reported in the literature, as systematic questioning may be less clinically pressing when the migraine diagnosis is more obvious. In our clinical history taking, the questions are standardised regardless of likely underlying diagnosis so we felt that this may increase patient reporting of symptoms, despite it possibly leading to a degree of reporting bias. In addition, we have been interested in CAS phenotype and laterality. The phenotype of symptoms likely mediated by cranial autonomic activation has emerged over time. One of these more recently identified symptoms is aural fullness [35,36,37], a sensation of the ear feeling full and uncomfortable, and sneezing [38, 39]. Whilst the majority of cranial vasculature innervation and therefore pain perception comes from V1 [24], we suggest based on previous work, that pain and CAS can be mediated via other divisions of the trigeminal nerve (in the absence of vascular dilatation) [30, 40].
In our experience in a specialist TAC clinic and in running a specialist Orofacial Pain clinic [41], patients with TAC’s and indeed migraine, do report pain outside of the V1 dermatome. We have witnessed the reporting of voice change and/or a sensation of throat swelling, which may be possible CAS, by patients affected by the primary headache disorders. These symptoms are not yet reported in the literature and may represent additional symptoms in the broadening CAS phenotype, perhaps associated with involvement of the V3 division of the trigeminal nerve.
In this study, we therefore sought to examine the prevalence and phenotype of CAS reported by migraineurs within our clinic, and to look at association with headache laterality and baseline headache frequency. We also aimed to evaluate the reporting of voice change and/or throat swelling as possible CAS within a separate cohort of those across migraine and TAC clinics, to evaluate how often these symptoms were reported, their co-occurrence with other CAS and association with pain site.
