Hydrocephalus after aneurysmal subarachnoid hemorrhage

Hydrocephalus after aneurysmal subarachnoid hemorrhage

Epidemiology

Hydrocephalus complicates the clinical course of greater than 20% of patients with aneurysmal subarachnoid hemorrhage 1) 2) , and its onset can be acute, within 48 hours after SAH, or rarely chronic, occurring in a delayed fashion weeks and even months after the hemorrhage.

Etiology

The etiology of hydrocephalus following aSAH has yet to be fully elucidated, but is likely to include the following: obstruction of CSF flow within the basal cisterns and/or ventricles by clotted blood, diminished absorption at the arachnoid granulations, and inflammation 3) 4) 5) 6).

Na et al. found that higher sodium, lower potassium, and higher glucose levels were predictive values for shunt-dependent hydrocephalus from postoperative day (POD) 1 to POD 12-16 after subarachnoid hemorrhage. Strict correction of electrolyte imbalance seems necessary to reduce shunt-dependent hydrocephalus. Further large studies are warranted to confirm the findings 7).

Data suggest that the volume of the third ventricle in the initial CT is a strong predictor for shunt dependency after aSAH 8).

Diagnosis

Early recognition of its signs and symptoms and accurate interpretation of computed tomography (CT) studies are important for the management of patients with SAH. Clinically, a poor neurologic grade has the highest correlation with an increased incidence of hydrocephalus. Radiographically, the bicaudate index on CT studies has emerged as the best marker of this condition. Although further studies are needed to understand the complex pathophysiology of this condition, hydrocephalus after SAH can be treated effectively using current technology 9).


Most readmissions after aneurysmal subarachnoid hemorrhage (SAH) relate to late consequences of hemorrhage, such as hydrocephalus, or medical complications secondary to severe neurological injury. Although a minority of readmissions may potentially be avoided with closer medical follow-up in the transitional care environment, readmission after SAH is an insensitive and likely inappropriate hospital performance metric 10).

Data demonstrate that gender influences acute hydrocephalus development in a rat SAH model. Future studies should determine the role of estrogen in SAH-induced hydrocephalus 11).

Hydrocephalus might cause gradual obtundation in the first few hours or days; it can be treated by lumbar puncture or ventricular drainage, dependent on the site of obstruction

Aneurysmal subarachnoid hemorrhage (SAH) has been reported to induce an intrathecal inflammatory reaction reflected by cytokine release, particularly interleukin-6 (IL-6), which correlates with early brain damage and poor outcome.

Treatment

Hydrocephalus might cause gradual obtundation in the first few hours or days; it can be treated by lumbar puncture or ventricular drainage, dependent on the site of obstruction 12).

Outcome

Hydrocephalus is a common and potentially devastating complication of aneurysmal subarachnoid hemorrhage (SAH).

Hydrocephalus leads to prolonged hospital and ICU stays, well as to repeated surgical interventions, readmissions, and complications associated with ventriculoperitoneal shunts, including shunt failure and shunt infection. Whether variations in surgical technique at the time of aneurysm treatment may modify rates of shunt dependency remains a matter of debate 13).

Shunt dependency

The indication for and the timing of a permanent shunt operation in patients following acute hydrocephalus (HC) after subarachnoid hemorrhage (SAH) remains controversial because risk factors for chronic HC fail to predict permanent shunt dependency. The amount of cerebrospinal fluid (CSF) drained via an external ventricular drain (EVD) may predict shunt dependency.

Results suggest that the daily amount of external CSF drainage volume in the acute state of SAH might influence the development of HC 14).


CSF IL-6 values of ≥10,000 pg/ml in the early post-SAH period may be a useful diagnostic tool for predicting shunt dependency in patients with acute posthemorrhagic hydrocephalus. The development of shunt-dependent posthemorrhagic hydrocephalus remains a multifactorial process 15).

Reliable prognostic tools to estimate the case fatality rate (CFR) and the development of chronic hydrocephalus (CHC) in aneurysmal subarachnoid hemorrhage (SAH) are not well defined.

Graeb Score or LeRoux score improve the prediction of shunt dependency and in parts of CFR in aneurysmal SAH patients therefore confirming the relevance of the extent and distribution of intraventricular blood for the clinical course in SAH 16).

Case series

One-hundred and fifty-two patients who had undergone an operation for SAH were enrolled in this study. Clinical data, radiological data, and procedural data were investigated. Procedural data included the operating technique (clipping vs. EVT) and the use of additional procedures (no procedure, lumbar drainage, or EVD). Delayed hydrocephalus was defined as a condition in which the Evan’s index was 0.3 or higher, as assessed using brain computed tomography more than 2 weeks after surgery, requiring shunt placement due to neurological deterioration.

Of the 152 patients, 45 (29.6%) underwent surgical clipping and 107 (70.4%) underwent EVT. Twenty-five (16.4%) patients developed delayed hydrocephalus. Age (p = 0.019), procedure duration (p = 0.004), and acute hydrocephalus (p = 0.030) were significantly correlated with the incidence of delayed hydrocephalus. However, the operation technique (p = 0.593) and use of an additional procedure (p = 0.378) were not significantly correlated with delayed hydrocephalus incidence.

No significant difference in the incidence of delayed hydrocephalus was associated with operation technique or use of an additional procedure in patients with SAH. However, delayed hydrocephalus was significantly correlated with old age, long procedural duration, and acute hydrocephalus. Therefore, they recommend that additional procedures should be discontinued as soon as possible 17).

2017

Winkler et al. conducted a retrospective review of 663 consecutive patients with aSAH treated from 2005 to 2015 by open microsurgery via a pterional or orbitozygomatic craniotomy by the senior author (M.T.L.). Data collected from review of the electronic medical record included age, Hunt and Hess grade, Fisher grade, need for an external ventricular drain, and opening pressure. Patients were stratified into those undergoing no fenestration and those undergoing tandem fenestration of the LT and MoL at the time of surgical repair. Outcome variables, including VP shunt placement and timing of shunt placement, were recorded and statistically analyzed. RESULTS In total, shunt-dependent hydrocephalus was observed in 15.8% of patients undergoing open surgical repair following aSAH. Tandem microsurgical fenestration of the LT and MoL was associated with a statistically significant reduction in shunt dependency (17.9% vs 3.2%, p < 0.01). This effect was confirmed with multivariate analysis of collected variables (multivariate OR 0.09, 95% CI 0.03-0.30). Number-needed-to-treat analysis demonstrated that tandem fenestration was required in approximately 6.8 patients to prevent a single VP shunt placement. A statistically significant prolongation in days to VP shunt surgery was also observed in patients treated with tandem fenestration (26.6 ± 19.4 days vs 54.0 ± 36.5 days, p < 0.05). CONCLUSIONS Tandem fenestration of the LT and MoL at the time of open microsurgical clipping and/or bypass to secure ruptured anterior and posterior circulation aneurysms is associated with reductions in shunt-dependent hydrocephalus following aSAH. Future prospective randomized multicenter studies are needed to confirm this result 18).


181 participants with a mean age of 54.4 years. Higher sodium (hazard ratio, 1.53; 95% confidence interval, 1.13-2.07; p = 0.005), lower potassium, and higher glucose levels were associated with higher shunt-dependent hydrocephalus. The receiver operating characteristic curve analysis showed that the areas under the curve of sodium, potassium, and glucose were 0.649 (cutoff value, 142.75 mEq/L), 0.609 (cutoff value, 3.04 mmol/L), and 0.664 (cutoff value, 140.51 mg/dL), respectively.

Despite the exploratory nature of this study, we found that higher sodium, lower potassium, and higher glucose levels were predictive values for shunt-dependent hydrocephalus from postoperative day (POD) 1 to POD 12-16 after subarachnoid hemorrhage. Strict correction of electrolyte imbalance seems necessary to reduce shunt-dependent hydrocephalus. Further large studies are warranted to confirm our findings 19).

2016

The study is designed to determine the efficacy of lamina terminalis fenestration on the reduction of SDH after aneurysm clipping.

METHODS/DESIGN: A total of 288 patients who meet the inclusion criteria will be randomized into single aneurysm clipping or aneurysm clipping plus FLT in the Department of Neurosurgery, West China Hospital. Follow-up was performed 1, 3, 6, and 12 months after aneurysm clipping. The primary outcome is the incidence of SDH and the secondary outcomes include cerebral vasospasm, functional outcome evaluated by the modified Rankin Scale and Extended Glasgow Outcome Scale, and mortality.

DISCUSSION: The FISH trial is a large randomized, parallel controlled clinical trial to define the therapeutic value of FLT, the results of which will help to guide the surgical procedure and resolve the long-puzzled debate in the neurosurgical community.

CONCLUSIONS: This protocol will determine the efficacy of FLT in the setting of aneurysmal subarachnoid hemorrhage 20).

2003

Seven hundred eighteen patients with aneurysmal subarachnoid hemorrhage who were treated between 1990 and 1999 were retrospectively studied, to identify factors contributing to shunt-dependent hydrocephalus. With these data, a stepwise logistic regression procedure was used to determine the effect of each variable on the development of hydrocephalus and to create a scoring system.

Overall, 152 of the 718 patients (21.2%) underwent shunting procedures for treatment of hydrocephalus. Four hundred seventy-nine of the patients (66.7%) were female. Of the factors investigated, the following were associated with shunt-dependent hydrocephalus, as determined with a variety of statistical methods: 1) increasing age (P < 0.001), 2) female sex (P = 0.015), 3) poor admission Hunt and Hess grade (P < 0.001), 4) thick subarachnoid hemorrhage on admission computed tomographic scans (P < 0.001), 5) intraventricular hemorrhage (P < 0.001), 6) radiological hydrocephalus at the time of admission (P < 0.001), 7) distal posterior circulation location of the ruptured aneurysm (P = 0.046), 8) clinical vasospasm (P < 0.001), and 9) endovascular treatment (P = 0.013). The presence of intracerebral hematomas, giant aneurysms, or multiple aneurysms did not influence the development of shunt-dependent hydrocephalus.

The results of this study can help identify patients with a high risk of developing shunt-dependent hydrocephalus. This may help neurosurgeons expedite treatment, may decrease the cost and length of hospital stays, and may result in improved outcomes 21).

2000

In 138 patients with ruptured cerebral aneurysms operated on within 48 to 72 hours after subarachnoid hemorrhage, an external ventricular drainage catheter was inserted before craniotomy and was used intermittently during the first week after surgery. In 51 patients, intracranial pressure (ICP) was measured intraoperatively. The majority of patients showed increased ICP intraoperatively irrespective of the preoperative Hunt and Hess grade and the amount of subarachnoid blood accumulation or intraventricular blood clot. Intraoperative drainage of cerebrospinal fluid allowed easy access for aneurysm dissection by making the brain slack in more than 90% of patients. Postoperative ICP measurements revealed that significant brain swelling did not occur in the majority of patients. In 7 patients, persistently elevated ICP (greater than 20 mm Hg) was recorded. Nine patients (8%) developed shunt-dependent hydrocephalus; all of these patients had suffered an intraventricular hemorrhage. Measurements of the volumes of cerebrospinal fluid drained did not allow prediction of shunt-dependent hydrocephalus 22).

1987

The incidence and clinical aspects of acute hydrocephalus were examined in 200 patients with recently ruptured intracranial aneurysms. The following conclusions were reached: Acute hydrocephalus is an important complication of aneurysmal subarachnoid hemorrhage that occurs in approximately 20% of all cases and exhibits an incidence that tends to parallel clinical grade (Grade I, 3%; Grade II, 5%; “Good” Grade III, 21%; “Bad”Grade III, 40%; Grade IV, 42%; Grade V, 26%). Impaired consciousness leading to a general downgrading of clinical status was the predominant clinical finding (93%), but neither this nor other nonspecific signs of increased intracranial pressure were distinguishable from the effects of the precipitating hemorrhage. The computed tomographic signs of acute hydrocephalus are distinctive and consist of selective ballooning of the frontal horns, rostral-caudal enlargement of the cerebral ventricles, and a halo of periventricular hyperdensity (edema) that evolves in sequence with ventricular changes. The treatment of choice is external ventricular drainage, which results in prompt and often dramatic improvement in approximately two-thirds of the patients 23).

1985

Hydrocephalus, defined as a bicaudate index above the 95th percentile for age, was found in 34 (20%) of 174 prospectively studied patients with subarachnoid hemorrhage (SAH) who survived the first 24 hours and who underwent computerized tomography (CT) scanning within 72 hours. The occurrence of acute hydrocephalus was related to the presence of intraventricular blood, and not to the extent of cisternal hemorrhage. The level of consciousness was depressed in 30 of the 34 patients. Characteristic clinical features were present in 19 patients, including a gradual obtundation after the initial hemorrhage in 16 patients and small nonreactive pupils in nine patients (all with a Glasgow Coma Scale score of 7 or less). In the remaining 15 patients (44%), the diagnosis could be made only by CT scanning. After 1 month, 20 of the 34 patients had died: six from rebleeding (four after shunting), 11 from cerebral infarction (eight after an initial improvement), and three from other or mixed causes. Only one of nine patients in whom a shunt was placed survived, despite rapid improvement in all immediately after shunting. The mortality rate among patients with acute hydrocephalus was significantly higher than in those without, with the higher incidence caused by cerebral infarction (11 of 34 versus 12 of 140 cases, respectively; p less than 0.001). Death from infarction could not be attributed to the extent of cisternal hemorrhage, the use of antifibrinolytic drugs, or failure to apply surgical drainage, but could often be explained by the development of hyponatremia, probably accompanied by hypovolemia 24).

1984

Seventeen patients suffering from SAH and/or intraventricular hemorrhage were studied; all were admitted in Grades II to V according to Hunt and Hess. Eleven patients had a proven aneurysm. The ICP, monitored via an intraventricular catheter, was above 15 mm Hg (2 kPa) during part of the monitoring period in all patients. B-waves at 1/min were noted in all patients. Resistance to outflow of CSF was determined by the following techniques: 1) bolus injection; 2) constant-rate steady-state infusion; or 3) controlled withdrawal (“inverse infusion”). Resistance to outflow of CSF was increased in all patients, ranging from 11.5 to 85 mm Hg/ml/min. The ICP was linearly correlated with outflow resistance. Four (50%) of the eight survivors required a shunt. Neither the presence of hydrocephalus on admission, nor the level of ICP, nor the magnitude of resistance to outflow of CSF was clearly related to the requirement of a permanent CSF diversion 25).

References

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Recurrent glioblastoma treatment

Recurrent glioblastoma treatment

Less than 10% of recurrent gliomas recur away from the original tumor site 1).

Reoperation extends survival by an additional 36 weeks in patients with glioblastoma, and 88 weeks in anaplastic astrocytoma 2) 3) (duration of high quality survival was 10 weeks and 83 weeks, respectively, and was lower with pre-op Karnofsky score < 70). In addition to Karnofsky performance score, significant prognosticators for response to repeat surgery include: age and time from the first operation to reoperation (shorter times → worse prognosis) 4). Morbidity is higher with reoperation (5–18%); the infection rate is ≈ 3x that for first operation, wound dehiscence is more likely


The standard of care management for newly diagnosed GBM includes surgery, radiation, temozolomide (TMZ) chemotherapy, and tumor treating fields 5).

There is no consensus as to the standard of care as no therapeutic options have produced substantial survival benefit for recurrent glioblastomas (GBMs) 6) 7).

A purely radiological diagnosis of recurrence or progression can be hampered by flaws induced by pseudoprogression, pseudoresponse, or radionecrosis.

Based on parameters like localization and tumor volume, patient’s Karnofsky Performance Score, time from initial diagnosis, and availability of alternative salvage therapies, reoperation can be considered as a treatment option to extend the overall survival and quality of life of the patient.

The achieved extent of resection of the relapsed tumor—especially with the intention of having a safe, complete resection of the enhancing tumor—most likely plays a crucial role in the ultimate outcome and prognosis of the patient, regardless of other modes of treatment. Validated scores to predict the prognosis after reoperation of a patient with a recurrent glioblastoma can help to select suitable candidates for surgery. Safety issues and complication avoidance are pivotal to maximally preserve the patient’s quality of life. Besides a possible direct oncological effect, resampling of the recurrent tumor with detailed pathological and molecular analysis might have an impact on the development, testing, and validation of new salvage therapies 8).

Options

Options include repeat surgical resection, repeat fractionated radiation, radiosurgery.

Bevacizumab (BEV) plus daily temozolomide (TMZ) as a salvage therapy have been recommended to recurrent glioma.

Given the lack of consensus on optimal management of recurrent GBM, knowledge of care patterns used for these patients and the criteria used to determine therapeutic strategy is germane to clinicians who care for these patients.


In a study, Hundsberger et al investigated which treatments are currently being used for recurrent GBM within a single nation (Switzerland) and how clinicians are deciding to use them 9)

The authors surveyed Swiss hospitals with comprehensive multidisciplinary neuro-oncology practices (neurosurgery, radiation therapy, medical neuro-oncology, and a dedicated neuro-oncology tumor board) about treatment recommendations for recurrent GBM. They identified relevant clinical decision-making criteria, called diagnostic nodes or “dodes,” and compared treatment recommendations using a decision-tree format.

Eight hospitals participated. The most common treatment options for recurrent GBM were combination repeat surgical resection with temozolomide or bevacizumab, monotherapy temozolomide or bevacizumab, and best supportive care. Alternative therapies, including radiotherapy, were less common. Despite widespread disagreement between centers in clinical decision making, the decision-tree analysis found agreement (>63%) between most centers for only 4 specific clinical scenarios. Patients without an appropriate performance status were usually managed with best supportive care. Patients with rapid recurrence, nonresectable tumors, unmethylated O(6)-methylguanine DNA methyltransferase (MGMT) promoter, and high performance status were usually managed with bevacizumab. Patients with late recurrence, nonresectable tumors, overt clinical symptoms, methylated MGMT promoter, multifocal disease, and high performance status were usually managed with repeat temozolomide therapy. Patients with late recurrence, nonresectable tumors, no clinical symptoms, methylated MGMT promoter, tumor multifocality, and high performance status were usually managed with temozolomide.The findings of this study underscore the lack of effective first- and second-line treatments for GBM, and the interhospital variability in practice patterns is not surprising. It seems likely that similar heterogeneity would also be noted in a study of American neuro-oncology centers. It is interesting to note that despite the availability of an increasing number of molecular markers for GBM stratification, MGMT promoter methylation appears to be the only biological marker widely used across multiple centers in this study. It remains to be seen when and how broadly other markers such as the epidermal growth factor receptor variant III or isocitrate dehydrogenase mutations will be adopted for clinical decision making.The authors are to be congratulated for identifying core clinical decision-making criteria that may be useful in future studies of recurrent GBM. This decision tree is an excellent reference for clinical trial development, and several active clinical trials already target the dodes identified in this study. Subsequent studies may help to determine whether similar decision trees exist in American neuro-oncologic centers now or will exist in the future 10).

Figure. A through F, clinical decision-making tree for recurrent glioblastoma multiforme (GBM) based on clinical scenarios that achieved a majority recommendation (ie, at least 5 of 8 Swiss hospitals). BEV, bevacizumab; BSC, best supportive care; rGBM, recurrent glioblastoma multiforme; TMZ, temozolomide. Modified with kind permission from Springer Science+Business Media: Journal of Neuro-Oncology, Patterns of care in recurrent glioblastoma in Switzerland: a multicenter national approach based on diagnostic nodes (published online ahead of print October 12. 2015), Hundsberger T, Hottinger AF, Roelcke U, et al [doi: 10.1007/s11060-015-1957-0. Available at: http://link.springer.com/article/10.1007%2Fs11060-015-1957-0 ].

Resection

Temozolomide

Temozolomide rechallenge is a treatment option for MGMT promoter-methylated recurrent glioblastoma. Alternative strategies need to be considered for patients with progressive glioblastoma without MGMT promoter methylation 11).

Bevacizumab

Intraarterial chemotharapy

Intrarterial chemotherapy is a viable methodology in recurrent GBM patients to prolong survival at the risk of procedure-related complications and in newly diagnosed patients with the benefit of decreased complications 12).

Low-dose fractionated radiotherapy LD-FRT and chemotherapy for recurrent/progressive GBM have a good toxicity profile and clinical outcomes, even though further investigation of this novel palliative treatment approach is warranted 13).

Second surgery plus carmustine wafers followed by intravenous fotemustine

Second surgery plus carmustine wafers followed by intravenous fotemustine in twenty-four patients were analyzed. The median age was 53.6; all patients had KPS between 90 and 100; 19 patients (79%) performed a gross total resection > 98% and 5 (21%) a gross total resection > 90%. The median progression-free survival from second surgery was 6 months (95% CI 3.9-8.05) and the median OS was 14 months (95% CI 11.1-16.8 months). Toxicity was predominantly haematological: 5 patients (21%) experienced grade 3-4 thrombocytopenia and 3 patients (12%) grade 3-4 leukopenia.

This multimodal strategy may be feasible in patients with recurrent glioblastoma, in particular, for patients in good clinical conditions 14).

Immunotherapy

The HSPPC-96 vaccine is safe and warrants further study of efficacy for the treatment of recurrent GBM. Significant pretreatment lymphopenia may impact the outcomes of immunotherapy and deserves additional investigation 15).

Laser induced interstitial thermotherapy

see Laser interstitial thermotherapy.

Galldiks et al monitored the metabolic effects of stereotaxy-guided LITT in a patient with a recurrent GBM using amino acid positron emission tomography (PET). Serial 11C-methyl-L-methionine positron emission tomography (MET-PET) and contrast-enhanced computed tomography (CT) were performed using a hybrid PET/CT system in a patient with recurrent GBM before and after LITT. To monitor the biologic activity of the effects of stereotaxy-guided LITT, a threshold-based volume of interest analysis of the metabolically active tumor volume (MET uptake index of ≥ 1.3) was performed. A continuous decline in metabolically active tumor volume after LITT could be observed. MET-PET seems to be useful for monitoring the short-term therapeutic effects of LITT, especially when patients have been pretreated with a multistep therapeutic regimen. MET-PET seems to be an appropriate tool to monitor and guide experimental LITT regimens and should be studied in a larger patient group to confirm its clinical value 16).

Outcome

A more favorable prognosis following surgery for recurrence or progression is associated with younger age, smaller tumor volume (~50%), motor speech-middle cerebral artery scoring and preoperative Karnofsky performance score (KPS) >80% 17) 18).

Reviews

Optimal treatment for recurrent high grade glioma continues to evolve. Currently, however, there is no consensus in the literature on the role of reoperation in the management of these patients.

In a analysis, of reoperation in patients with World Health Organization grade III or IV recurrent gliomas, focusing on how reoperation affects outcome, perioperative complications, and quality of life. An extensive literature review was performed through the use of the PubMed and Ovid Medline databases for January 1980 through August 2013. A total 31 studies were included in the final analysis. Of the 31 studies with significant data from single or multiple institutions, 29 demonstrated a survival benefit or improved functional status after reoperation for recurrent high-grade glioma. Indications for reoperation included new focal neurological deficits, tumor mass effect, signs of elevated intracranial pressure, headaches, increased seizure frequency, and radiographic evidence of tumor progression. Age was not a contraindication to reoperation. Time interval of at least 6 months between operations and favorable performance status (Karnofsky Performance Status score ≥70) were important predictors of benefit from reoperation. Extent of resection at reoperation improved survival, even in patients with subtotal resection at initial operation. Careful patient selection such as avoiding those individuals with poor performance status and bevacizumab within 4 weeks of surgery is important. Although limited to retrospective analysis and patient selection bias, mounting evidence suggests a survival benefit in patients receiving a reoperation at the time of high-grade glioma recurrence 19).

Case series

2018

Twenty patients with recurrent glioma were treated with BEV (5-10 mg/kg, i.v. every 2 weeks) plus daily TMZ (daily, 50 mg/m2). The treatment response was evaluated via the RANO criteria. HRQL were measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire core 30 (QLQ-C30) and Brain Module (QLQ-BN20).

Twenty patients received a total of 85 cycles of BEV with a median number of 4 cycles (range: 2-10). No patients showed complete response (CR) to treatment. Twelve patients had partial response (PR), stable disease (SD) in 5 patients with, and 3 patients showed progressive disease (PD). In the functioning domains of QLQ-C30, physical functioning, cognitive functioning and emotional functioning significantly improved after the second cycle of BEV compared to baseline, with the mean score of 45.0 vs. 64.0 (p = 0.020), 55.8 vs. 71.7 (p = 0.020) and 48.3 vs. 67.5 (p = 0.015), respectively. In the symptom scales, the scores of pain and nausea/vomiting significantly decreased compared to baseline from the mean score of 39.1 to 20.0 (p = 0.020) and 29.2 to 16.7 (p = 0.049), respectively. Score of global health status also increased from 47.5 to 63.3 (p = 0.001). As determined with the QLQ-BN20, motor dysfunction (43.3 vs. 25.0, p = 0.021), weakness of legs (36.7 vs. 18.3, p = 0.049), headache (38.3 vs. 20.0, p = 0.040), and drowsiness (50.0 vs. 30.0, p = 0.026) after the second cycle of BEV also significantly improved compared to baseline.

BEV plus daily TMZ as a salvage therapy improved HRQL in patients with recurrent glioma 20).

References

2016

Quick-Weller et al. performed tumour resections in seven patients with rGBM, combining 5-ALA (20 mg/kg bodyweight) with iMRI (0.15 T). Radiologically complete resections were intended in all seven patients.

They assessed intraoperative fluorescence findings and compared these with intraoperative imaging. All patients had early postoperative MRI (3 T) to verify final iMRI scans and received adjuvant treatment according to interdisciplinary tumour board decision.

Median patient age was 63 years. Median KPS score was 90, and median tumour volume was 8.2 cm(3). In six of seven patients (85%), 5-ALA induced fluorescence of tumour-tissue was detected intraoperatively. All tumours were good to visualise with iMRI and contrast media. One patient received additional resection of residual contrast enhancing tissue on intraoperative imaging, which did not show fluorescence. Radiologically complete resections according to early postoperative MRI were achieved in all patients. Median survival since second surgery was 7.6 months and overall survival since diagnosis was 27.8 months.

5-ALA and iMRI are important surgical tools to maximise tumour resection also in rGBM. However, not all rGBMs exhibit fluorescence after 5-ALA administration. They propose the combined use of 5-ALA and iMRI in the surgery of rGBM 21).

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Stupp R, Taillibert S, Kanner A et al (2017) Effect of tumortreating fields plus maintenance temozolomide vs maintenance temozolomide alone on survival in patients with glioblastoma: a randomized clinical trial. JAMA 318:2306–2316
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Dejaegher J, De Vleeschouwer S. Recurring Glioblastoma: A Case for Reoperation? In: De Vleeschouwer S, editor. Glioblastoma [Internet]. Brisbane (AU): Codon Publications; 2017 Sep 27. Chapter 14. Available from http://www.ncbi.nlm.nih.gov/books/NBK469991/ PubMed PMID: 29251867.
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Hundsberger T, Hottinger AF, Roelcke U, et al.. Patterns of care in recurrent glioblastoma in Switzerland: a multicentre national approach based on diagnostic nodes [published online ahead of print October 12, 2015]. J Neuro Oncol. doi: 10.1007/s11060-015-1957-0. Available at: http://link.springer.com/article/10.1007%2Fs11060-015-1957-0.
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Zussman BM, Engh JA. Patterns of Care and Clinical Decision Making for Recurrent Glioblastoma Multiforme. Neurosurgery. 2016 Feb;78(2):N12-4. doi: 10.1227/01.neu.0000479889.72124.20. PubMed PMID: 26779791.
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Weller M, Tabatabai G, Kästner B, Felsberg J, Steinbach JP, Wick A, Schnell O, Hau P, Herrlinger U, Sabel MC, Wirsching HG, Ketter R, Bähr O, Platten M, Tonn JC, Schlegel U, Marosi C, Goldbrunner R, Stupp R, Homicsko K, Pichler J, Nikkhah G, Meixensberger J, Vajkoczy P, Kollias S, Hüsing J, Reifenberger G, Wick W; DIRECTOR Study Group. MGMT Promoter Methylation Is a Strong Prognostic Biomarker for Benefit from Dose-Intensified Temozolomide Rechallenge in Progressive Glioblastoma: The DIRECTOR Trial. Clin Cancer Res. 2015 May 1;21(9):2057-64. doi: 10.1158/1078-0432.CCR-14-2737. Epub 2015 Feb 5. PubMed PMID: 25655102.
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Linezolid

Linezolid

MRSA and MRSE (with MIC > 1 mcg/ml) or patient with vancomycin allergy Linezolid 600mg IV or PO q 12 hrs

Linezolid is an antibiotic used for the treatment of serious infections caused by Gram positive bacteria that are resistant to other antibiotics. Linezolid is active against most Gram-positive bacteria that cause disease, including streptococci, vancomycin-resistant enterococci (VRE), and methicillin resistant Staphylococcus aureus (MRSA).

The main uses are infections of the skin and pneumonia although it may be use for a variety of other infections.

When administered for short periods, linezolid is a relatively safe antibiotic. It can be used in people of all ages and in people with liver disease or poor kidney function. Common adverse effects of short-term use include headache, diarrhea, and nausea. Long-term use, however, has been associated with serious adverse effects such as bone marrow suppression and low platelet counts, particularly when used for more than two weeks. If used for longer periods still, it may cause sometimes irreversible chemotherapy-induced peripheral neuropathy and optic nerve damage, and lactic acidosis (a buildup of lactic acid in the body), all most likely due to mitochondrial toxicity.

As a protein synthesis inhibitor, it stops the growth of bacteria by disrupting their production of proteins, that is, it is a bacteriostatic agent, not bacteriocidal. Although many antibiotics work this way, the exact mechanism of action of linezolid appears to be unique in that it blocks the initiation of protein production, and not one of the later steps.

Bacterial resistance to linezolid has remained very low since it was first detected in 1999, although it may be increasing. It is a member of the oxazolidinone class of drugs.

Linezolid was discovered in the 1990s by a team at Pharmacia and Upjohn Company and first approved for use in 2000. It is on the World Health Organization’s List of Essential Medicines, the most important medications needed in a basic health system.

Linezolid costs approximately US$100 per tablet in the United States. Nonetheless, it appears to be more cost-effective than generic alternatives such as vancomycin, mostly because of the possibility of switching from intravenous to oral administration as soon as patients are stable enough, without the need for dose adjustments.


In animal studies of meningitis caused by Streptococcus pneumoniae, linezolid was found to penetrate well into cerebrospinal fluid, but its effectiveness was inferior to that of other antibiotics.

There does not appear to be enough high-quality evidence to support the routine use of linezolid to treat bacterial meningitis. Nonetheless, it has been used successfully in many cases of central nervous system infection—including meningitis—caused by susceptible bacteria, and has also been suggested as a reasonable choice for this indication when treatment options are limited or when other antibiotics have failed.

The guidelines of the Infectious Diseases Society of America recommend linezolid as the first-line drug of choice for VRE meningitis, and as an alternative to vancomycin for MRSA meningitis.

Linezolid appears superior to vancomycin in treating community-acquired MRSA infections of the central nervous system, although very few cases of such infections have been published (as of 2009).

Effectiveness in Neurosurgery

Evidence for the effectiveness of linezolid in neurosurgical infections (NSIs) is growing. The comfortable oral dosage and tolerance of linezolid opens the possibility for sequential antimicrobial treatment (SAT) in stable patients after a period of intravenous treatment 1).

Reviews

Relevant studies were identified through searches of the PubMed, Current Contents, and Cochrane databases (publications archived until October 2006).

Case reports, case series, prospective and retrospective studies, and randomized controlled trials were eligible for inclusion in our review if they evaluated the effectiveness and safety of linezolid for the treatment of patients with CNS infections.

In 18 (42.9%) of the 42 relevant cases identified, patients had undergone neurosurgical operations and/or had prosthetic devices. Meningitis was the most common CNS infection, accounting for 20 (47.6%) cases. Other CNS infections included brain abscesses (14; 33.3%), ventriculitis (5; 11.9%), and ventriculo-peritoneal shunt infection (3; 7.1%). In the 39 patients in whom the responsible pathogen was isolated, those predominantly responsible for the CNS infections were: penicillin-nonsusceptible Streptococcus pneumoniae (7; 17.9%), vancomycin-resistant enterococci (6; 15.4%), Nocardia spp. (5; 12.8%), methicillin-resistant Staphylococcus epidermidis (4; 10.3%), and methicillin-resistant Staphylococcus aureus (3; 7.7%). Of the 42 patients who received linezolid for the treatment of CNS infections, 38 (90.5%) were either cured or showed clinical improvement of the infection. The mean duration of follow-up was 7.2 months; no recurrent CNS infection was reported.

The limited published data suggest that linezolid may be considered for the treatment of patients with CNS infections in cases of failure of previously administered treatment or limited available options 2).

Case series

To evaluate the efficacy and safety of SAT with oral linezolid in patients with NSI and to analyse the cost implications, an observational, non-comparative, prospective cohort study was conducted on clinically stable consecutive adult patients at the Neurosurgical Service. Following intravenous treatment, patients were discharged with SAT with oral linezolid.

A total of 77 patients were included. The most common NSIs were: 41 surgical wound infections, 20 subdural empyemas, 18 epidural abscesses, and 16 brain abscesses. Forty-four percent of patients presented two or more concomitant NSIs. Aetiological agents commonly isolated were: Propionibacterium acnes (36 %), Staphylococcus aureus (23 %), Staphylococcus epidermidis (21 %) and Streptococcus spp. (13 %). The median duration of the SAT was 15 days (range, 3-42). The SAT was interrupted in five cases due to adverse events. The remainder of the patients were cured at the end of the SAT. A total of 1,163 days of hospitalisation were saved. An overall cost reduction of €516,188 was attributed to the SAT. Eight patients with device infections did not require removal of the device, with an additional cost reduction of €190,595. The mean cost saving per patient was €9,179.

SAT with linezolid was safe and effective for the treatment of NSI. SAT reduces hospitalisation times, which means significant savings of health and economic resources 3).

References

1)

Jahoda D, Nyc O, Pokorný D, Landor I, Sosna A. [Linezolid in the treatment of antibiotic-resistant gram-positive infections of the musculoskeletal system]. Acta Chir Orthop Traumatol Cech. 2006 Oct;73(5):329-33. Czech. PubMed PMID: 17140514.
2)

Ntziora F, Falagas ME. Linezolid for the treatment of patients with central nervous system infection. Ann Pharmacother. 2007 Feb;41(2):296-308. Epub 2007 Feb 6. Review. PubMed PMID: 17284501.
3)

Martín-Gandul C, Mayorga-Buiza MJ, Castillo-Ojeda E, Gómez-Gómez MJ, Rivero-Garvía M, Gil-Navarro MV, Márquez-Rivas FJ, Jiménez-Mejías ME. Sequential antimicrobial treatment with linezolid for neurosurgical infections: efficacy, safety and cost study. Acta Neurochir (Wien). 2016 Oct;158(10):1837-43. doi: 10.1007/s00701-016-2915-0. Epub 2016 Aug 13. PubMed PMID: 27520361.
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