Abstract
Background
Cranial autonomic symptoms (CAS) seem to appear in around half of migraine patients.
Objective
Our aim was to analyse the prevalence and profile of CAS, mainly of cranial autonomic parasympathetic symptoms (CAPS), in a series of patients with chronic migraine (CM) according the new criteria for autonomic symptoms in the current IHS classification.
Patients and methods
We recruited consecutive CM patients attending our headache clinic. Five CPAS were surveyed: lacrimation, conjunctival injection, eyelid oedema, ear fullness and nasal congestion. They were graded as 0 (absent), 1 (present and mild) and 2 (present and conspicuous); therefore the score in this CAPS scale ranges from 0 to 10 points. As a cranial autonomic sympathetic symptom (CSAS), we also asked about the presence of ptosis.
Results
We interviewed 100 CM patients. Their mean age was 45 years (18–63 years); 93 were females. Eighteen had no CAPS, while 82 reported at least one CAPS. There were only six patients with scores higher than 5, the mean and median CAPS being 2.1 and 2, respectively. Prevalence of CAPS was lacrimation (49%), conjunctival injection (44%), eyelid oedema (39%), ear fullness (30%) and nasal congestion (20%). Ptosis was reported by 42.
Conclusion
These results, by using for the first time an easy quantitative scale, confirm that (mild) CAPS are not the exception but the rule in CM patients. The score in this CAPS scale could be of help as a further endpoint in clinical trials or to be correlated with potential biomarkers of parasympathetic activation in primary headaches.
Introduction
Migraine is a common, chronic and disabling disorder. Moderate-severe headache aggravated by exercise, noise and light and, in up to one-third of patients, aura are the most important symptoms required for its diagnosis. Most migraine patients, however, experience other clinical manifestations, for instance premonitory and resolutory symptoms (1,2). Involvement of the autonomic nervous system in migraine is very likely given the ‘general’ (nausea, vomiting, diarrhoea or polyuria) or ‘cranial’ (conjunctival injection, lacrimation, nasal congestion, ptosis, etc.) symptoms associated with migraine attacks (3). Migraine pathophysiology is complex, but either changes in the modulating nociceptive inputs from the locus ceruleus and raphe brainstem nuclei (4) or a cortical spreading depression phenomenon (5) are thought to activate the trigemino-vascular system (TVS), which consists of a brainstem connection between trigeminal afferents and parasympathetic efferents of the facial nerve that synapse in the sphenopalatine ganglion (6). Activation of this reflex releases pain-producing, vasoactive neuropeptides, mainly calcitonin gene-related peptide (CGRP) in the case of the afferent trigeminal arm and vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) via the parasympathetic efferences around leptomeningeal and extracranial vessels (7,8). Unquestionably, the trigeminal nerve, with its transmitter CGRP, is crucial (7,9), but activation of the cranial autonomic system could also play a notable role in migraine pathophysiology (10).
Cranial autonomic symptoms (CAS) have been shown to appear in up to three-quarters of migraine patients (11–17). This correlation is not limited to adults, but also includes two out of three adolescents or children with migraine as noticed in a recent study (18). Studies analysing CAS in migraine have several limitations: 1) the analysed symptoms were different among the studies; 2) they do not separate parasympathetic symptoms (CAPS), thought to be due to a true activation of the TVS, from symptoms, such as miosis and ptosis, which are the result of secondary sympathetic hypofunction; and 3) contrary to pain, none of these studies have tried to numerically quantify CAS, and in particular CAPS.
Our aim was to analyse the prevalence and profile of CAS, and mainly of CAPS, in a series of patients with chronic migraine (CM) according to the criteria for autonomic symptoms appearing in the new International Headache Society (IHS) classification and by using an ad hoc numerical scale.
Patients and methods
Consecutive adult patients attending our headache clinic at the University Hospital Central de Asturias who had been diagnosed by us as having CM according to current IHS criteria (19) were included in this study. Patients were interviewed by a neurologist and explicitly asked whether they experience each of the following five CAPS, based on the criteria of the new International Classification for Headache Disorders, third edition beta (ICHD-IIIβ), with their headaches: 1) lacrimation, 2) conjunctival injection, 3) eyelid oedema, 4) sensation of fullness in the ear and 5) nasal congestion and/or rhinorrhoea. We graded each CAPS as 0 (absent), 1 (present but mild) and 2 (present and conspicuous) (Figure 1). Therefore, the score in this CPAS scale ranges from 0 to 10 points. In addition, as a cranial sympathetic autonomic symptom (CASS), we also asked about the presence of ptosis with their headaches. This study was approved by our ethics committee.
Cranial autonomic parasympathetic symptom (CAPS) scale.
Results
We interviewed 100 consecutive CM patients. Of this sample, the majority (93) were females, their mean age was 45 years (range 18–63 years) and the average duration of illness was 9.5 years (range 18–63 years). Eighteen CM patients had no CAPS, while 82 reported at least one CAPS (Figure 2). There were only six patients with scores higher than 5, the mean and median of CAPS being 2.1 and 2, respectively (Figure 3). Fifty-two patients graded at least one CAPS as 2 (Figure 3). Prevalence of individual CAPS was: lacrimation (49%), conjunctival injection (44%), eyelid oedema (39%), sensation of ear fullness (30%), nasal congestion and/or rhinorrhoea (20) (Table 1). Ptosis, as the CASS analysed, was reported by 42% of the CM patients in this series.
Chronic migraine (CM) patients (in percentage) and number of symptoms on the cranial autonomic parasympathetic symptom (CAPS) scale. Percentage of chronic migraine (CM) patients with each score on the cranial autonomic parasympathetic symptom (CAPS) scale. Prevalence of CAS in our CM patients. CAS: cranial autonomic symptoms; CM: chronic migraine.
Discussion
This work confirms the high prevalence of CAS, and in particular of CAPS, in migraine patients, in this case specifically in patients suffering from CM. Eighty-two per cent of our CM patients noticed at least one CAPS. This percentage is even higher than the range, between 27% and 73%, reported in other studies which have analysed the prevalence of CAS in migraine patients (11–18). The higher rate of CAS found here can be explained by several reasons. First, patients were personally interviewed by one of us. Second, we examined patients with CM, that is, the most severe clinical form of migraine. Finally, in previous studies patients were asked about fewer symptoms, mainly as CAPS have been expanded in the new ICHD-IIIβ (19). In spite of their high prevalence, the grade of CAPS fell in the low range of our ad hoc scale. In fact, as an average, they scored 2 out of 10 and there were only six patients with scores higher than 5.
To our knowledge, this is the first attempt of designing a scale to try to evaluate and quantify CAPS in primary headaches. Among the nine potential autonomic symptoms/signs (conjunctival injection, lacrimation, nasal congestion and/or rhinorrhoea, eyelid oedema, forehead and facial sweating, forehead and facial flushing, sensation of fullness in the ear, miosis and ptosis) appearing in the current IHS Classification (19), we selected five to evaluate CAPS for several reasons. On the one hand, to try to prepare a scale ranging from 0 to 10, and therefore be as practical as possible, we graded the symptoms as just present or conspicuous. On the other hand, we decided not to include in the scale forehead and facial sweating and forehead and facial flushing, not only to keep just five symptoms within the scale, but as, at least in part, these symptoms also depend on the autonomic sympathetic system and also on the release of CGRP via the trigeminal nerve (20). Finally, though it was also evaluated, palpebral ptosis was not included in the scale, as it is considered a sign of sympathetic hypofunction; we decided not to ask about the presence of miosis for the same reason, but also as this is a sign which requires a high grade of shrewdness by the patients. In our opinion, this numerical scale can be useful for evaluating with several objectives the presence of CAPS in patients with primary headaches. For instance, it can be included as a secondary efficacy endpoint when evaluating both drugs or neuromodulation procedures in primary headaches or correlated with potential biomarkers of cranial parasympathetic activation, such as PACAP or VIP (21–24).
The most frequent symptoms were lacrimation and conjunctival injection, which were reported by almost half of our CM patients, while sensation of ear fullness and nasal congestion and/or rhinorrhoea were described in fewer than 30% of cases. It cannot be ruled out that the high rate of CAPS could be just an epiphenomenon secondary to migraine pain, but there is evidence indicating that the activation of the parasympathetic arm of the TVS plays a role in the pathophysiology of pain in primary headaches and specifically in migraine. Intranasal application of lidocaine, which may block the sphenopalatine ganglion, aborted migraine within 15 minutes in 36% of patients in a studied population (25). Yarnitsky et al. showed that patients with CPAS were more likely to experience pain relief by lidocaine than patients without CPAS, with a pain reduction of 53% and 15%, respectively (26). Based on the same rationale (27), high-frequency sphenopalatine stimulation, which seems to decrease parasympathetic output, is currently being evaluated in a randomized, controlled trial for the treatment of migraine pain, after some preliminary positive open results (28). In addition, levels of VIP are elevated in cranial venous blood during attacks in patients with CAPS and VIP and PACAP levels have been shown to be elevated ictally and interictally in CM patients in plasma (21–24). Both peptides, and especially PACAP, are able to induce head pain when administered in humans (29–32).
This work has several limitations. As occurs with the numeric ‘Glaxo’ 0 to 3 scale generally used in migraine clinical trials or with the visual analogue scale (VAS), our proposed CAPS scale contains an unquestionable subjective component. Our results have been obtained in a series of CM patients attending a specialised clinic and, therefore, are not necessarily applicable to migraine patients in general. One further possible confounding factor could be the influence of both symptomatic and/or preventive treatments on CPAS, which most of our CM patients were taking and that were not stopped for ethical reasons. These treatments should, in any case, reduce the rate of CAPS and given the high prevalence of CAPS found here, we do not think that treatments have had an outstanding influence on current results. Taking into account these limitations, our results confirm that (mild) CPAS are not the exception but the rule in CM patients, which suggests a role of the parasympathetic arm of the TVS both in migraine pain production and chronification.
Clinical implications
– This is the first attempt of designing a scale to try to evaluate and quantify (from 0 to 10) cranial autonomic parasympathetic symptoms (CAPS) in primary headaches. – CAPS appear in around 80% of chronic migraine (CM) patients during attacks. – In spite of their high prevalence, the grade of CAPS in CM fell in the low range of our ad hoc scale. – The most frequent symptoms were lacrimation and conjunctival injection, which were reported by almost half of our CM patients.
Footnotes
Funding
This work was supported by the PI11/00889 and PI14/00020 FISSS grants (Plan Nacional I + D + I, Fondos Feder, ISCIII, Ministry of Economy, Spain).
Conflict of interest
J.P. reports consultancy from Allergan. The other authors have nothing to declare.
Acknowledgements
Authors responsible: for conception and design (J.P., E.C.), acquisition of clinical data (N.R., A.I.P., L.V., C.G., J.M., P.S. J.P.) analysis and interpretation of data (E.C., J.P.), drafting of the manuscript (J.P.), obtaining funding (J.P., E.C.) and supervision (J.P.).