Background/Objectives: The outcome for aneurysmal subarachnoid hemorrhage (SAH) remains poor, particularly for patients presenting with World Federation of Neurological Surgeons (WFNS) grades IV–V. This study was designed to identify independent prognostic factors in this group of patients with poor-grade SAH. Methods: We prospectively analyzed 357 SAH patients with admission WFNS grades IV–V enrolled in nine primary stroke centers in Mie prefecture, Japan, from 2013 to 2022. This study compared clinical variables, including treatments for angiographic vasospasm and delayed cerebral ischemia (DCI), between patients with favorable (modified Rankin Scale [mRS] scores 0–2) and unfavorable (mRS scores 3–6) outcomes at 90 days post-onset. Multivariate analyses were then performed to identify independent determinants of favorable 90-day outcomes, followed by propensity score matching analyses. Results: The median age was 68 years, and 53.5% of patients had admission WFNS grade V. DCI occurred in 12.9% of patients, and 66.9% had unfavorable outcomes. Independent variables related to unfavorable outcomes were older age, admission WFNS grade V, ventricular drainage, edaravone administration, and delayed cerebral infarction, while those for favorable outcomes were spinal drainage (adjusted odds ratio [aOR] 6.118, 95% confidence interval [CI] 2.687–13.927, p < 0.001), modified Fisher grade 3 (aOR 2.929, 95% CI 1.668–5.143, p < 0.001), and triple prophylactic anti-DCI medication consisting of cilostazol, fasudil hydrochloride and eicosapentaenoic acid (aOR 1.869, 95% CI 1.065–3.279, p = 0.029). Nimodipine is not approved in Japan, and statin and cerebral vasospasm did not influence outcomes. As spinal drainage and the triple prophylactic anti-DCI medication were intervenable variables, propensity score matchings were performed, and they confirmed that both spinal drainage and the triple prophylactic anti-DCI medication were useful to achieve favorable outcomes. Conclusions: In poor-grade SAH, spinal drainage and the triple prophylactic anti-DCI medication may be effective in improving outcomes, possibly by suppressing DCI pathologies other than cerebral vasospasm.

Subarachnoid hemorrhage (SAH) due to ruptured cerebral aneurysms is the most severe form of stroke, and treatment outcomes remain poor. Brain damage after SAH can be broadly divided into early brain injury (EBI) and delayed cerebral ischemia (DCI). Although the causes of these events are multifactorial, free hemoglobin generated after hemolysis in the subarachnoid space is believed to be one of the most important causative factors. Recently, cerebral lymphatic vessels, previously thought to be non-existent, have been identified, suggesting their involvement not only in maintaining homeostasis but also in brain injury. Furthermore, new findings have been reported regarding cerebrospinal fluid (CSF) circulation. Because intracranial CSF circulation and lymphatic drainage to the extracranial blood and lymphatic vessels affect free hemoglobin metabolism in the CSF, these factors are likely to affect EBI and DCI. In addition, matricellular protein tenascin-C, which we have reported to be involved in the pathogenesis of EBI and DCI, has been reported to inhibit lymphatic vessel proliferation in non-central nervous system pathologies. However, the relationship between post-SAH brain injury and intracranial lymphatics remains unknown. This review aimed to summarize recent findings regarding intracranial lymphatics and CSF circulation and to discuss how they may affect post-SAH pathology.

Osteopontin (OPN), a matricellular protein, is produced as a full-length OPN (FL-OPN) and cleaved by thrombin, thus generating the N-terminal half of OPN (OPN N-half) with new functions. Although plasma FL-OPN levels have been associated with neurovascular events after aneurysmal subarachnoid hemorrhage (SAH), plasma OPN N-half levels have never been investigated. In this study, prospective clinical data and plasma samples were collected from 108 consecutive SAH patients with ruptured aneurysms undergoing acute treatment via surgery, and FL-OPN and OPN N-half levels were measured in plasma with a particular focus on delayed cerebral infarction (DCIn), which has the greatest impact on outcomes. Plasma FL-OPN and OPN N-half levels were intercorrelated and significantly higher in patients with DCIn at days 10–12 post-SAH; a greater area under the receiver-operating characteristic curve was observed for OPN N-half levels, with a cut-off value of 70.42 pmol/L. Multivariate analyses revealed that plasma OPN N-half levels of ≥70.42 pmol/L at days 10–12 were independently associated with DCIn development (adjusted odds ratio, 5.65; 95% confidence interval, 1.68–18.97; p = 0.005). Based on the findings of this study and previous reports, an increase in the OPN N-half level may be indicative of a protective mechanism against DCIn development, and, thus, it holds promise as a new therapeutic target against DCIn after aneurysmal SAH.

Shunt-dependent hydrocephalus (SDHC) is a delayed complication of aneurysmal subarachnoid hemorrhage (SAH), and meningeal fibrotic remodeling may contribute to its development. Secreted protein acidic and rich in cysteine (SPARC) regulates collagen processing and extracellular matrix organization. We examined whether serial plasma SPARC concentrations were associated with subsequent SDHC development. We retrospectively analyzed prospectively collected data from 186 patients with aneurysmal SAH enrolled in a multicenter registry. Plasma SPARC was measured at days 1–3, 4–6, 7–9, and 10–12 and analyzed using log-scale linear mixed-effects models. SDHC developed in 54 patients (29.0%). Model-estimated SPARC concentrations increased across periods in both SDHC and no-SDHC groups without a significant SDHC-by-period interaction, whereas all the SDHC/no-SDHC geometric mean ratios were below 1. The clearest difference occurred at days 4–6 and remained significant after adjustment for age, admission World Federation of Neurological Surgeons grade V, modified Fisher grade 4, and acute hydrocephalus (geometric mean ratio, 0.73; 95% confidence interval, 0.57–0.93; Holm-adjusted p = 0.040). In a post hoc exploratory multivariable analysis, each 10 ng/mL increase in SPARC at days 4–6 was associated with lower odds of subsequent SDHC development (adjusted odds ratio, 0.91; 95% confidence interval, 0.84–0.98; p = 0.011). Lower plasma SPARC concentrations, particularly at days 4–6, were associated with subsequent SDHC development.