Hiren C. Patel

Cerebrospinal fluid and plasma cytokines after subarachnoid haemorrhage: CSF interleukin-6 may be an early marker of infection

AbstractBackgroundCytokines and cytokine receptor concentrations increase in plasma and cerebrospinal fluid (CSF) of patients following subarachnoid haemorrhage (SAH). The relationship between plasma and CSF cytokines, and factors affecting this, are not clear.MethodsTo help define the relationship, paired plasma and cerebrospinal fluid (CSF) samples were collected from patients subject to ventriculostomy. Concentrations of key inflammatory cytokines, interleukin (IL)-1ß, IL-1 receptor antagonist (IL-1Ra), IL-1 receptor 2, IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-α, and TNF receptors (TNF-R) 1 and 2 were determined by immunoassay of CSF and plasma from 21 patients, where samples were available at three or more time points.ResultsPlasma concentrations of IL-1ß, IL-1Ra, IL-10, TNF-α and TNF-R1 were similar to those in CSF. Plasma TNF-R2 and IL-1R2 concentrations were higher than in CSF. Concentrations of IL-8 and IL-6 in CSF were approximately10 to 1,000-fold higher than in plasma. There was a weak correlation between CSF and plasma IL-8 concentrations (r = 0.26), but no correlation for IL-6. Differences between the central and peripheral pattern of IL-6 were associated with episodes of ventriculostomy-related infection (VRI). A VRI was associated with CSF IL-6 >10,000 pg/mL (P = 0.0002), although peripheral infection was not significantly associated with plasma IL-6.ConclusionsThese data suggest that plasma cytokine concentrations cannot be used to identify relative changes in the CSF, but that measurement of CSF IL-6 could provide a useful marker of VRI.

External ventricular drain infection: Improved technique can reduce infection rates

Abstract Introduction. The placement of external ventricular drain (EVD) is a common neurosurgical procedure to drain cerebrospinal fluid (CSF) in many acute neurosurgical conditions that disrupt the normal CSF absorption pathway. Infection is the primary complication with infection rates ranging between 0% and 45%, and this is associated with significant morbidity and mortality, prolonged hospital stay and increased hospital costs.This article compares and discusses the differences in rates of EVD CSF infection between clinical neurosurgical practice and the infection rates in a group of research patients where EVDs were sampled frequently as part of the study. Materials and methods. Patients who had EVD placed were identified by review of theatre logs from 2005–2008. A retrospective case-note review was performed with the primary end point being those patients treated with intrathecal antibiotics. Patients within the research group were identified from established data and the same primary endpoint was used. A standard silicone catheter was the EVD used in both cohorts. Patients were excluded if the EVD was placed for diagnoses other than hydrocephalus associated with aneurysmal subarachnoid haemorrhage (SAH). Results. Ninety-four patients had 156 EVDs placed within the clinical group, 49 patients were treated giving an infection rate within this group of 52.1% per patient and 31.4% per EVD. Thirty-nine patients had 39 EVDs placed within the research group, four patients were treated, the infection rate within this group was 10.3% per EVD, p = 0.0001. Conclusion. Sampling or irrigating ventricular drainage systems does not increase the risk of CNS infection providing the operator has appropriate experience and has used theatre standard aseptic technique.

Accuracy and Clinical Usefulness of Intracerebral Hemorrhage Grading Scores: A Direct Comparison in a UK Population

Background and Purpose— Various grading scores to predict survival after intracerebral hemorrhage (ICH) have been described. We aimed to test the accuracy and clinical usefulness of 3 well-known scores (original ICH score, modified ICH score, and ICH grading scale) in a large unselected cohort of typical ICH patients. Methods— A total of 1364 ICH cases were referred to our center from January 1, 2008, to October 17, 2010. Clinical details were prospectively recorded, and the first computed tomography brain scan was retrospectively reviewed to determine ICH volume and location and to identify intraventricular hemorrhage. The original ICH, ICH grading scale, and modified ICH score were calculated. Receiver operating characteristic and decision curves for 30-day mortality were generated. Results— A total of 1175 patients were included in the final analysis. All 3 scores and the Glasgow Coma Scale (GCS) divided cases into groups with highly significant differences in mortality. The area under the receiver operating characteristic curve was very similar for original ICH (0.861), ICH grading scale (0.874), and GCS (0.872), but was less for modified ICH score (0.824). Age was much less predictive (0.565). Combining GCS with age, log ICH volume, and intraventricular hemorrhage to derive a multifactorial risk of death at 30 days significantly increased the area under the receiver operating characteristic curve (0.897). All scores and GCS demonstrated a similar net benefit for threshold probabilities of 10% to 95%. Above 95%, the net benefit of GCS became inferior to the prognostic scores. Conclusions— Although existing grading scores are highly predictive of 30-day mortality, GCS alone was as predictive in our cohort, but age was not.

Silver-impregnated external-ventricular-drain-related cerebrospinal fluid infections: a meta-analysis

BACKGROUND Cerebrospinal fluid (CSF) infection is the primary complication associated with placement of an external ventricular drain (EVD). The use of silver-impregnated EVD catheters has become commonplace in many neurosurgical centres. AIM To assess the effect of silver-impregnated EVD catheter usage on catheter-related CSF infections. METHODS A meta-analysis was performed by systematically searching Medline, Embase and the Cochrane Library. All randomized controlled trials (RCTs) and non-RCTs comparing silver-impregnated and plain EVD catheters were identified and analysed. FINDINGS Six non-RCTs were included. The crude infection rate was 10.8% for plain catheters and 8.9% for silver-impregnated catheters [pooled odds ratio (OR) 0.71, 95% confidence interval (CI) 0.46-1.08; P = 0.11]. In a microbiological spectrum analysis, silver-impregnated catheters demonstrated a significantly lower rate of CSF infections caused by Gram-positive organisms (2.0% vs 6.7% in the silver-impregnated and plain catheter groups, respectively; pooled OR 0.27, 95% CI 0.11-0.63; P = 0.002). CONCLUSION The antimicrobial effects of silver-impregnated EVD catheters may be selective, and may need to be evaluated further in a prospective, controlled manner.

Reduction of inflammation after administration of interleukin-1 receptor antagonist following aneurysmal subarachnoid hemorrhage: results of the Subcutaneous Interleukin-1Ra in SAH (SCIL-SAH) study

OBJECTIVE Aneurysmal subarachnoid hemorrhage (aSAH) is a devastating cerebrovascular event with long-term morbidity and mortality. Patients who survive the initial bleeding are likely to suffer further early brain injury arising from a plethora of pathological processes. These may result in a worsening of outcome or death in approximately 25% of patients and may contribute to longer-term cognitive dysfunction in survivors. Inflammation, mediated by the cytokine interleukin-1 (IL-1), is an important contributor to cerebral ischemia after diverse forms of brain injury, including aSAH. Its effects are attenuated by its naturally occurring antagonist, IL-1 receptor antagonist (IL-1Ra [anakinra]). The authors hypothesized that administration of additional subcutaneous IL-1Ra would reduce inflammation and associated plasma markers associated with poor outcome following aSAH. METHODS This was a randomized, open-label, single-blinded study of 100 mg subcutaneous IL-1Ra, administered twice daily in patients with aSAH, starting within 3 days of ictus and continuing until 21 days postictus or discharge from the neurosurgical center, whichever was earlier. Blood samples were taken at admission (baseline) and at Days 3-8, 14, and 21 postictus for measurement of inflammatory markers. The primary outcome was difference in plasma IL-6 measured as area under the curve between Days 3 and 8, corrected for baseline value. Secondary outcome measures included similar area under the curve analyses for other inflammatory markers, plasma pharmacokinetics for IL-1Ra, and clinical outcome at 6 months. RESULTS Interleukin-1Ra significantly reduced levels of IL-6 and C-reactive protein (p < 0.001). Fibrinogen levels were also reduced in the active arm of the study (p < 0.002). Subcutaneous IL-1Ra was safe, well tolerated, and had a predictable plasma pharmacokinetic profile. Although the study was not powered to investigate clinical effect, scores of the Glasgow Outcome Scale-extended at 6 months were better in the active group; however, this outcome did not reach statistical significance. CONCLUSIONS Subcutaneous IL-1Ra is safe and well tolerated in aSAH. It is effective in reducing peripheral inflammation. These data support a Phase III study investigating the effect of IL-1Ra on outcome following aSAH. Clinical trial registration no.: EudraCT: 2011-001855-35 ( www.clinicaltrialsregister.eu ).

Improved cerebrovascular reactivity following low flow EC/IC bypass in patients with occlusive carotid disease

Patients with major cerebral artery occlusive disease can suffer cerebral hypoperfusion and be at an increased risk of future strokes. EC/IC bypass has been shown to reduce this risk. Patients with cerebral hypoperfusion, and who are at risk of haemodynamic ischaemia, can be identified by the use of xenon computerised tomography (XeCT) to demonstrate severe impairment of the cerebrovascular reserve (CVR). We report our series on the effect of low flow EC/IC bypass on CVR in patients with symptomatic cerebral haemodynamic ischaemia. Thirteen patients with clinical and radiological features of cerebral hypoperfusion were assessed with acetazolamide activated XeCT. Pre- and postoperative regional cerebral blood flow (rCBF) and CVR were assessed. The change in CVR from pre- to post surgery was calculated (%CVR). Values were compared using ANOVA and Students paired t-test. Unless otherwise stated, values are given as mean ± standard error of the mean. Statistical significance was taken at p < 0.05. Pre-operative symptomatic hemisphere CBF was 38 ± 2 mls/100g/min compared to 40 ± 3.2 mls/100 g/min in the asymptomatic hemisphere, with the greatest difference observed in the MCA territory (38.6 ± 2 cf 45.4 ± 3.2 mls/100g/min). Baseline CBF was not significantly improved post EC/IC bypass. However CVR was significantly improved in the symptomatic hemisphere post-operatively (p = 0.015), with the greatest increase (28%) seen in the MCA territory (p = 0.0105). First, 85% of patients had either an improvement in symptoms or no further symptoms. There was a 93% graft patency and no operative mortality. Low flow EC/IC bypass can improve CVR in patients with symptomatic cerebral ischaemia in the presence of occlusive carotid disease. However, therapy must be individualised, with careful patient selection and minimal surgical morbidity.

Predictors of Outcome in Aneurysmal Subarachnoid Hemorrhage Patients: Observations From a Multicenter Data Set

Background and Purpose— The mortality and morbidity after aneurysmal subarachnoid hemorrhage has improved because of better diagnosis, early treatment to secure the aneurysm, and better management of disease-specific complications. With these improvements in care, it is not clear if the previously identified independent predictors of a negative outcome have changed. The aim of this study was to identify the independent predictors of an unfavorable outcome (Glasgow Outcome Score 1, 2, and 3) in aneurysmal subarachnoid hemorrhage patients. Methods— Univariate and multivariate analysis of prospectively collected data on patients presenting with an aneurysmal subarachnoid hemorrhage was performed. Outcome was assessed at discharge. Data were collected from 14 centers in the United Kingdom over a period of 4 years (September 2011–2015). Results— The median age (interquartile range) at presentation of 3341 patients with aneurysmal subarachnoid hemorrhage was 55 (18) years. Most patients were female (n=2288 [68.5%]), presented in good grade (2397 [70%]; World Federation of Neurological Surgeons grade 1 and 2), and were treated by endovascular coiling (n=2600; 75%). The independent predictors of an unfavorable outcome (95% confidence interval [CI]) were increasing age (odds ratio [OR], 1.04; 95% CI, 1.03–1.05; P<0.001), World Federation of Neurological Surgeons grade (OR, 2.06; 95% CI, 1.91–2.22; P<0.001), preoperative rebleeding (OR, 7.41; 95% CI, 4.48–12.30; P<0.001), need for cerebrospinal fluid diversion (OR, 3.25; 95% CI, 2.58–4.09; P<0.001), and delayed cerebral ischemia (OR, 2.21; 95% CI, 1.72–2.83; P<0.001). Conclusions— These data suggest that potentially modifiable risk factors of preoperative rebleeding and delayed cerebral ischemia are associated with unfavorable outcomes. Understanding the reasons why patients requiring cerebrospinal fluid diversion have 3.25-fold higher adjusted odds of a poor outcome at discharge needs to be studied.

Lumbar puncture and the diagnosis of CT negative subarachnoid haemorrhage: time for a new approach?

Abstract Objective. Because of potential risks of poor outcome, lumbar puncture (LP) is recommended to exclude the presence of blood breakdown products in patients with suspected subarachnoid haemorrhage (SAH) and a normal CT scan. The aim of this study was to document how often this test proved useful. Method. A retrospective analysis of prospectively recorded data was conducted. Patients with suspected SAH and a normal CT scan in whom LP was recommended between May 2008 and May 2010 were identified using the neurosurgical referral database. CT scan results, LP results, inpatient stay, investigations and interventions were recorded. Results. One hundred and sixty-three patients were identified in whom LP was recommended after a reported negative CT scan. Thirty-six of these 163 patients had a positive LP of which seven had evidence of SAH on the initial CT scan. In 66 patients, the LP was not diagnostic and 59/66 (90%) patients underwent secondary imaging in whom five with aneurysms were identified and treated. Conclusion. LP-driven decision making in patients with a normal scan and suspected SAH is suboptimal in over a third of cases. Patients with a non-diagnostic LP harboured five aneurysms that merited treatment. These results support the need for secondary investigations following suspected SAH, but suggest that these could take the form of secondary imaging rather than a lumbar puncture.

Difficulties with recruiting into neurosurgical clinical trials: The Surgical Trial in IntraCerebral Haemorrhage II as an example

Background: Spontaneous supratentorial intracerebral haemorrhage (ICH) is a devastating condition with a high morbidity and mortality, and uncertainty remains regarding the role of surgery in many cases. The Surgical Trial in IntraCerebral Haemorrhage II (STICH II) was initiated to look at subjects with superficial lobar ICH, as the initial STICH trial showed the greatest benefit from early surgery in this subgroup. Our aim was to estimate how many patients with ICH referred to the Greater Manchester Neurosciences Centre (GMNC) met the inclusion and exclusion criteria of the STICH II trial. Methods: The number of patients eligible for STICH II was determined from the GMNC referral database and admissions to the stroke unit over 1 year (2008). Eligibility was determined by predefined criteria, and equipoise was agreed by two consultant neurosurgeons. Results: One hundred and sixty-eight (38.7%) of 434 ICH referrals were lobar ICH; 53 (31.5% of lobar ICH) of these met the radiological and Glasgow Coma Scale (GCS) criteria for STICH II, but only 16 (9.5% of lobar ICH; 3.7% of all ICH) had equipoise agreed on by two neurosurgeons. Thirty-five ICH patients were admitted to the stroke unit, and 12 (34.3%) of these had lobar ICH; none were eligible for STICH II. Conclusions: The number of patients eligible for recruitment into STICH II is small, necessitating an aggressive recruitment approach. Recruitment should focus on neuroscience centres with neurosurgical units as opposed to stroke units.

Outcome in patients presenting with an aneurysm related intracerebral haemorrhage in the post-ISAT era.

Abstract Background. The outcome in patients who present with an aneurysm related intracerebral haemorrhage (ICH) is poor. There are many treatment strategies now available to treat this group of patients. The management approach is dominated by a direct surgical approach for both aneurysm treatment and clot evacuation. It remains unclear, however, whether overall outcomes justify an aggressive treatment approach in this group of patients. We report our results of a pragmatic strategy based on availability of expertise and patient condition in patients presenting with an aneurysm related intracerebral haemorrhage. Methods. We retrospectively identified and analysed prospectively collected data of SAH patients with concurrent ICH. The grade at presentation, treatment decision, complications, length of hospital stay, discharge destination, and 6 month outcome (Glasgow Outcome Score (GOS) at 6 months) were recorded. Findings. Between August 2008 and January 2010, 40 patients (9.2%) with ICH were identified from the 433 patients with SAH. Twenty five patients (63%) were transferred across to the neurosurgical centre for further investigations and management. Most patients presented with poor WFNS grade (61%) and had right sided middle cerebral artery aneurysms (58%) with frontotemporal (42%) or temporoparietal (42%) haematomas. Management included craniotomy/craniectomy and clipping of the aneurysm in 18 patients (72%), coiling followed by surgical clot evacuation in five (20%), and craniectomy and coiling (4%) or coiling alone (4%). The outcome in treated patients was favourable (GOS 4 or 5) in 46% of patients with a 35% overall mortality. Conclusion. The presence of an aneurysm related ICH does not justify a nihilistic approach, as aggressive treatment is associated with a favourable outcome in 46% of patients. In the post-ISAT era, management should be patient specific and consideration should be given to both endovascular and open surgical therapy.