Summary Background 5-aminolevulinic acid is a non-fluorescent prodrug that leads to intracellular accumulation of fluorescent porphyrins in malignant gliomas—a finding that is under investigation for intraoperative identification and resection of these tumours. We aimed to assess the effect of fluorescence-guided resection with 5-aminolevulinic acid on surgical radicality, progression-free survival, overall survival, and morbidity. Methods 322 patients aged 23–73 years with suspected malignant glioma amenable to complete resection of contrast-enhancing tumour were randomly assigned to 20 mg/kg bodyweight 5-aminolevulinic acid for fluorescence-guided resection (n=161) or to conventional microsurgery with white light (n=161). The primary endpoints were the number of patients without contrast-enhancing tumour on early MRI (ie, that obtained within 72 h after surgery) and 6-month progression-free survival as assessed by MRI. Secondary endpoints were volume of residual tumour on postoperative MRI, overall survival, neurological deficit, and toxic effects. We report the results of an interim analysis with 270 patients in the full-analysis population (139 assigned 5-aminolevulinic acid, 131 assigned white light), which excluded patients with ineligible histological and radiological findings as assessed by central reviewers who were masked as to treatment allocation; the interim analysis resulted in termination of the study as defined by the protocol. Primary and secondary endpoints were analysed by intention to treat in the full-analysis population. The study is registered at http://www.clinicaltrials.gov as NCT00241670. Findings Median follow-up was 35·4 months (95% CI 1·0–56·7). Contrast-enhancing tumour was resected completely in 90 (65%) of 139 patients assigned 5-aminolevulinic acid compared with 47 (36%) of 131 assigned white light (difference between groups 29% [95% CI 17–40], p vs 21·1% [14·0–28·2]; difference between groups 19·9% [9·1–30·7], p=0·0003, Z test). Groups did not differ in the frequency of severe adverse events or adverse events in any organ system class reported within 7 days after surgery. Interpretation Tumour fluorescence derived from 5-aminolevulinic acid enables more complete resections of contrast-enhancing tumour, leading to improved progression-free survival in patients with malignant glioma.

https://www.thelancet.com/pdfs/journals/lanonc/PIIS1470-2045(06)70665-9.pdf

Fluorescence-guided surgery with 5-aminolevulinic acid for resection of malignant glioma: a randomised controlled multicentre phase III trial.

The scope and purpose of this work is 2-fold: to synthesize the available evidence and to translate it into recommendations. This document provides recommendations only when there is evidence to support them. As such, they do not constitute a complete protocol for clinical use. Our intention is that these recommendations be used by others to develop treatment protocols, which necessarily need to incorporate consensus and clinical judgment in areas where current evidence is lacking or insufficient. We think it is important to have evidence-based recommendations to clarify what aspects of practice currently can and cannot be supported by evidence, to encourage use of evidence-based treatments that exist, and to encourage creativity in treatment and research in areas where evidence does not exist. The communities of neurosurgery and neuro-intensive care have been early pioneers and supporters of evidence-based medicine and plan to continue in this endeavor. The complete guideline document, which summarizes and evaluates the literature for each topic, and supplemental appendices (A-I) are available online at https://www.braintrauma.org/coma/guidelines.

Guidelines for the Management of Severe Traumatic Brain Injury, Fourth Edition

Traumatic brain injury (TBI) is a major health and socioeconomic problem that affects all societies. In recent years, patterns of injury have been changing, with more injuries, particularly contusions, occurring in older patients. Blast injuries have been identified as a novel entity with specific characteristics. Traditional approaches to the classification of clinical severity are the subject of debate owing to the widespread policy of early sedation and ventilation in more severely injured patients, and are being supplemented with structural and functional neuroimaging. Basic science research has greatly advanced our knowledge of the mechanisms involved in secondary damage, creating opportunities for medical intervention and targeted therapies; however, translating this research into patient benefit remains a challenge. Clinical management has become much more structured and evidence based since the publication of guidelines covering many aspects of care. In this Review, we summarise new developments and current knowledge and controversies, focusing on moderate and severe TBI in adults. Suggestions are provided for the way forward, with an emphasis on epidemiological monitoring, trauma organisation, and approaches to management.

https://www.thelancet.com/pdfs/journals/laneur/PIIS1474-4422(08)70164-9.pdf

Moderate and severe traumatic brain injury in adults.

Various tumours, classically specified as either neuroendocrine or non-neuroendocrine, contain high numbers of somatostatin receptors, which enable in vivo localization of the primary tumour and its metastases by scintigraphy with the radiolabelled somatostatin analogue octreotide. In addition granulomas and autoimmune processes can be visualized because of local accumulation of somatostatin receptor-positive activated mononuclear leucocytes. In many instances a positive scintigram predicts a favourable response to treatment with octreotide. It is tempting to speculate that octreotide labelled with an appropriate radionuclide might be used in cancer therapy. The successful application of radiolabelled octreotide in scintigraphy indicates the possible usefulness of other radiolabelled peptides, either native peptides or derivatives of these, in, for example, nuclear oncology. The small size of these peptides, e.g. bombesin and substance P, is of the utmost importance for a relatively fast blood clearance, thus leading to low background radioactivity. In this way peptides are powerful alternatives to (fragments of) monoclonal antibodies, the application of which to scintigraphic localization of specific cell surface antigen-bearing tumours is plagued by slow blood clearance and, hence, high background levels.

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Somatostatin receptor scintigraphy with [111In-DTPA-d-Phe1]- and [123I-Tyr3]-octreotide: the Rotterdam experience with more than 1000 patients

The incidence of subarachnoid haemorrhage (SAH) is stable, at around six cases per 100 000 patient years. Any apparent decrease is attributable to a higher rate of CT scanning, by which other haemorrhagic conditions are excluded. Most patients are <60 years of age. Risk factors are the same as for stroke in general; genetic factors operate in only a minority. Case fatality is approximately 50% overall (including pre-hospital deaths) and one-third of survivors remain dependent. Sudden, explosive headache is a cardinal but non-specific feature in the diagnosis of SAH: in general practice, the cause is innocuous in nine out of 10 patients in whom this is the only symptom. CT scanning is mandatory in all, to be followed by (delayed) lumbar puncture if CT is negative. The cause of SAH is a ruptured aneurysm in 85% of cases, non-aneurysmal perimesencephalic haemorrhage (with excellent prognosis) in 10%, and a variety of rare conditions in 5%. Catheter angiography for detecting aneurysms is gradually being replaced by CT angiography. A poor clinical condition on admission may be caused by a remediable complication of the initial bleed or a recurrent haemorrhage in the form of intracranial haematoma, acute hydrocephalus or global brain ischaemia. Occlusion of the aneurysm effectively prevents rebleeding, but there is a dearth of controlled trials assessing the relative benefits of early operation (within 3 days) versus late operation (day 10-12), or that of endovascular treatment versus any operation. Antifibrinolytic drugs reduce the risk of rebleeding, but do not improve overall outcome. Measures of proven value in decreasing the risk of delayed cerebral ischaemia are a liberal supply of fluids, avoidance of antihypertensive drugs and administration of nimodipine. Once ischaemia has occurred, treatment regimens such as a combination of induced hypertension and hypervolaemia, or transluminal angioplasty, are plausible, but of unproven benefit.

/pdf/subarachnoid-haemorrhage-diagnosis-causes-and-management-2bxfcfscjw.pdf

Subarachnoid haemorrhage: diagnosis, causes and management

Methods for assessing early characteristics and late outcome after severe head injury have been devised and applied to 700 cases in three countries (Scotland, Netherlands, and USA) There was a close similarity between the initial features of patients in the three series; in spite of differences on organisation of care and in details of management , the mortality was exactly the same in each country This data bank of cases (which is still being enlarged) can be used for predicting outcome in new cases, and for setting up trials of management

https://jnnp.bmj.com/content/jnnp/40/3/291.full.pdf

Severe head injuries in three countries.

OBJECTIVE Ensuring adequate cerebral oxygenation and perfusion is of fundamental importance in the treatment of patients with acute cerebral disorders Online continuous monitoring of brain oxygenation is possible with a parenchymal microelectrode that measures local brain oxygen tension The ultimate question is whether therapeutic approaches can be targeted on the basis of such monitoring Before this question can be addressed, the technique requires validation in the clinical setting The frequency of occurrence of low values and its relation to outcome need to be established METHODS One hundred one comatose head-injured patients (Glasgow Coma Scale score < or = 8) were studied Local brain oxygen tension probes were inserted in an undamaged part of the frontal region Patients were treated in conformance with the European Brain Injury Consortium guidelines Outcome at 6 months was determined by Glasgow Outcome Scale score RESULTS Early brain tissue hypoxia was frequently observed, despite aggressive treatment for intracranial pressure and cerebral perfusion pressure Values lower than 15 mm Hg, for a duration longer than 30 minutes, were observed in 57 patients Values lower than 10 mm Hg in 42 patients, and lower than 5 mm Hg in 22 patients, were observed during the first 24 hours Depth and duration of tissue hypoxia were related to outcome and proved to be an independent predictor of unfavorable outcome and death CONCLUSION Monitoring the partial oxygen pressure of local brain tissue is a safe and reliable method for regulating cerebral oxygenation Because brain tissue hypoxia occurs frequently and is significantly related to poor outcome, future efforts should be aimed at the treatment of brain tissue hypoxia The effects of such brain hypoxia-targeted treatment need to be established in a multicenter study

Brain oxygen tension in severe head injury.

Ischemia is one of the major factors causing secondary brain damage after severe head injury. We have investigated the value of continuous partial pressure of brain tissue oxygen (PbrO2) monitoring as a parameter for cerebral oxygenation in 22 patients with severe head injury (Glasgow Coma Scale score, < or = 8). Jugular bulb oxygenation, intracranial pressure, and cerebral perfusion pressure were simultaneously recorded. O2 and CO2 reactivity tests were performed daily to evaluate oxygen autoregulatory mechanisms. PbrO2 monitoring was started an average of 7.0 hours after trauma with a mean duration of 74.3 hours. No complications were seen, and the calibration of the catheters after measurement showed a zero drift of 1.2 +/- 0.8 mm Hg and a sensitivity drift of 9.7 +/- 5.3%. In 86% of patients, PbrO2 was < 20 mm Hg in the acute phase. Mean PbrO2 significantly increased during the first 24 hours after injury. Two distinct patterns of change of PbrO2 over time were noted. The first pattern was characterized by normal stable levels after 24 hours, and the second was characterized by transiently elevated levels of PbrO2 during the second and third days. PbrO2 values < or = 5 mm Hg within 24 hours after trauma negatively correlated with outcome. O2 reactivity was significantly lower in patients with good outcomes. CO2 reactivity showed no constant pattern of change over time and was not correlated with outcome. Increased hyperventilation was shown to decrease PbrO2 in some patients. Accurate detection of the moment of cerebral death was possible on the basis of the PbrO2 measurements. The correlation between PbrO2 and other parameters, such as intracranial pressure and cerebral perfusion pressure, was weak. We conclude that PbrO2 monitoring is a safe and clinically applicable method in patients with severe head injury. The early occurrence of ischemia after head injury can be monitored on a continuous basis. Deficiency of oxygen autoregulatory mechanisms can be demonstrated, and their occurrence is inversely related to outcome. For practical clinical use, the method seemed to be superior to jugular oximetry.

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Continuous monitoring of partial pressure of brain tissue oxygen in patients with severe head injury

In six anaesthetised and ventilated dogs the CSF pulse pressure was compared with the volume-pressure response (VPR) during continuous inflation of an extradural balloon. Both pulse pressure and VPR increased linearly with the ventricular fluid pressure (VFP) up to a mean VFP of 60 mmHg. At this pressure a breakpoint occurred above which the CSF pulse pressure showed a steeper linear increase, while the VPR remained constant. It is suggested that the breakpoint is related to failure of autoregulation, and that in non-autoregulating patients the CSF pulse pressure is a better parameter of the clinical state than the VPR.

https://jnnp.bmj.com/content/jnnp/42/8/687.full.pdf

Cerebrospinal fluid pulse pressure and intracranial volume-pressure relationships.

The authors examined whether measurement of resistance to outflow of cerebrospinal fluid (Rcsf) predicts outcome after shunting for patients with normal-pressure hydrocephalus (NPH). In four centers 101 patients (most of whom had idiopathic NPH) who fulfilled strict entry criteria underwent shunt placement irrespective of their level of Rcsf obtained by lumbar constant flow infusion. Gait disturbance and dementia were quantified by using an NPH scale and the patient's level of disability was assessed by using the modified Rankin scale (mRS). In addition the Modified Mini-Mental State Examination was performed. Patients were assessed prior to and 1, 3, 6, 9, and 12 months after surgery. Primary outcome measures were based on differences between the preoperative and last NPH scale scores and mRS grades. Improvement was defined as a change measuring at least 15% in the NPH scale score and at least one mRS grade. Intention-to-treat analysis of all patients at 1 year yielded improvement for 57% in NPH scale score and 59% in mRS grade. Efficacy analysis, excluding serious events and deaths that were unrelated to NPH, was performed for 95 patients. Improvement rose to 76% in NPH scale score and 69% in mRS grade. Six cut-off levels of Rcsf were related to improvement in NPH scale score using two-by-two tables. Positive predictive values were approximately 80% for an Rcsf of 10, 12, or 15 mm Hg/ml/minute, 92% for an Rcsf of 18 mm Hg/ml/minute, and 100% for an Rcsf of 24 mm Hg/ml/minute. Negative predictive values were low. More important was the highest likelihood ratio of 3.5 for an Rcsf of 18 mm Hg/ml/minute. Extensive comorbidity was a major prognostic factor. Measurement of Rcsf reliably predicts outcome if the limit for shunting is raised to 18 mm Hg/ml/minute. At lower Rcsf values the decision depends mainly on the extent to which clinical and computerized tomography findings are typical of NPH.

Cees J. J. Avezaat

Papers

Severe head injuries in three countries.

Brain oxygen tension in severe head injury.

Continuous monitoring of partial pressure of brain tissue oxygen in patients with severe head injury

Cerebrospinal fluid pulse pressure and intracranial volume-pressure relationships.

Dutch Normal-Pressure Hydrocephalus Study: prediction of outcome after shunting by resistance to outflow of cerebrospinal fluid