Aneurysmal subarachnoid hemorrhage (SAH) constitutes a devastating and life-threatening neurosurgical emergency with an estimated global incidence of 9.1 per 100,000 individuals per year (1,2). Due to its catastrophic short-term complications, SAH remains a major cause of morbidity and mortality worldwide, even though novel diagnostic and treatment techniques have been developed over the past decades. Indeed, during the early stages of aneurysmal SAH, there is a high risk of re-bleeding, hydrocephalus, intracerebral hematoma, generalized cerebral edema and vasospasm, while long-term complications include delayed cerebral ischemia (DCI) (3-5).

The severity of the clinical presentation upon admission, re-bleeding, the timing of the surgery and the type of treatment are predictors of neurological outcomes and SAH-related disability (6,7). Furthermore, patients with higher Hunt and Hess grades (grades 4 and 5) upon admission, particularly the elderly, are more likely to have poor clinical outcomes (8).

Upon the diagnosis of a ruptured intracranial aneurysm, the main goal is to secure the aneurysm as soon as possible to prevent re-bleeding. Before the 1990s, microsurgical clipping was the only available treatment option for ruptured intracranial aneurysms and while it still confers satisfactory long-term results regarding re-operation rates, it is characterized by high peri-operative complications and long periods of hospitalization (4,5,9,10). On the other hand, the introduction of endovascular treatment has led to lower peri-interventional complication rates; however, this is associated with a higher rate of incomplete occlusion and in-hospital case fatalities (11,12).

The timing of the surgery plays a crucial role concerning the risk of re-bleeding and mortality rates, particularly in patients with a good clinical condition upon admission (13-16). Over a number of years, there has been a debate as regards the most suitable timing of surgery (17,18). The early clipping of the cerebral aneurysm may permit for the secure preface of hypertensive management prevented at the development and/or treatment of DCI (14). On the other hand, delayed surgical management may decrease the morbidity and mortality of the microsurgical intervention due to improvements in surgical conditions and the general condition of individual patients, mainly in those with higher Hunt and Hess grades (grades 4 and 5) upon admission (13).

The present retrospective study aimed to investigate the association between the timing of treatment and the outcomes of patients who underwent the clipping of ruptured intracranial aneurysms. The present study and also aimed to provide contemporary data for a more balanced approach when assessing the optimal treatment strategy for a given aneurysm, microsurgical vs. endovascular, when both options are available.

Patient population and aneurysm characteristics. A retrospective analysis of 92 of 142 consecutive patients who were diagnosed with anterior circulation ruptured aneurysms and treated only by microsurgical clipping was conducted between January, 2013 and December, 2018 (AHEPA University Hospital, Aristotle University School of Medicine, Thessaloniki, Greece).

The study protocol was approved by the Ethics Committee of the hospital-(AHEPA University Hospital, Aristotle School of Medicine Thessaloniki, Greece; Ref. no. 1085-2023). In compliance with the current legislation, the National Data Protection Authority was notified on its conduction (Ref. no. 985-2024). The study was conducted in accordance with the ethical standards laid down in the Declaration of Helsinki 1964 and its later amendments. Written informed consent was obtained from all included patients or their next-of-kin prior to surgery. All patients were >18 years of age.

Patients with posterior circulation aneurysms and non-saccular aneurysms were excluded from the study. In the final pool, 92 patients were included, and these patients were divided into two groups. Data collection was performed, and the data were reviewed and analyzed by two physicians (GF and DP) based on the following inclusion criteria: Patients aged >18 years who underwent microsurgical clipping for ruptured anterior circulation aneurysm between 2013 and 2018. Cases with incomplete medical files and cases lost to follow-up were excluded (Fig. 1).

Demographic data including age, sex, comorbidities and post-operative outcomes were collected prospectively. Baseline characteristics included age, sex, risk factors, aneurysm size and location, clinical presentation upon admission, Fisher grade, and the timing of surgery (Table I). Risk factors for aneurysm formation and rupture, including hypertension, diabetes mellitus, hypercholesterolemia and smoking were documented and the data are also presented in Table I. The clinical presentation of the patient upon admission was assessed according to Hunt and Hess grading scale (Table I). Clinical status upon admission was dichotomized as good (grade ≤2) and severe (grade ≥3). At the emergency department, all patients underwent urgent Computed Tomography (CT) angiography. Aneurysm location, size, and extent of SAH according to Fisher grading scale were documented and the presence of multiple aneurysms was also investigated (Table I). The timing of the surgery was dichotomized as early (within the first 3 days after SAH) and late (after ≥4 days).

The results of the present study demonstrated that the outcomes of patients who underwent microsurgical clipping for ruptured anterior circulation aneurysms ≥3 days after admission or rupture occurrence, exhibited favorable outcomes compared to patients operated on during the first 2 days of occurrence. The good clinical condition concerning SAH-related complications (no complications); the development of post-operative hemiplegia related to DCI, and mortality were all independent factors associated with good outcomes (≥2 mRS). In addition, even though the majority of the cases (78.4%) were admitted with Fisher grading scale 3 or 4, in the present study the mortality rate was 16.3%. On the other hand, risk factors for aneurysm formation and rupture, including hypertension, diabetes mellitus, hypercholesterolemia and smoking were not statistically significant parameters reinforcing the initial hypothesis that the timing of the surgery plays a role in patient outcomes.

Early surgery, within the first 3 days, seems to be associated with lower likelihood of a positive outcome, especially in those patients in good clinical condition on admission [13]. For this reason, most centers now intend to operate on an aneurysm within two days of the SAH (20,21). However, microsurgical management for aneurysmal SAH may be more dangerous during this two-day interval, and thus treatment management must comprise contemplations concerning the risk of re-hemorrhage (20). In addition, for these patients, who are only suitable for surgery three days after SAH, it is significant to identify the most favorable timing for aneurysm clipping occlusion, i.e. whether it should be until 14 days after SAH (22). In the present study, surgical morbidity and mortality, between patients submitted to early, intermediate, or late surgery, was statistically significant, with patients who underwent surgical aneurysm repair in an interval ≥3 days indicating a more favorable outcome.

On the other hand, there were studies that the timing of surgery did not have a significant role in surgical outcomes, apart from clinical condition on admission (15,23). Additional subgroup analysis proposed a tendency that recommended greater advantages with early intervention, which, in other words, encouraged a policy of surgery as early as possible (23). In addition, based on these results, it was recommended that clipping between five and ten days after the event of aneurysmal rupture did not lead to a higher possibility of DCI (22). Instead, operating on the swollen and vulnerable brain tissue led to high rates of perioperative complications (24). The present study demonstrated that clinical outcomes were improved when aneurysm occlusion was performed at a later stage after SAH after differences. It is imperative to understand that patients were not randomized for the timing of the surgery, and the unfavorable outcome in the group of patients operated on in the early stages, was possibly associated with the causes of the post-operative condition, such as a poor clinical condition on admission, early re-hemorrhage, or early worsening from other reasons. Notably, in the present study, re-bleeding did not occur more often in patients operated on after day 3, and this is a critical factor when deciding on patients' management.

A previous study on endovascular management report that the embolization of ruptured intracranial aneurysms can be applied safely to patients who were admitted between post-hemorrhage days 4 and 10, with no significant increase in mortality, and regardless of a higher risk of vasospasm at the time of treatment (25). In the present study, the mortality rate was lower in those patients who were operated on 3 days after aneurysm rupture occurrence.

The present study had several limitations, such as that it was a retrospective study of medical records analysis and was performed in a single center with a limited number of cases. In addition, the neurological outcomes of patients with SAH is dependent on the underlying initial pathology and the subsequent vasospasm. Another limitation was the restrictions concerning the lack of inclusion of patients presenting with a worse overall clinical condition.

In conclusion, the present study revealed that the outcomes of patients who underwent microsurgical clipping for ruptured anterior circulation aneurysms ≥3 days after admission or rupture occurrence, exhibited favorable outcomes compared to patients operated on during the first 2 days of occurrence. The good clinical condition concerning SAH-related complications (no complications), the development of post-operative hemiplegia related to DCI and mortality were all independent factors associated with good outcomes. In addition, even though the majority of the cases were admitted with Fisher grading scale scores of 3 or 4, in the present study, the mortality rate was 16.3%. Although the endovascular treatment of anterior circulation ruptured aneurysms, during the past years, has been the treatment of choice following SAH, clipping may be considered a valid alternative.