Higher Plasma Osteopontin Concentrations Associated with Subsequent Development of Chronic Shunt-Dependent Hydrocephalus After Aneurysmal Subarachnoid Hemorrhage

概要

Introduction
Chronic hydrocephalus is one of the most encountered sequelae among patients who suffered from aneurysmal subarachnoid hemorrhage (SAR). Osteopontin (OPN) is a matricellular protein, which is an inducible, secretable and multifunctional glycoprotein. In experimental SAR, OPN has been reported to be neuroprotective by suppressing neuronal apoptosis, blood・brain barrier (BBB) disruption, microcirculatory dysfunctions and cerebral vasospasm. In a clinical setting, severer SAR induced more OPN in peripheral blood and cerebrospinal fluid (CSF) in an acute phase of SAR, and it was suggested that increased OPN might have healing effects on the preceding tissue injuries. OPN is also known to be upregulated by inflammation and oxidative stress, and redundant OPN is reported to promote excessive fibrosis in lung and heart.

Background
A matricellular protein osteopontin is considered to exert neuroprotective and healing effects on neurovascular injuries in an acute phase of aneurysmal subarachnoid hemorrhage. However, the relationships between OPN expression and chronic shunt-dependent hydrocephalus (SDHC) have never been investigated.

Objectives
In this study, the authors hypothesized that prolonged OPN expression may contribute to the development of chronic shunt-dependent hydrocephalus, and aimed to examine if prolonged higher plasma levels of OPN is related to the occurrence of chronic SDHC after aneurysmal SAH.

Methods
In 166 SAH patients (derivation and validation cohorts, 110 and 56, respectively), plasma OPN levels were serially measured at daysl-3, 4-6, 7-9, and 10-12 after aneurysmal obliteration. The OPN levels and clinical factors were compared between patients with and without subsequent development of chronic SDHC.

Results
Plasma OPN levels in the SDHC patients increased from days 1・3 to days 4・6 and remained high thereafter, while those in the non-SDHC patients peaked at days 4・6 and then decreased over time. Univariate analyses showed that age, modified Fisher grade, acute hydrocephalus, cerebrospinal fluid drainage, plasma OPN and serum C・reactive protein levels at days 10・12 were significantly different between patients with and without SDHC. Multivariate analyses revealed that higher plasma OPN levels at days 10・12 was an independent factor associated with the development of SDHC, in addition to a more frequent use of cerebrospinal fluid drainage and higher modified Fisher grade at admission.

Consideration
Prolonged higher expression of OPN may contribute to the development of post・ SAH SDHC, possibly by excessive repairing effects promoting fibrosis in the subarachnoid space.