Abstract
Objectives: To study the clinical profiles, imaging findings and outcomes and field test the diagnostic criteria proposed by the International Classification of Headache Disorders, 2nd edition (ICHD-II) in patients with headache associated with sexual activity (HSA).
Methods: We recruited 30 patients (16 men, 14 women, mean age at onset 40.2 ± 10.0 years) with headache associated with sexual activity at a headache clinic from 2004 to 2009. None of the patients had neurological deficits at onset.
Results: Twenty patients (67%) had secondary causes, including one subarachnoid hemorrhage, one basilar artery dissection, and 18 cases reversible cerebral vasoconstriction syndrome (RCVS). Ten patients (33%) had primary HSA. The demographics, headache profiles, drug response and clinical course were similar between primary and secondary HSA. Compared to prior studies done in Western societies, our patients had similar clinical features but with a higher ratio of females (50%) and a higher frequency of chronic course (39%).
Discussion: Sixty-seven percent of patients with RCVS could not fulfill the criteria of reversible angiopathy of the central nervous system (Code 6.7.3) proposed by the ICHD-II. The most common reason was headache resolution in more than two months. In addition, 40% of patients with primary HSA could not fulfill the ICHD-II criteria for primary HSA (Code 4.4).
Conclusions: Our study found that intracranial vascular disorders were very common in patients with HSA. Thorough neurovascular imaging is required for all patients with HSA.
Keywords
Introduction
Field-testing of the ICHD-II criteria for primary HSA and headache attributed to benign (or reversible) angiopathy of the CNS
ICHD-II = International Classification of Headache Disorders, 2nd ed. HSA = headache associated with sexual activity. CNS = central nervous system. 1On first onset of orgasmic headache it is mandatory to exclude conditions such as subarachnoid hemorrhage and arterial dissection.
HSA can present with an abrupt and severe headache, which is similar to thunderclap headache, that is, a sudden-onset, severe headache that reaches maximum intensity within one minute (4). When thunderclap headache is associated with reversible vasoconstriction, the diagnosis is reversible cerebral vasoconstriction syndromes (RCVS) (8), an eponymic syndrome of ‘headache attributed to benign (or reversible) angiopathy of the central nervous system (CNS)’, as proposed by ICHD-II (code 6.7.3) (4). RCVS can occur spontaneously or be precipitated by intense exertion or Valsalva maneuvers. Sexual activity is also recognized as an important trigger for RCVS (9–11). One study suggested routine use of angiography to exclude RCVS in patients with acute HSA (12), but the relationship between HSA and RCVS has not been fully investigated.
In this study, we analyzed the demographics, headache profiles, neuroimaging results, treatment and clinical course of patients with HSA. The relationship between HSA and RCVS was also investigated. We also evaluated the applicability of the diagnostic criteria for primary HSA and benign angiopathy of the central nervous system (CNS) proposed in the ICHD-II (Table 1).
Methods
Patients and clinical settings
This study was conducted from July 2004 to July 2009 in the headache clinic of Taipei Veterans General Hospital (Taipei-VGH), a medical center in Taiwan. Consecutive patients who had at least two attacks of headache related to sexual activity were prospectively enrolled. All patients completed a detailed headache intake form and received neurological examinations. The study protocol was approved by the Institutional Review Board at Taipei-VGH and all patients signed informed consent forms before entering the study.
Data collection at baseline
Demographics; self-reported medical illnesses; headache profiles, including frequency, duration of pain, location, quality, intensity and associated symptoms; imaging results; and response to treatment were all recorded.
Neuroimaging
All patients underwent MRI or CT of their brain to investigate the possibility of intracranial lesions. Patients without SAH also underwent neurovascular studies using the same protocols as those used in our previous study on RCVS (9). The procedure has been detailed elsewhere (9,13). Magnetic resonance angiography (MRA) using a 1.5-tesla MRI machine was performed to assess cerebrovascular abnormalities such as segmental arterial vasoconstriction or aneurysm. The degree of stenosis of intracranial vessels was graded by source images, and by maximum intensity projection reconstruction of multi-slab, three-dimensional, time-of-flight MRA. MRA vasoconstriction was defined as a lumen narrowing of more than 25% of diameter, for least a short segment of vessels. Sequential MRAs were performed to determine whether the cerebral arterial narrowing was reversible, or was caused by atherosclerosis. Follow-up intervals depended on clinical condition. Follow-up MRA examinations were conducted until normalization of vasoconstrictions or for six months (13).
Headache diagnosis
In this study, HSAs were categorized into primary and secondary based on the absence or presence of intracranial lesions. We also classified patients as pre-orgasmic, orgasmic and post-orgasmic headache subtypes according to the temporal relationship of the headache and orgasm. Post-orgasmic headache was defined if the headache started within minutes to less than one hour after orgasm. In this study, we tested the application of the ICHD-II criteria of primary HSA (coded 4.4.1 and 4.4.2) and headache attributed to benign (or reversible) angiopathy of the CNS (6.7.3) (4) in our participants (Table 1).
Treatment
In our clinic, physicians treated HSA with indomethacin as preemptive therapy. Response to treatment was recorded as a good response (headache frequency and intensity both improved more than 50%) or a poor response.
Follow-up
Follow-up with telephone interview was done by one physician (YC Yeh) in 2009. A structured questionnaire was designed to determine clinical course and prognosis. Clinical course was divided into two patterns: (a) episodic course with or without relapsing bouts, and (b) chronic course. In this study, a ‘bout’ was defined as at least two sex-induced headaches occurring in the acute stage regardless of the frequency, with no further attacks for ≥4 weeks despite continuing sexual activity. An episodic course meant that the first bout of HSA lasted for less than one year. A chronic course was defined as HSA lasting for ≥1 year with no remission longer than ≥4 weeks (14).
Statistics
SPSS Version 17.0 for Windows (SPSS Inc., Chicago, IL, USA) was used for statistical analysis. Descriptive statistics are presented as means ± standard deviation or as percentages. Some parameters were not normally distributed, so median values were used. The clinical profiles of primary and secondary HSA were compared as follows: quantitative data by nonparametric Mann-Whitney-U-test and categorical data by χ2 or Fisher exact tests, as appropriate. Statistical significance was defined as a p value of less than .05.
Results
Study participants
During the study period, 31 of 4526 patients (0.7%) presented at our headache clinic fulfilling our inclusion criteria for HSA. One patient was excluded due to loss to follow-up. A total of 30 patients (16 men, 14 women, mean age 40.2 ± 10.0, range 23–58 years) were eligible for the final analysis. The time from the onset of the first headache to visiting our headache clinic varied widely, with a median of 34 days (range 1 day–6 years). All patients had normal neurological examinations on the first visit and underwent neuroimaging studies, either CT (N = 1), MRI (N = 24) or both (N = 5). One patient (post-orgasmic) underwent lumbar puncture, and the open pressure and CSF samples were normal. Five patients (17%) had a history of hypertension. Twelve patients (40%) had other primary headache disorders, either migraine (N = 10, 33%), or tension-type headache (N = 2, 7%).
Classification of headache associated with sexual activity
Twenty patients (67%) had secondary causes, including one SAH, one basilar artery dissection, and 18 cases of RCVS. Patients with RCVS showed vasoconstriction in their initial MRA studies during the acute stage, which, in all cases, resolved at follow-up (Figure 1). Two patients (11%) reported exposure to nasal decongestants as a potential precipitating factor for cerebral vasoconstriction. None developed posterior reversible encephalopathy syndrome or ischemic stroke.
A 50-year-old woman had orgasmic headache with reversible cerebral vasoconstriction syndrome. Her symptoms had resolved completely three months later. Magnetic resonance angiography showed multiple segmental cerebral vasoconstrictions 14 days after headache onset (arrowheads, (a)). The vasoconstrictions were no longer apparent after three months (b).
Ten patients (33%) were diagnosed as primary HSA, because no structural lesions could be identified in neuroimaging studies of brain parenchyma and cerebral vasculature.
Profiles of headache associated with sexual activity
Three patients (10%) had pre-orgasmic headache, 22 (73%) had orgasmic headache and one (4%) had post-orgasmic headache. Of note, four patients (13%) experienced both pre-orgasmic and orgasmic headache (mixed type). Sudden severe headache occurred in two patients (67%) in the pre-orgasmic group, 20 (91%) in the orgasmic group, one (100%) in the post-orgasmic group and four (100%) in the mixed group. Headache was bilateral in 22 patients (73%) and unilateral in eight (27%). Pain was predominantly in the occipital regions (N = 23, 77%) followed by the temporal (N = 12, 40%). The intensity of headache was reported as severe in 28 patients (93%) and mild in two (7%). The quality of headache was explosive in 23 patients (77%), throbbing in 21 (70%) and dull in 10 (33%). The duration of pain for HSA attacks varied markedly (median: 30 minutes; range: 20 seconds–24 hours). In the acute stage, 28 patients (93%) had frequent attacks (in ≥50% of sexual activities) and two (7%) had infrequent attacks (in <50% of sexual activities).
Response to indomethacin treatment
As preemptive treatment, 20 patients with either primary HSA or RCVS received indomethacin 25–100 mg per day or 25 mg 1–2 hours before sexual activity. Of these, 14 (70%) had a good response and six (30%) did not respond well.
Clinical course and prognosis
All patients completed the follow-up study, with a mean follow-up of 23.9 ± 19.6 (median: 18.5, range 3–63) months. The patient with SAH underwent surgical clipping. No relapsing bouts were reported over a follow-up period of 25 months. The patient with basilar artery dissection received aspirin treatment, and no relapsing bout was reported over a follow-up period of four months.
In 26 patients with primary HSA or RCVS, 17 (61%) had an episodic course. The mean duration of the first bout was 2.7 ± 2.2 months (median: 2.0, range 0.8–9), with five patients (18%) experiencing a relapsing bout after a mean disease-free interval of 28.0 ± 11.9 months (range 12–45), and one of these five experienced a second relapsing bout after a second headache-free interval of 13 months. Eleven patients (39%) had a chronic course (≥1 year), with a mean duration of 52.8 ± 40.9 (median: 33, range 12–120) months. Four of these (14%) experienced remission after a mean duration of 42.0 ± 39.8 months (median: 30, range 12–96). The other seven patients (25%) had no remission, but the intensity of headache decreased as time passed.
Comparisons between primary HSA and RCVS
Comparisons between patients with primary HSA and RCVS
HSA, headache associated with sexual activity; RVCS, reversible vasoconstriction syndrome.
Field-testing of the ICHD-II criteria
In application of the ICHD-II criteria for benign angiopathy of CNS (code 6.3.7; Table 1), 17 patients with RCVS (94%) fulfilled the criteria after excluding criterion D. One patient (6%) presented with mild pre-orgasmic headache, because he stopped sexual activities at the beginning of headache, which does not meet criterion A. Only six patients (33%) met criterion D, that is, resolution of headache within two months. No patient recovered within the usual time span of RCVS (1–3 weeks) (11), whereas eight patients (44%) recovered within three months, which is the duration defined for RCVS (8). Overall, the mean duration of the first bout was 3.1 ± 2.4 (median 3.0, range 0.8–9) months in 13 patients with an episodic course (72%), and five of them (28%) had a relapsing bout. Five patients (28%) ran a chronic course (≥1 year), even though vasoconstriction reversal had been demonstrated.
Six (60%) of the 10 patients with primary HSA fulfilled all ICHD-II criteria of primary HSA (code 4.4; Table 1). Two patients with pre-orgasmic headache had throbbing pain instead of dull ache and did not have neck and/or jaw contraction (criterion A). One of them had sudden severe headache without a gradual increment with sexual excitement (criterion B). The third patient had headache onset at orgasm, but the intensity increased gradually to a severe and explosive pain, which failed to meet criterion A of an orgasmic headache. The fourth patient had post-orgasmic headache, but this did not meet the criteria adopted by the ICHD-II for a primary HSA.
Discussion
Our study found that a large proportion (67%) of patients with HSA had secondary causes. The clinical features were indistinguishable between primary and secondary HSA. Without of a systemic evaluation of cerebral vasculature, these underlying causes may have been missed in prior studies.
Compared with a clinic-based study done in Germany, our patients showed similar clinical features (14,15), including age of onset, other comorbid primary headache disorders, headache characteristics and drug response. However, some differences do exist. A higher proportion of our patients had a chronic course compared to those in the German study (39% vs. 25%). Furthermore, over a shorter follow-up period, the relapse rate in our patients with episodic HSA was still higher than that in the German study (29% in 2 year vs. 25% in 6 years). Finally, the proportion of female patients was higher in our study (50%) than that found in Western studies (15%–26%) (6,7,14–18). The cause for these discrepancies is unknown, although differences in ethnicity and clinical settings might be contributory.
Proposed revised criteria for primary headache associated with sexual activity
1It is mandatory to exclude conditions such as subarachnoid hemorrhage, arterial dissection, and reversible cerebral vasoconstriction syndromes.
The pathophysiology of primary HSA remains unclear. The consistent clinical picture in our patients with either primary HSA or RCVS suggests that the two diagnostic entities may be spectra of the same disorder. A neurogenic mechanism with aberrant central sympathetic response and disturbance in cerebral arterial tone have both been proposed to play an important role in RCVS (8,20). These hypotheses explain why RCVS attacks are frequently precipitated by events that increase sympathetic tone. In support of this view, sympathetic activity increases in both the plasma and CSF during sexual arousal and orgasm (21). One cerebral hemodynamic study using the acetazolamide test and stress Doppler sonography suggested that patients with orgasmic headache have an impaired metabolic component of cerebral vasoneuronal coupling (22). Therefore, RCVS and primary HSA may share similar underlying mechanisms.
Our study has limitations. First, MRA cannot replace the ‘gold standard’ of catheter angiography for the evaluation of cerebral vasculature. Vasoconstriction at distal cerebral arterial branches may not be detected by MRA, leading to underestimates of the frequency of vasoconstriction in our patients. Any movement artifact can cause the impression of vascular irregularities, which may lead to an overestimation of vasoconstriction. However, this issue could be resolved if a standard grading method for vasoconstriction was used (13). Second, CSF studies are usually considered part of the basic evaluation for thunderclap headache or RCVS (8). In this study, the lower rate of spinal tap reflects a negative view of this procedure in our society. Therefore, the possibility of SAH cannot be completely ruled out, but it is expected to be low, because CT, MRI and MRA were negative for SAH or aneurysms. Third, our study is a hospital-based series and therefore may not adequately represent all those who did not seek medical care. Fourth, the exact efficacy of indomethacin cannot be assessed in this open-label study, because of the possibility of spontaneous resolution of both RCVS and primary HSA.
In conclusion, many of our patients with HSA had RCVS . Compared with Western studies, the clinical profile of HSA in our patients were similar except for a higher female ratio and higher fraction of patients with a chronic course. Neuroimaging studies of both brain parenchyma and cerebral vasculature are recommended for all patients with HSA. The ICHD-II criteria for primary HSA and benign angiopathy of CNS are restrictive and would likely benefit from modifications in future revisions.
Footnotes
Acknowledgements
This study was supported in part by a grant from National Science Council of Taiwan (97-2628-B-010-007-MY3) and Taipei Veterans General Hospital (V99C1-063).