The occurrence and prevention of CSF leakage: Application of a patch in different neurosurgical indications

Abstract

This Ph.D. thesis describes further applications of a novel dural sealant patch to prevent cerebrospinal fluid (CSF) leakage. CSF leakage is a well-known complication after neurosurgical procedures. To mitigate the risk of CSF leakage a novel medical device to prevent CSF leakage, Dura Sealant Patch (DSP) (Liqoseal®, Polyganics B.V. Groningen, The Netherlands), was developed to augment watertight dural closure after suturing. We have described the health-economic consequences of CSF leakage after cranial surgery from a hospital perspective in the Netherlands. Mean cost difference between patients with and without CSF leakage was €9,665 (95%-Confidence Interval (CI), €5,125 to €14,205). This study furthermore modelled the potential cost savings if CSF leakage were to be reduced. A maximum cost reduction of -€653,025 (95% CI -€ 1,204,243 to -€169,120) per 1,000 patients could be achieved if CSF leakage would be reduced with 75% in all patients, with 72 cases of CSF leakage avoided. The protocol of a randomized-controlled trial evaluating the safety and efficacy of DSP as compared to standard of care, which is currently carried out, is presented. This study aims to recruit 228 patients undergoing elective infratentorial surgery and is designed as a non-inferiority trial. We have provided provides a bench mark of the incidence of CSF leakage after transsphenoidal surgery (3.4%), a form of cranial surgery in a meta-analysis of recent studies. Furthermore, the results of ex vivo experiments of application of DSP in a transsphenoidal procedure and application of DSP as a salvage treatment in 3 patients are presented. The burst pressure of DSP in this transsphenoidal model is well above physiological intracranial pressure. None of the patients had a postoperative CSF leakage. An in vivo pig model was used to evaluate safety of spinal implantation of DSP. The comparison of spinal MRI and histological data showed similar reactions to DSP as a previous cranial porcine model. This thesis furthermore comprises studies evaluating incidence and risk factors of CSF leakage in the pediatric patients. The results of our meta-analysis show a wide interval of presumed risk of CSF leakage in children (0-38%) with an average risk of 4.4%. Two subsequent multi-center, international, historical cohort studies including cranial cases and spinal cases, respectively, are presented. We found that the incidence of CSF leakage after cranial surgery in children is comparable to that in adults (7.5%). Craniectomy and hydrocephalus were identified as independent risk-factors. CSF leakage after intradural spinal surgery, on the other hand, was relatively rare (2.7%). Nevertheless, the clinical consequences with respect to secondary complications such as infection, necessity for invasive treatment and prolonged hospitalization are serious. The findings presented in this thesis indicate the need for effective preventative strategies for CSF leakage. Such preventative strategies may also be beneficial from an economic perspective. DSP proofs safe and potentially efficacious for cranial use, including transsphenoidal procedures, in adults. Furthermore, this thesis has laid the ground work for future clinical studies for spinal use and use in pediatric population.