Preventive effects of cilostazol against the development of shunt-dependent hydrocephalus after subarachnoid hemorrhage

Abstract

OBJECTIVE Chronic hydrocephalus develops in association with the induction of tenascin-C (TNC), a matricellular protein, after aneurysmal subarachnoid hemorrhage (SAH). The aim of this study was to examine if cilostazol, a selective inhibitor of phosphodiesterase Type III, suppresses the development of chronic hydrocephalus by inhibiting TNC induction in aneurysmal SAH patients. METHODS The authors retrospectively reviewed the factors influencing the development of chronic shunt-dependent hydrocephalus in 87 patients with Fisher Grade 3 SAH using multivariate logistic regression analyses. Cilostazol (50 or 100 mg administered 2 or 3 times per day) was administered from the day following aneurysmal obliteration according to the preference of the attending neurosurgeon. As a separate study, the effects of different dosages of cilostazol on the serum TNC levels were chronologically examined from Days 1 to 12 in 38 SAH patients with Fisher Grade 3 SAH. RESULTS Chronic hydrocephalus occurred in 12 of 36 (33.3%), 5 of 39 (12.8%), and 1 of 12 (8.3%) patients in the 0 mg/day, 100 to 200 mg/day, and 300 mg/day cilostazol groups, respectively. The multivariate analyses showed that older age (OR 1.10, 95% CI 1.13-1.24; p = 0.012), acute hydrocephalus (OR 23.28, 95% CI 1.75-729.83; p = 0.016), and cilostazol (OR 0.23, 95% CI 0.05-0.93; p = 0.038) independently affected the development of chronic hydrocephalus. Higher dosages of cilostazol more effectively suppressed the serum TNC levels through Days 1 to 12 post-SAH. CONCLUSIONS Cilostazol may prevent the development of chronic hydrocephalus and reduce shunt surgery, possibly by the inhibition of TNC induction after SAH.

Inflammation: a Good Research Target to Improve Outcomes of Poor-Grade Subarachnoid Hemorrhage

“…A local environment such as extracellular pH is reported to affect tenascin-C's function [1,38], and the functional relationships between tenascin-C and other matricellular proteins such as galectin-3 [1], periostin [39][40][41], and osteopontin [42,43] should be also investigated in EBI and delayed cerebral ischemia. An antiplatelet cilostazol inhibited post-SAH tenascin-C induction [44] and improved outcomes associated with reduced incidence of delayed cerebral infarction in a clinical setting [3].…”

Quantitative versus qualitative blood amount assessment as a predictor for shunt-dependent hydrocephalus following aneurysmal subarachnoid hemorrhage

“…As reported by many authors, acute hydrocephalus is an independent factor directly related to SDHC. 8,28,39 Blood location, specifically in the third and fourth ventricles, plays a critical role in prognosis and SDHC development. 16,33,39 Therefore, mGraeb is a robust predictive model because it integrates several independent risk factors for SDHC in one scale: blood quantity, blood location, and acute hydrocephalus.…”

“…A recent report by Nakatsuka et al suggested the use of cilostazol, an inhibitor of phosphodiesterase, as a preventive treatment for SDHC in SAH patients. 28 In a retrospective review of 87 patients they found that the incidence of SDHC was significantly lower in the groups receiving ci-lostazol (8.3%-12.8% vs 33.3%; p < 0.05). Microsurgical fenestration of the lamina terminalis has also been pointed out as a strategy to reduce SDHC incidence.…”

The Role of Periostin in Brain Injury Caused by Subarachnoid Hemorrhage

“…The treatment target could be periostin itself, or the receptor integrins and the related molecules. In order to inhibit the post-aSAH induction of a representative of the periostin-related protein tenascin-C, cilostazol was used in a clinical setting of aSAH and promising efficacy was found [73,74]. In consideration of the diverse signal transduction associated with periostin, it is believed that periostin may be involved in multiple pathophysiologies other than the blood-brain barrier disruption in aSAH.…”