Similarities and differences between SUNCT and SUNA: a cross-sectional, multicentre study of 76 patients in China

Short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA) have been investigated from diverse perspectives, but both are regarded as unusual conditions among trigeminal autonomic cephalalgias (TACs) [1]. SUNCT was first described in 1978 by Sjaastad et al. [2], and the diagnostic criteria were formally established in 2004, in the second edition of the International Classification of Headache Diseases (ICHD-2) [3]. In the ICHD-2 appendix, SUNCT was categorised as a subset of SUNA as some patients do not have both conjunctival injection and tearing despite otherwise fulfilling the criteria for SUNCT. The two diseases were classified as one entity, short-lasting unilateral neuralgiform headache attacks (SUNHA), in both the ICHD third edition, version β (ICHD-3β) and ICHD third edition (ICHD-3), but with recognition of their distinct cranial autonomic symptoms [1, 4].

Earlier studies have explored the characteristics of, and relationship between, SUNCT and SUNA [5‐18]. Some specialists have suggested that the classifications should be revised. Lambru et al. used new diagnostic criteria to merge the two diseases; it was suggested that the conditions differed simply in terms of the extent of cranial autonomic symptoms [11]. However, more cohorts from other regions require evaluation. Few such studies have been reported from China. As the first multicentre clinical cohort study of SUNCT and SUNA in China, this study characterised and analysed the demographics and clinical phenotypes of patients with SUNCT and SUNA. A comparison of our results with those of previous, representative clinical series contributes to a better understanding of the relationship between SUNCT and SUNA.

This multicentre cross-sectional study was conducted at the International Headache Centre, Department of Neurology, of the Chinese PLA General Hospital and at seven other headache clinics between April 2009 and July 2022. The study was approved by the Ethics Committee of the Chinese PLA General Hospital and complied with the World Medical Association’s Declaration of Helsinki.

This is the first multicentre cohort study on SUNCT and SUNA conducted in China. The demographic and clinical characteristics of patients with these uncommon and underreported headaches were determined. Consistent with the literature, the core phenotypes of SUNCT and SUNA were shown to be essentially similar in terms of a female predominance, attack locations concentrated in V1 and V2, and common cranial autonomic symptoms and triggers. However, differences between SUNCT and SUNA were detected, and our results contradicted those of previous studies to some extent.

Our patients with SUNCT and SUNA had an age at onset of around the fourth decade, earlier than in most previous studies [7‐10, 14] (Table 5), and similar to the findings of Lambru et al. [11]. Whether the lower age at onset in the Chinese population is due to racial, lifestyle, or cultural factors remains to be determined in studies with larger sample sizes and patients from different regions.

The female predominance was more pronounced in the SUNCT and SUNA patients of the present study than in most other studies [7‐10, 14], consistent with the findings of Lambru et al. [11] (Table 5). An increased proportion of females was also noted among those with cluster headache (CH) [19]. We consider that the female predominance is caused by two factors. First, given the rarity of both diseases, the sex ratios of many previous studies may be inaccurate, given the low numbers of patients; female predominance began to emerge in the present study and that of Lambru et al. [11] (with larger cohorts). Second, similar to CH, social factors such as recent increases in female stress [20] may explain the rise in headache attacks. However, possible evolution of the pathogenesis and regional bias must also be explored. We also found that menstruation was an aggravating factor of attacks, with attacks being more frequent during menstruation in a SUNCT patient. Montes et al. also reported a patient with SUNCT whose attacks were associated with the menstrual cycle, appearing around ovulation. Furthermore, significant relief of the attacks was found to coincide with the end of a pregnancy [21]. These observations suggest that hormones, especially oestrogen, contribute at least partially to the female predominance of SUNCT and SUNA. Support for this hypothesis comes from studies showing effective treatment of refractory SUNCT with clomiphene citrate [22, 23], an oestrogen antagonist that binds to oestrogen receptors, thus also regulating orexin A. Thus, hormone modulation therapy may effectively treat SUNCT, but more data are required.

The reported locations of SUNCT and SUNA attacks vary among studies, but most were in the regions innervated by V1 and V2 (Table 5). SUNCT appeared to involve the temporal region more often, and SUNA the parietal region. However, considering that the temporal and parietal regions share several similar underlying anatomical structures, the differences between them may not be clinically significant. Pain in V3 or outside the trigeminal distribution (C2–C3), such as in the occipital region, was also reported as a radiating location in our cohort, consistent with the findings of Lambru [11] but less commonly described in other studies. This demonstrates the overlap of SUNCT, SUNA and trigeminal neuralgia (TN) in terms of attack location, consistent with previous reports that SUNCT and SUNA attacks mostly involve V1 and V2 and TN attacks V2 and V3 [24, 25]. Some clinicians argue that the boundaries between SUNHA and TN are blurry, and that the two diseases should be considered as a continuum of the same condition with varying degrees of severity [25]. The overlap in the involved locations of the three diseases supports this view.

Among our patients, those with SUNCT had a higher rate and more diverse range of cranial autonomic symptoms than those reported by SUNA patients, and lacrimation was most common in both diseases, consistent with previous studies from Western countries [6‐10, 12, 14] (Table 5). However, in the latter, eyelid oedema, ptosis, and miosis were prominent [6, 7, 9, 10, 14], whereas they were less frequent in the SUNCT group and absent in the SUNA group in this study. This discrepancy in the proportion of autonomic symptoms was also a finding of studies of cluster headache, in which the rates of eyelid oedema, ptosis, and miosis were low [26, 27]. The difference might be due to ethnic, social, and cultural differences between Eastern and Western populations.

SUNCT and SUNA can occur spontaneously or can be triggered by cephalic and facial activities, oral and skin irritation, or odour and temperature changes, as determined in our study and previous studies [7‐10, 12, 14] (Table 5). The absence of a significant difference in the triggers of SUNCT and SUNA supports the current classification of the two diseases.

Notably, the delay to the correct diagnosis was shorter for SUNCT than SUNA patients, consistent with the findings of Cohen et al. [7]. This difference may reflect the broader and more prominent array of cranial autonomic symptoms of SUNCT, such that individuals who experience these symptoms seek medical help sooner. Because SUNCT is diagnosed based on the presence of both autonomic symptoms of lacrimation and conjunctival injection, according to ICHD-3, while SUNA has greater variability in the range of cranial autonomic symptoms, a diagnosis of SUNA is more likely to be delayed.

This multicentre clinical study of SUNCT and SUNA is the first of its kind in China, and it established a new cohort for investigating the characteristics of SUNCT and SUNA in the Asian population. Our results as well as those of previous studies revealed statistical differences in some of the clinical features between SUNCT and SUNA, but the shared core phenotypes support the consideration of SUNCT and SUNA as a single clinical entity, in line with the current classification, at least until more data are collected. Definitive conclusions will require a larger number of cases to allow analyses of genetic differences, physiological measurements, and functional imaging.