In this large cohort of SIH patients, sex-related differences in the clinical manifestations, treatment response to the EBP, and the risk of SDH were demonstrated. Although SIH was more common in women, SIH in men was more complicated, as evidenced by a delayed presentation, a poorer response to the first EBPs, a higher risk of developing SDH as a complication, as well as greater thickness, and a greater potential need for surgical drainage in those with SDH. Caution should be exercised in the clinical evaluation and management of SIH in men, as more aggressive measures, such as earlier and/or multiple EBPs, could be necessary. To our knowledge, this is the first comprehensive study to bring up this issue in SIH, although the findings need to be confirmed by other research groups.
The strengths of the present study included the sample size, reliability of the data, and generalizability to ordinary SIH patients. The current study recruited a relatively large cohort of SIH patients (n = 442), which deserves special attention, particularly for a disease that is uncommon.32 A large sample size could reduce selection bias, and provides a panoramic view of the disease. Besides, the evaluation and treatment of these patients were carried out with a standardized protocol. Therefore, the data were of high quality and reliability. In addition, 93.7% (n = 414) of the patients had not been treated with EBP before the initial presentation to our hospital. Therefore, the results of the current study could have more practical implications for physicians treating SIH patients associated with spinal CSF leaks at the initial encounter.
It was found that SIH in men was characterized by a delayed presentation, and the average intervals between the disease onset and initial hospital presentation in men were nearly twice as long as those in women. The finding was in keeping with a study from Japan (n = 40), in which it took longer for men to make the first consultation.33 Besides, in the present study, men were less likely to have nausea, vomiting, photophobia, and tinnitus despite similar severities of headache, structural changes in the brain, and spinal CSF leakages. In fact, the overall percentages of patients reporting individual associated symptoms in our study were similar to those reported in the literature,1,20 although whether there could be sex differences has rarely been looked upon specifically. However, such sex differences in headache-associated symptoms were similar to those observed in migraine.12,34,35 It is possible that women could be more sensitive or susceptible to pathophysiological changes in SIH such that they might develop more prominent clinical manifestations and seek medical attention earlier.
Men with SIH had poorer response to the first EBP when compared to women, although the disparity between the sexes was no longer present after the second EBP (Fig. 3). The underlying mechanisms were uncertain, although anatomical characteristics in women are likely to play an important role. In the process of EBP, autologous blood injected in the epidural space is supposed to “patch” the dural defects,36,37 and a larger EBP volume typically results in a better treatment response.20,38 Since women typically have smaller spinal canals,36,37 it would be easier to seal and tamponade the dural defects despite smaller EBP volumes in women than in men. On the other hand, it is worth emphasizing the importance of repeat EBPs in those not responding to the first attempt. In the literature, the responder rates to up to two EBPs ranged from 53–95%, and estimates reported in Asian countries (87.2%-95%)39,40, including the current report, were generally higher than those in Caucasians (53–77%)41–43. The discrepancy in responder rates could be attributed to differences in methodology, and possibly ethnicity. For instance, although spinal meningeal diverticula (42.3%) were the most common cause for SIH in a large US series (n = 568),21 they were relatively uncommon (1.4%) in the current cohort, which was consistent with our prior report.26 Further studies are needed to better characterize such ethnic differences. Nevertheless, for patients not responding to the first EBPs, repeat EBPs should be a reasonable option before considering more invasive measures, such as surgical repair. In particular, the cumulative response rate to up to four EBPs was 99.2% in the current cohort.
In the present study, men with SIH were at a higher risk of developing SDH as a complication. In patients who developed SDH, the maximal thickness of SDH and the likelihood of having surgical drainage were both greater in men than in women. In contrast to the female preponderance in the occurrence of SIH, it was found that the male gender increased the odds of having SDH to 3.5 folds when compared with the female gender. The finding was independent of age and delays in presentation, and was consistent with some prior reports.5,33,44 In fact, SDH in general is also more common in men than in women.45,46 A recent study from China reported the male gender appeared to be a risk factor for SDH in univariable but not multivariable analysis.47 However, the study included only 25 SIH patients with SDH, and might not be adequately powered to identify sex differences. On the other hand, it remains uncertain whether men with SIH were also at risk of developing CVT as a complication since only a limited number of patients (n = 8, 1.8%) in the current series developed CVT. Of note, in the current study, it was found that the male gender was associated with not only the risk of SDH, but also a more-than-10-fold increase in the odds of having surgical drainage in patients who developed SDH, as well as a poorer outcome. After excluding the only female patient who expired due to the underlying malignancy, both of the remaining two cases with mortality or significant disability were men. In fact, the findings were consistent with a prior report on coma as a complication of SIH, which was more much more common in men (n = 12/207) than in women (n = 3/376).48 Therefore, SIH in men should be managed with a high level of caution in light of the frequently delayed presentation, higher risks of SDH, and potentially poorer neurological outcome. Early EBPs may be considered as the first-line treatment for men with SIH, rather than being reserved until conservative treatment fails. Besides, more aggressive measures, such as multiple EBPs, may be considered for men with SIH. Even though men tended to have poorer response to the first EBP, such a sex-related difference was amenable to repeated attempts.
This study had some limitations. First, the results were from a single headache center, and selection bias could be a concern. However, in our healthcare system, patients could have direct access to our hospital without a referral. Therefore, our data could reflect the general condition of SIH patients to a great extent. Besides, the majority of cases (93.7%) were not treated with EBP before the initial presentation to our hospital, and the findings could be more applicable to the initial evaluation and management of SIH in the acute setting. Second, the treatment response seemed to be better than that in some other series, and cases receiving surgical repair of CSF leaks were relatively uncommon. As most Taiwanese patients are more conservative or even cautious about surgical interventions, multiple EBPs were preferred over surgical repair. Besides, the treatment response to multiple EBPs was comparable to some other series.39,40,43 Third, cases with CSF-venous fistula appeared to be under-presented in the present series. It is possible that such a condition was under-diagnosed since neither digital subtraction myelography49 nor CT myelography50 was performed in the majority of our cases. However, ethnic differences could also be an important factor. As mentioned above, the proportions of patients with meningeal diverticula are very different between a US cohort21 and the current series (42.3% vs. 1.4%), and the majority of our patients had type I CSF leaks, i.e., dural tears. Whether our findings could be generalizable to patients with other types of CSF leaks need to be further clarified.