Abstract
Unilateral cranial autonomic symptoms (UAs) such as lacrimation, conjunctival injection, eyelid oedema and nasal congestion, which are the hallmark of trigeminal autonomic cephalgias, may also occur in an as yet undetermined proportion of migraine patients. We studied 177 consecutive migraineurs to assess the frequency of UAs and the clinical characteristics of such patients. UAs were reported by 81 patients (45.8%), ocular symptoms alone or in combination with nasal symptoms being the most frequent. The headache was more severe (P< 0.0002) and more strictly unilateral (P< 0.0004) in patients who reported UAs than in those without. Thus, the presence of UAs suggests an activation of the trigeminal-autonomic reflex, probably related to an over-activation of the trigeminal afferent arm. These findings could have therapeutic implications, given the potential large-scale recruitment of peripheral neurovascular 5-HT1B/1D receptors (the target of acute migraine treatment) in such patients.
Introduction
Systemic autonomic symptoms such as nausea and vomiting typically accompany a migraine attack and contribute to a large extent to its debilitating effect. The pathophysiology of these symptoms probably involves the connections between the trigeminal nerve and the nucleus tractus solitarius. Unilateral cranial autonomic symptoms (UAs) such as lacrimation, conjunctival injection, eyelid oedema and nasal congestion, consequent to the activation of the cranial parasympathetic system, are distinctive features of some short-lasting primary headaches like cluster headache, paroxysmal hemicrania and SUNCT (trigeminal autonomic cephalgias, TACs) (1).
Interestingly, UAs may occur together with systemic autonomic symptoms in some migraineurs during attacks (2–4). Although it is not uncommon to encounter migraineurs who report UAs in clinical practice, neither the frequency nor the clinical features of UAs have yet been systematically investigated. Therefore, in an attempt to better characterize these patients, we assessed the frequency of UAs in migraineurs and their clinical characteristics.
Methods
We investigated all the patients affected by migraine with or without aura (5) consecutively seen at the Headache Centre of the Department of Neurological Sciences, University ‘La Sapienza’, Rome, from 1 January 2001 to 31 March 2001. Information on the sociodemographics and clinical features, including age of onset, family history of migraine, presence of aura, attack frequency and duration, location, quality and intensity of pain, prodromes, systemic associated symptoms, abortive and/or preventive treatment, current prophylaxis, concomitant headaches, and use of oral contraceptives was gathered in all patients by means of face-to-face interviews using a structured questionnaire.
The presence of UAs was screened by means of the following question: ‘During the migraine attack, do you also have unilateral eye redness and/or lacrimation and/or eyelid oedema and/or nasal stuffiness/rhinorrhoea?’. Patients reporting at least one of the above symptoms during the attack were considered migraineurs with UAs, while the remaining patients were considered migraineurs without UAs. The demographics and clinical features of patients with and without UAs were compared by means of Student's t-test for unpaired data and χ2 test. All analyses were performed with BMPD New System software.
Results
One hundred and seventy-seven migraine patients were investigated (Table 1). Eighty-one (45.8%) of these patients reported the presence of at least one UAs, homolateral to pain, during the attack. In 73 patients with UAs the pain was always unilateral. The remaining eight patients with UAs had either unilateral or bilateral attacks, but described UAs only during unilateral headaches.
Characteristics of migraine patients
UAs, Cranial unilateral autonomic symptoms; MwA, migraine without aura; MA, migraine with aura; TTH, tension-type headache.
Isolated ocular symptoms (lacrimation and/or conjunctival injection and/or eyelid oedema) occurred in 33 patients (40.7%) and in association with nasal symptoms (nasal congestion and/or rhinorrhoea) in 37 (45.7%), while isolated nasal symptoms were present in 11 patients (13.6%). Twenty-two patients (27.2%) had one UAs, 23 (28.4%) had two UAs, while the remaining 36 (44.4%) had three or more. Table 2 lists the type and combination of UAs.
Characteristics of unilateral autonomic symptoms in migraineurs with cranial unilateral autonomic symptoms (UAs)
Migraine headache was more severe (P<0.0002) and more strictly unilateral (P<0.0004) in migraineurs with UAs than in those without UAs (Table 1). No significant differences were found in the other clinical characteristics and demographics between migraine patients with and those without UAs. The type (ocular and/or nasal) or the number of UAs in each patient did not correlate with any clinical or demographic features.
Discussion
UAs, the hallmark of TACs, may also be present in an as yet unspecified proportion of migraine patients (2–4). We found that 45.8% of migraineurs who attended a tertiary-referral centre reported UAs during the attack, the most frequent being ocular symptoms alone (conjunctival injection, lacrimation and eyelid oedema) or in combination with nasal symptoms (nasal stuffiness or rhinorrhoea).
The relatively high frequency of UAs in our sample deserves some consideration. First, the prevalence of migraine-associated symptoms is usually higher in clinic-based than in population-based studies, probably because more effective interviewing techniques and better-defined criteria are used in the clinical setting (6). Second, UAs are spontaneously reported by migraineurs with more marked symptoms, but may emerge only following specific questioning in migraineurs with milder symptoms. Lastly, we cannot exclude a selection bias toward patients with more severe headache, which may result in more symptoms being reported (6).
From a clinical point of view, we found that headache in migraineurs with UAs differs in location and intensity from that of patients without UAs. In fact, migraine headache is more strictly unilateral and more severe in the former than in the latter. This is in agreement with previous observations reporting that UAs appear to be associated most frequently with severe attacks of unilateral migraine (4). Moreover, it is noteworthy that migraineurs with UAs are clinically easily distinguishable from patients affected by the migraine–cluster headache syndrome, the latter being characterized by ‘a headache with predominant symptoms of migraine with at least one major timing factor plus three lesser features of cluster headache, or five lesser features of cluster headache’ (7).
A careful examination of the clinical features of migraine (migraine phenotype) may help in understanding its pathophysiology (migraine biotype). For example, the unilaterality of pain suggests the activation of the trigeminovascular system, its throbbing nature may indicate vascular innervation, aggravation by movement is probably a reflection of neurogenic inflammation, while the occurrence of systemic autonomic symptoms is a sign of the involvement of the nucleus tractus solitarius (8). Accordingly, the presence of UAs suggests an activation of the cranial parasympathetic system in migraineurs with UAs, as confirmed by the finding of high levels of vasoactive intestinal polypeptide in the cranial venous circulation in two migraineurs with cranial autonomic symptoms during attacks (9). Nevertheless, it has to be considered that some ocular symptoms might also be due to neurogenic inflammation (10). Migraineurs with UAs display an activation of both the afferent and the efferent arms of the trigeminal-autonomic reflex, whereas only the trigeminal afferent arm is normally active in migraine. This reflex consists of functional connections between trigeminal afferences and parasympathetic efferences which exit the brainstem via the seventh cranial nerve, traverse the geniculate ganglion and synapse in the sphenopalatine, otic and carotid miniganglia, thereby providing secretomotor innervation to structures such as the lacrimal glands and nasal mucosa (1, 11). In migraineurs with UAs, the activation of the trigeminal-autonomic reflex may be related to the severity of pain, there probably being a pain threshold above which the systemic autonomic symptoms and the UAs occur (1, 12).
These findings might have therapeutic implications. In fact, if migraine patients with UAs have an over-activation of trigeminal afferents, they could also be characterized by a large-scale recruitment of peripheral neurovascular 5-HT1B/1D receptors, the target of acute migraine treatment. Hence, it would be interesting to assess whether migraineurs with UAs behave differently from the remainder of the migraine population in terms of responsiveness to triptans.
Footnotes
Acknowledgements
The authors thank Dr Antonio Bisceglia and Dr Francesco Cesarino for the referral of patients.