ABSTRACT
BACKGROUND: The molecular mechanisms underlying development of posthemorrhagic hydrocephalus (PHH) following subarachnoid hemorrhage (SAH) remain incompletely understood. Consequently, treatment strategies tailored towards the individual patient remain limited. This study aimed to identify proteomic cerebrospinal fluid (CSF) biomarkers capable of predicting shunt dependency and functional outcome in patients with SAH in order to improve informed clinical decision making. METHODS: Ventricular CSF samples were collected twice from 23 patients with SAH who required external ventricular drain (EVD) insertion (12 patients with successful EVD weaning, 11 patients in need of permanent CSF shunting due to development of PHH). The paired CSF samples were collected acutely after ictus and later upon EVD removal. Cisternal CSF samples were collected from 10 healthy control subjects undergoing vascular clipping of an unruptured aneurysm. All CSF samples were subjected to mass spectrometry-based proteomics analysis. Proteomic biomarkers were quantified using area under the curve (AUC) estimates from a receiver operating curve (ROC). RESULTS: CSF from patients with SAH displayed a distinct proteomic profile in comparison to that of healthy control subjects. The CSF collected acutely after ictus from patients with SAH was moreover distinct from that collected weeks later but appeared similar in the weaned and shunted patient groups. Sixteen unique proteins were identified as potential predictors of shunt dependency, while three proteins were identified as potential predictors of functional outcome assessed six months after ictus with the modified Rankin Scale. CONCLUSIONS: We here identified several potential proteomic biomarkers in CSF from patients with SAH capable of predicting (i) shunt dependency and thus development of PHH and (ii) the functional outcome assessed six months after ictus. These proteomic biomarkers may have the potential to aid clinical decision making by predicting shunt dependency and functional outcome following SAH.
ABSTRACT
BACKGROUND: Insertion of an external ventricular drain (EVD) is a first-line treatment of acute hydrocephalus caused by aneurysmal subarachnoid haemorrhage (aSAH). Once the patient is clinically stable, the EVD is either removed or replaced by a permanent internal shunt. The optimal strategy for cessation of the EVD is unknown. Prompt closure carries a risk of acute hydrocephalus or redundant shunt implantations, whereas gradual weaning may increase the risk of EVD-related infections. METHODS: DRAIN (Danish RAndomised Trial of External Ventricular Drainage Cessation IN Aneurysmal Subarachnoid Haemorrhage) is an international multicentre randomised clinical trial comparing prompt closure versus gradual weaning of the EVD after aSAH. The primary outcome is a composite of VP-shunt implantation, all-cause mortality, or EVD-related infection. Secondary outcomes are serious adverse events excluding mortality and health-related quality of life (EQ-5D-5L). Exploratory outcomes are modified Rankin Scale, Fatigue Severity Scale, Glasgow Outcome Scale Extended, and length of stay in the neurointensive care unit and hospital. Outcome assessment will be performed 6 months after ictus. Based on the sample size calculation (event proportion 80% in the gradual weaning group, relative risk reduction 20%, alpha 5%, power 80%), 122 participants are required in each intervention group. Outcome assessment for the primary outcome, statistical analyses, and conclusion drawing will be blinded. Two independent statistical analyses and reports will be tracked using a version control system, and both will be published. Based on the final statistical report, the blinded steering group will formulate two abstracts. CONCLUSION: We present a pre-defined statistical analysis plan for the randomised DRAIN trial, which limits bias, p-hacking, and data-driven interpretations. This statistical analysis plan is accompanied by tables with simulated data, which increases transparency and reproducibility. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03948256. Registered on May 13, 2019.
Subject(s)
Drainage , Hydrocephalus , Randomized Controlled Trials as Topic , Subarachnoid Hemorrhage , Humans , Subarachnoid Hemorrhage/complications , Subarachnoid Hemorrhage/surgery , Subarachnoid Hemorrhage/therapy , Hydrocephalus/etiology , Hydrocephalus/surgery , Drainage/adverse effects , Drainage/methods , Treatment Outcome , Time Factors , Multicenter Studies as Topic , Data Interpretation, Statistical , Quality of Life , Denmark , Ventriculoperitoneal Shunt/adverse effectsABSTRACT
Introduction: Telemetric monitoring of intracranial pressure (ICP) in children with a complex cerebrospinal disorder might help parents distinguish acute and potential life-threatening symptoms of hydrocephalus from other illnesses. Research question: What is patient and parent perceptions of system utility of telemetric ICP monitoring, and how does a long-term telemetric implant influence daily life of both patients and their families? Material and methods: A qualitative case study design with a focus group interview including parents of children with a complex cerebrospinal fluid disorder and an implanted telemetric ICP sensor. Results: Three parents participated. Based on thematic analysis, three themes were created: 'Daily living with telemetric ICP monitoring', 'Parenting a child with a CSF disorder', and 'The healthy sibling'. The ICP sensor provided the parents with security and made them trust their intuition, while the possibility of home monitoring ensured stability for the entire family and had a calming effect on healthy siblings. Home monitoring was seen as the system's greatest advantages, whereas size, weight, and functionality of the external monitoring equipment were highlighted as disadvantages. Discussion and conclusion: All parents supported the telemetric ICP sensor as a valued tool in treatment guidance of their child and stated that advantages exceeded disadvantages. It was stated that the possibility of conducting ICP measurements at home reduced the need for acute hospital admissions, which consequently led to a more stable daily life for the entire family. Suggestions regarding technical improvements with focus on more compatible external monitoring equipment were raised by all parents included.
ABSTRACT
OBJECTIVE: Optimizing the treatment of several neurosurgical and neurological disorders relies on knowledge of the intracranial pressure (ICP). However, exploration of normal ICP and intracranial pressure pulse wave amplitude (PWA) values in healthy individuals poses ethical challenges, and thus the current documentation remains scarce. This study explores ICP and PWA values for healthy adults without intracranial pathology expected to influence ICP. METHODS: Adult patients (age > 18 years) undergoing surgery for an unruptured intracranial aneurysm without any other neurological co-morbidities were included. Patients had a telemetric ICP sensor inserted, and ICP was measured in four different positions: supine, lateral recumbent, standing upright, and 45-degree sitting, at day 1, 14, 30, and 90 following the surgery. RESULTS: ICP in each position did not change with time after surgery. Median ICP was 6.7 mmHg and median PWA 2.1 mmHg in the supine position, while in the upright standing position median ICP was - 3.4 mmHg and median PWA was 1.9 mmHg. After standardization of the measurements from the transducer site to the external acoustic meatus, the median ICPmidbrain was 8.3 mmHg in the supine position and 1.2 mmHg in the upright standing position. CONCLUSION: Our study provides insights into normal ICP dynamics in healthy adults following a uncomplicated surgery for an unruptured aneurysm. These results suggest a slightly wider normal reference range for invasive intracranial pressure than previously suggested, and present the first normal values for PWA in different positions. Further studies are, however, essential to enhance our understanding of normal ICP. Trial registration The study was preregistered at www. CLINICALTRIALS: gov (NCT03594136) (11 July 2018).
Subject(s)
Intracranial Aneurysm , Intracranial Pressure , Adult , Aged , Female , Humans , Male , Middle Aged , Intracranial Aneurysm/surgery , Intracranial Aneurysm/physiopathology , Intracranial Pressure/physiology , Neurosurgical Procedures , Posture/physiology , Pulse Wave Analysis , Prospective StudiesABSTRACT
PURPOSE: Telemetric monitoring of intracranial pressure (ICP) facilitates long-term measurements and home monitoring, thus potentially reducing diagnostic imaging and acute hospital admissions in favour of outpatient appointments. Especially in paediatric patients, telemetric ICP monitoring requires a high level of collaboration and compliance from patients and parents. In this study, we aim to systematically investigate (1) patient and parent perception of telemetric ICP system utility and (2) hospital contact history and thus the potential cost-benefit of telemetric ICP monitoring in paediatric patients with a cerebrospinal fluid disorder. METHODS: We conducted a nationwide questionnaire study, including paediatric patients with either a current or previous telemetric ICP sensor and their parents. Additionally, a retrospective review of electronic health records for all included children was performed. RESULTS: We included 16 children (age range 3-16 years), with a total of 41 telemetric ICP sensors implanted. Following sensor implantation, the frequency of telephone contacts and outpatient visits increased. No corresponding decrease in hospital admissions or total length of stay was found. The telemetric ICP sensor provided most parents with an improved sense of security and was seen as a necessary and valuable tool in treatment guidance. The size and shape of the sensor itself were reported as disadvantages, while the external monitoring equipment was reported as easy to use but too large and heavy for a child to carry. CONCLUSION: Though, in quantitative terms, there was no cost-benefit of the telemetric ICP sensor, it contributed to extended parental involvement and a sense of improved safety.
Subject(s)
Intracranial Pressure , Telemetry , Humans , Child , Adolescent , Female , Male , Child, Preschool , Intracranial Pressure/physiology , Surveys and Questionnaires , Telemetry/methods , Retrospective Studies , Monitoring, Physiologic/methods , Monitoring, Physiologic/instrumentation , ParentsABSTRACT
BACKGROUND: No standard has been established regarding timing and choice of strategy for discontinuation of external ventricular drainage (EVD) in patients with aneurysmal subarachnoid haemorrhage (aSAH), and little is known about the importance of clinical variables. A proportion of the patients who initially pass their discontinuation attempt return with delayed hydrocephalus and the need of a permanent shunt. Early differentiation between patients who need a shunt and those who do not would facilitate care. We conducted a retrospective analysis on patients with aSAH and an EVD to search significant differences in treatment and clinical variables between patients who received a permanent shunt during initial hospitalization or after readmission, and those who never received a shunt. METHODS: We included 183 patients with aSAH who received an EVD over a 4-year period between 2015 and 2018 and divided them into three groups: those who received a shunt during primary admission, those who were readmitted for delayed hydrocephalus and received a shunt, and those who never needed a shunt. Between these groups, we compared selected clinical variables as well as outcome at discharge and after 6 months. Additionally, we assessed the ability of a shunt dependency score (SDASH) to predict the need for permanent drainage in the patients. RESULTS: Of 183 included patients, 108 (59%) ultimately received a ventriculoperitoneal (VP) shunt. Of these, 89 (82%) failed discontinuation during the primary admission and received a permanent shunt before discharge from the neurosurgical department. The remaining 19 (18%) were discharged after successful discontinuation, but subsequently developed delayed hydrocephalus and were admitted for shunt placement a median of 39 (range: 18-235) days after ictus. Ninety-four patients were discharged after successful discontinuation of the EVD, consisting of those who never developed the need for a permanent shunt and the 19 who were readmitted with delayed hydrocephalus, corresponding to a 20% (19/94) readmittance rate. Clinical variables such as drainage volume or discontinuation strategy did not differ across the three groups of patients. The SDASH score failed to provide any clinically useful information regarding prediction of shunt placement. CONCLUSION: In this study, clinical variables including use of the predictive score SDASH predicted neither the overall need for nor the timing of shunt placement after aSAH. The homogeneous distribution of data between the three different groups renders strong independent clinical predictive factors unlikely. Thus, attempts to predict a permanent shunt requirement from these variables may be futile in these patients.
Subject(s)
Hydrocephalus , Subarachnoid Hemorrhage , Humans , Hydrocephalus/etiology , Hydrocephalus/surgery , Retrospective Studies , Subarachnoid Hemorrhage/surgery , Ventriculoperitoneal ShuntABSTRACT
INTRODUCTION: We present a unique case of monozygotic female twins with virtually identical clinical and radiological presentations of supratentorial hydrocephalus and cystic formations from the suprasellar cistern. DISCUSSION: Evaluating genetic predispositions and prenatal exposures is crucial for hydrocephalus in twins. Familial cases imply a genetic contribution to the development of these anomalies, including chromosomal abnormalities and specific variants linked to arachnoid cyst formation in various syndromes. Extensive genetic analyses found no pathogenic variants in the twins. Prenatal exposure to anti-epileptic medication was known during pregnancy and may be associated with fetal abnormalities, but not central nervous system (CNS) malformations, and was therefore not considered the cause of the condition in the twins. The twins presenting simultaneously with hydrocephalus caused by suprasellar cysts (SAC) underwent a two-step surgical management: initial ventriculoperitoneal shunt (VPS) placement followed by fenestration. Postoperative imaging showed cyst reduction, but a secondary VPS was necessary in both cases. CONCLUSION: Genetic analysis is less likely to identify a monogenic etiology in non-syndromic cases of SACs, which are assumed to be multifactorial. There is no established evidence linking a teratogenic effect of anti-epileptic drugs to CNS malformations. Moreover, the surgical treatment of this complex condition constitutes a point of discussion.
Subject(s)
Arachnoid Cysts , Hydrocephalus , Pregnancy , Female , Humans , Hydrocephalus/diagnostic imaging , Hydrocephalus/genetics , Hydrocephalus/surgery , Anticonvulsants , Genetic Predisposition to Disease , Postoperative PeriodABSTRACT
BACKGROUND: By applying an unbiased proteomic approach, we aimed to search for cerebrospinal fluid (CSF) protein biomarkers distinguishing between obstructive and communicating hydrocephalus in order to improve appropriate surgical selection for endoscopic third ventriculostomy vs. shunt implants. Our second study purpose was to look for potential CSF biomarkers distinguishing between patients with adult chronic hydrocephalus benefitting from surgery (responders) vs. those who did not (non-responders). METHODS: Ventricular CSF samples were collected from 62 patients with communicating hydrocephalus and 28 patients with obstructive hydrocephalus. CSF was collected in relation to the patients' surgical treatment. As a control group, CSF was collected from ten patients with unruptured aneurysm undergoing preventive surgery (vascular clipping). RESULTS: Mass spectrometry-based proteomic analysis of the samples identified 1251 unique proteins. No proteins differed significantly between the communicating hydrocephalus group and the obstructive hydrocephalus group. Four proteins were found to be significantly less abundant in CSF from communicating hydrocephalus patients compared to control subjects. A PCA plot revealed similar proteomic CSF profiles of obstructive and communicating hydrocephalus and control samples. For obstructive hydrocephalus, ten proteins were found to predict responders from non-responders. CONCLUSION: Here, we show that the proteomic profile of ventricular CSF from patients with hydrocephalus differs slightly from control subjects. Furthermore, we find ten predictors of response to surgical outcome (endoscopic third ventriculostomy or ventriculo-peritoneal shunt) in patients with obstructive hydrocephalus.
Subject(s)
Hydrocephalus , Third Ventricle , Adult , Humans , Proteomics , Hydrocephalus/surgery , Ventriculostomy/adverse effects , Treatment Outcome , Biomarkers , Third Ventricle/surgeryABSTRACT
BACKGROUND: Repetitive transient intracranial pressure waveform elevations up to 50 mmHg (ICP B-waves) are often used to define pathological conditions and determine indications for ICP-reducing treatment. We recently showed that nocturnal transient ICP elevations are present in patients without structural brain lesions or hydrocephalus in whom they are associated with sleep apnea. However, whether this signifies a general association between ICP macropatterns and sleep apnea remains unknown. METHODS: We included 34 patients with hydrocephalus, or idiopathic intracranial hypertension (IIH), who were referred to the Neurosurgical Department, Copenhagen, Denmark, from 2017 to 2021. Every patient underwent diagnostic overnight ICP monitoring for clinical indications, with simultaneous polysomnography (PSG) sleep studies. All transient ICP elevations were objectively quantified in all patients. Three patients were monitored with continuous positive airway pressure (CPAP) treatment for an additional night. RESULTS: All patients had transient ICP elevations associated with sleep apnea. The mean temporal delay from sleep apnea to transient ICP elevations for all patients was 3.6 s (SEM 0.2 s). Ramp-type transient ICP elevations with a large increase in ICP were associated with rapid eye movement (REM) sleep and sinusoidal-type elevations with non-REM (NREM) sleep. In three patients treated with CPAP, the treatment reduced the number of transient ICP elevations with a mean of 37%. CPAP treatment resulted in insignificant changes in the average ICP in two patients but elevated the average ICP during sleep in one patient by 5.6 mmHg. CONCLUSION: The findings suggest that sleep apnea causes a significant proportion of transient ICP elevations, such as B-waves, and sleep apnea should be considered in ICP evaluation. Treatment of sleep apnea with CPAP can reduce the occurrence of transient ICP elevations. More research is needed on the impact of slow oscillating mechanisms on transient ICP elevations during high ICP and REM sleep.
Subject(s)
Hydrocephalus , Intracranial Hypertension , Sleep Apnea Syndromes , Humans , Intracranial Pressure , Sleep Apnea Syndromes/complications , Sleep Apnea Syndromes/therapy , Sleep, REM , Continuous Positive Airway Pressure/methodsABSTRACT
Patients with subarachnoid hemorrhage (SAH) may develop posthemorrhagic hydrocephalus (PHH), which is treated with surgical cerebrospinal fluid (CSF) diversion. This diversion is associated with risk of infection and shunt failure. Biomarkers for PHH etiology, CSF dynamics disturbances, and potentially subsequent shunt dependency are therefore in demand. With the recent demonstration of lipid-mediated CSF hypersecretion contributing to PHH, exploration of the CSF lipid signature in relation to brain pathology is of interest. Despite being a relatively new addition to the omic's landscape, lipidomics are increasingly recognized as a tool for biomarker identification, as they provide a comprehensive overview of lipid profiles in biological systems. We here employ an untargeted mass spectroscopy-based platform and reveal the complete lipid profile of cisternal CSF from healthy control subjects and demonstrate its bimodal fluctuation with age. Various classes of lipids, in addition to select individual lipids, were elevated in the ventricular CSF obtained from patients with SAH during placement of an external ventricular drain. The lipidomic signature of the CSF in the patients with SAH suggests dysregulation of the lipids in the CSF in this patient group. Our data thereby reveal possible biomarkers present in a brain pathology with a hemorrhagic event, some of which could be potential future biomarkers for hypersecretion contributing to ventriculomegaly and thus pharmacological targets for pathologies involving disturbed CSF dynamics.
ABSTRACT
The quality of clinical trials is essential to advance treatment, inform regulatory decisions and meta-analysis. With the increased incidence of idiopathic intracranial hypertension and the emergence of clinical trials for novel therapies in this condition, the International Headache Society Guidelines for Controlled Clinical Trials in Idiopathic Intracranial Hypertension aims to establish guidelines for designing state-of-the-art controlled clinical trials for idiopathic intracranial hypertension.
Subject(s)
Headache , Pseudotumor Cerebri , Humans , Headache/therapy , Pseudotumor Cerebri/therapy , Controlled Clinical Trials as TopicABSTRACT
The molecular mechanisms underlying the development of posthemorrhagic hydrocephalus (PHH) remain incompletely understood. As the disease pathogenesis often cannot be attributed to visible cerebrospinal fluid (CSF) drainage obstructions, we here aimed to elucidate whether elevated CSF osmolality following subarachnoid hemorrhage (SAH) could potentiate the formation of ventricular fluid, and thereby contribute to the pathological CSF accumulation observed in PHH. The CSF osmolality was determined in 32 patients with acute SAH after external ventricular drainage (EVD) placement and again upon EVD removal and compared with the CSF osmolality from 14 healthy control subjects undergoing vascular clipping of an unruptured aneurism. However, we found no evidence of elevated CSF osmolality or electrolyte concentration in patients with SAH when compared to that of healthy control subjects. We detected no difference in CSF osmolality and electrolyte content in patients with successful EVD weaning versus those that were shunted due to PHH. Taken together, elevated CSF osmolality does not appear to underlie the development of PHH following SAH. The pathological CSF accumulation observed in this patient group must thus instead be attributed to other pathological alterations associated with the abnormal presence of blood within the CSF compartments following SAH.
Subject(s)
Hydrocephalus , Subarachnoid Hemorrhage , Humans , Cerebrospinal Fluid Shunts/adverse effects , Hydrocephalus/etiology , Neurosurgical Procedures/adverse effects , Subarachnoid Hemorrhage/complicationsABSTRACT
BACKGROUND AND PURPOSE: Idiopathic normal pressure hydrocephalus (iNPH) is a potentially treatable disorder, but prognostic tests or biomarkers are lacking. The aim was to study the predictive power of clinical, neuroimaging and lumbar infusion test parameters (resistance to outflow Rout , cardiac-related pulse amplitude PA and the PA to intracranial pressure ICP ratio). METHODS: In all, 127 patients diagnosed with iNPH who had a lumbar infusion test, a subsequent ventriculo-peritoneal shunt operation and at least 2 months of postoperative follow-up were retrospectively included. Preoperative magnetic resonance images were visually scored for NPH features using the iNPH Radscale. Preoperative and postoperative assessment was performed using cognitive testing, as well as gait and incontinence scales. RESULTS: At follow-up (7.4 months, range 2-20 months), an overall positive response was seen in 82% of the patients. Gait was more severely impaired at baseline in responders compared to non-responders. The iNPH Radscale score was borderline significantly higher in responders compared with non-responders, whereas no significant differences in infusion test parameters were seen between responders and non-responders. Infusion test parameters performed modestly with high positive (75%-92%) but low negative (17%-23%) predictive values. Although not significant, PA and PA/ICP seemed to perform better than Rout , and the odds ratio for shunt response seemed to increase in patients with higher PA/ICP, especially in patients with lower iNPH Radscale scores. CONCLUSION: Although only indicative, lumbar infusion test results increased the likelihood of a positive shunt outcome. Pulse amplitude measures showed promising results that should be further explored in prospective studies.
Subject(s)
Hydrocephalus, Normal Pressure , Humans , Hydrocephalus, Normal Pressure/diagnostic imaging , Hydrocephalus, Normal Pressure/surgery , Prospective Studies , Retrospective Studies , Intracranial Pressure/physiology , PrognosisABSTRACT
Cerebellar mutism syndrome (CMS) has received increasing attention over the last decades as a complication of posterior fossa tumour surgery in children. Risk factors, aetiological aspects, and treatment measures of the syndrome have been investigated, yet the incidence of CMS remains unchanged. Overall, we are currently able to identify patients at risk, but we are unable to prevent it from occurring.Once CMS sets in, several symptomatic pharmacological treatments have been suggested, but only in smaller case series and not in randomized controlled trials, and it is not clear whether the treatment or time itself had a helpful effect.Within weeks to months, most patients regain their ability to speak after a phase with mutism or severely reduced speech; however, many patients continue to have speech and language deficits. At this point, anti-cancer treatment with chemotherapy and radiotherapy may be of focus more than the prognosis of CMS; however, many patients continue to have speech and language problems for months and years to come, and they are at high risk of other neurocognitive sequelae as well.Without reliable measures to prevent or treat the syndrome, we may look towards improving the prognosis of speech and neurocognitive functioning in these patients. As speech and language impairment is the cardinal symptom and late effect of CMS, the effect of intense and early-onset speech and language therapy as a standard of care in these patients should be investigated in relation to its effect on regaining speech capacity.
Subject(s)
Brain Neoplasms , Cerebellar Diseases , Infratentorial Neoplasms , Mutism , Child , Humans , Mutism/diagnosis , Cerebellar Diseases/diagnosis , Brain Neoplasms/complications , Infratentorial Neoplasms/complications , Risk Assessment , Syndrome , Disease Progression , Postoperative Complications/diagnosisABSTRACT
Cerebellar mutism syndrome (CMS) is a well-known complication of posterior fossa (PF) tumour surgery. CMS has previously been reported in cases of non-tumour surgical aetiology in a limited number of publications. We report a case of a 10-year-old girl who suffered a cerebellar haemorrhage and subsequent CMS following surgical treatment of a ruptured arteriovenous malformation (AVM) in the cerebellar vermis. The AVM was removed acutely through a transvermian access, and hydrocephalus was treated with temporary external drainage. In the postoperative period, she suffered diffuse vasospasms of the anterior cerebral circulation and had a permanent shunt placed for hydrocephalus. Her mutism resolved after 45 days but severe ataxia persisted. To our knowledge, this is the first reported case of CMS related to a vermian haemorrhagic stroke with postoperative diffuse vasospasms. Based on this case, we present a literature review on CMS of non-tumour surgical origin in children.
Subject(s)
Brain Neoplasms , Cerebellar Diseases , Cerebellar Neoplasms , Hydrocephalus , Infratentorial Neoplasms , Mutism , Humans , Child , Female , Mutism/etiology , Cerebellar Diseases/complications , Brain Neoplasms/surgery , Infratentorial Neoplasms/complications , Syndrome , Postoperative Complications/diagnostic imaging , Postoperative Complications/etiology , Hydrocephalus/diagnostic imaging , Hydrocephalus/etiology , Hydrocephalus/surgery , Cerebellar Neoplasms/complications , Cerebellar Neoplasms/diagnostic imaging , Cerebellar Neoplasms/surgeryABSTRACT
The mechanisms underlying post-hemorrhagic hydrocephalus (PHH) development following subarachnoid hemorrhage (SAH) are not fully understood, which complicates informed clinical decisions regarding the duration of external ventricular drain (EVD) treatment and prevents the prediction of shunt-dependency in the individual patient. The aim of this study was to identify potential inflammatory cerebrospinal fluid (CSF) biomarkers of PHH and, thus, shunt-dependency and functional outcome in patients with SAH. This study was a prospective observational study designed to evaluate inflammatory markers in ventricular CSF. In total, 31 Patients with SAH who required an EVD between June 2019 and September 2021 at the Department of Neurosurgery, Rigshospitalet, Copenhagen, Denmark, were included. CSF samples were collected twice from each patient and analyzed for 92 inflammatory markers via proximity extension assay (PEA), and the prognostic ability of the markers was investigated. In total, 12 patients developed PHH, while 19 were weaned from their EVD. Their 6-month functional outcome was determined with the modified Rankin Scale. Of the 92 analyzed inflammatory biomarkers, 79 were identified in the samples. Seven markers (SCF, OPG, LAP TGFß1, Flt3L, FGF19, CST5, and CSF1) were found to be predictors of shunt dependency, and four markers (TNFα, CXCL5, CCL20, and IL8) were found to be predictors of functional outcome. In this study, we identified promising inflammatory biomarkers that are able to predict (i) the functional outcome in patients with SAH and (ii) the development of PHH and, thus, the shunt dependency of the individual patients. These inflammatory markers may have the potential to be employed as predictive biomarkers of shunt dependency and functional outcome following SAH and could, as such, be applied in the clinic.
ABSTRACT
BACKGROUND: Aneurysmal subarachnoid haemorrhage (aSAH) is a life-threatening disease caused by rupture of an intracranial aneurysm. A common complication following aSAH is hydrocephalus, for which placement of an external ventricular drain (EVD) is an important first-line treatment. Once the patient is clinically stable, the EVD is either removed or replaced by a ventriculoperitoneal shunt. The optimal strategy for cessation of EVD treatment is, however, unknown. Gradual weaning may increase the risk of EVD-related infection, whereas prompt closure carries a risk of acute hydrocephalus and redundant shunt implantations. We designed a randomised clinical trial comparing the two commonly used strategies for cessation of EVD treatment in patients with aSAH. METHODS: DRAIN is an international multi-centre randomised clinical trial with a parallel group design comparing gradual weaning versus prompt closure of EVD treatment in patients with aSAH. Participants are randomised to either gradual weaning which comprises a multi-step increase of resistance over days, or prompt closure of the EVD. The primary outcome is a composite outcome of VP-shunt implantation, all-cause mortality, or ventriculostomy-related infection. Secondary outcomes are serious adverse events excluding mortality, functional outcome (modified Rankin scale), health-related quality of life (EQ-5D) and Fatigue Severity Scale (FSS). Outcome assessment will be performed 6 months after ictus. Based on the sample size calculation (event proportion 80% in the gradual weaning group, relative risk reduction 20%, type I error 5%, power 80%), 122 patients are needed in each intervention group. Outcome assessment for the primary outcome, statistical analyses and conclusion drawing will be blinded. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT03948256.
Subject(s)
Hydrocephalus , Subarachnoid Hemorrhage , Humans , Subarachnoid Hemorrhage/complications , Subarachnoid Hemorrhage/therapy , Quality of Life , Weaning , Hydrocephalus/etiology , Hydrocephalus/surgery , Drainage/adverse effects , Drainage/methods , Retrospective Studies , Randomized Controlled Trials as Topic , Multicenter Studies as TopicABSTRACT
BACKGROUND: Pathological cerebral conditions may manifest in altered composition of the cerebrospinal fluid (CSF). Although diagnostic CSF analysis seeks to establish pathological disturbances in the brain proper, CSF is generally sampled from the lumbar compartment for reasons of technical ease and ethical considerations. We here aimed to compare the molecular composition of CSF obtained from the ventricular versus the lumbar CSF compartments to establish a relevance for employing lumbar CSF as a proxy for the CSF bathing the brain tissue. METHODS: CSF was collected from 46 patients with idiopathic normal pressure hydrocephalus (iNPH) patients during their diagnostic workup (lumbar samples) and in connection with their subsequent CSF diversion shunt surgery (ventricular samples). The mass-spectrometry-based proteomic profile was determined in these samples and in addition, selected biomarkers were quantified with ELISA (S100B, neurofilament light (NfL), amyloid-ß (Aß40, Aß42), and total tau (T-tau) and phosphorylated tau (P-tau) forms). The latter analysis was extended to include paired porcine samples obtained from the lumbar compartment and the cerebromedullary cistern closely related to the ventricles. RESULTS: In total 1231 proteins were detected in the human CSF. Of these, 216 distributed equally in the two CSF compartments, whereas 22 were preferentially (or solely) present in the ventricular CSF and four in the lumbar CSF. The selected biomarkers of neurodegeneration and Alzheimer's disease displayed differential distribution, some with higher (S100B, T-tau, and P-tau) and some with lower (NfL, Aß40, Aß42) levels in the ventricular compartment. In the porcine samples, all biomarkers were most abundant in the lumbar CSF. CONCLUSIONS: The overall proteomic profile differs between the ventricular and the lumbar CSF compartments, and so does the distribution of clinically employed biomarkers. However, for a range of CSF proteins and biomarkers, one can reliably employ lumbar CSF as a proxy for ventricular CSF if or a lumbar/cranial index for the particular molecule has been established. It is therefore important to verify the compartmental preference of the proteins or biomarkers of interest prior to extrapolating from lumbar CSF to that of the ventricular fluid bordering the brain.