Jean-Louis Caron

Scalp nerve blocks decrease the severity of pain after craniotomy

Up to 80% of patients report moderate to severe pain after craniotomy. In this study, we assessed the efficacy of scalp block for decreasing postoperative pain in brain surgery. Thirty patients scheduled for supratentorial craniotomy were enrolled. They were randomly divided into two groups: Ropivacaine (scalp block with 20 mL of ropivacaine 0.75%) and Saline (scalp block with 20 mL of saline 0.9%). Anesthesia was standardized. The scalp block was performed after skin closure and before awakening. Postoperative pain was assessed at 4, 8, 12, 16, 20, 24, and 48 h by using a 10-cm visual analog scale. Analgesia was provided with sub- cutaneous codeine as requested by the patient. Average visual analog scale scores were higher in the Saline group as compared with Ropivacaine (3.7 ± 2.4 vs 2.0 ± 1.6;P = 0.036). The total dose of codeine did not differ, nor did the duration of time before the first dose of codeine was required in the Ropivacaine (571 ± 765 min) versus Saline (319 ± 409 min;P = 0.17) group. In conclusion, we found that postoperative scalp block decreases the severity of pain after craniotomy and that this effect is long lasting, possibly through a preemptive mechanism.

Thrombolytic removal of intraventricular haemorrhage in treatment of severe stroke: results of the randomised, multicentre, multiregion, placebo-controlled CLEAR III trial

BACKGROUND Intraventricular haemorrhage is a subtype of intracerebral haemorrhage, with 50% mortality and serious disability for survivors. We aimed to test whether attempting to remove intraventricular haemorrhage with alteplase versus saline irrigation improved functional outcome. METHODS In this randomised, double-blinded, placebo-controlled, multiregional trial (CLEAR III), participants with a routinely placed extraventricular drain, in the intensive care unit with stable, non-traumatic intracerebral haemorrhage volume less than 30 mL, intraventricular haemorrhage obstructing the 3rd or 4th ventricles, and no underlying pathology were adaptively randomly assigned (1:1), via a web-based system to receive up to 12 doses, 8 h apart of 1 mg of alteplase or 0·9% saline via the extraventricular drain. The treating physician, clinical research staff, and participants were masked to treatment assignment. CT scans were obtained every 24 h throughout dosing. The primary efficacy outcome was good functional outcome, defined as a modified Rankin Scale score (mRS) of 3 or less at 180 days per central adjudication by blinded evaluators. This study is registered with ClinicalTrials.gov, NCT00784134. FINDINGS Between Sept 18, 2009, and Jan 13, 2015, 500 patients were randomised: 249 to the alteplase group and 251 to the saline group. 180-day follow-up data were available for analysis from 246 of 249 participants in the alteplase group and 245 of 251 participants in the placebo group. The primary efficacy outcome was similar in each group (good outcome in alteplase group 48% vs saline 45%; risk ratio [RR] 1·06 [95% CI 0·88-1·28; p=0·554]). A difference of 3·5% (RR 1·08 [95% CI 0·90-1·29], p=0·420) was found after adjustment for intraventricular haemorrhage size and thalamic intracerebral haemorrhage. At 180 days, the treatment group had lower case fatality (46 [18%] vs saline 73 [29%], hazard ratio 0·60 [95% CI 0·41-0·86], p=0·006), but a greater proportion with mRS 5 (42 [17%] vs 21 [9%]; RR 1·99 [95% CI 1·22-3·26], p=0·007). Ventriculitis (17 [7%] alteplase vs 31 [12%] saline; RR 0·55 [95% CI 0·31-0·97], p=0·048) and serious adverse events (114 [46%] alteplase vs 151 [60%] saline; RR 0·76 [95% CI 0·64-0·90], p=0·002) were less frequent with alteplase treatment. Symptomatic bleeding (six [2%] in the alteplase group vs five [2%] in the saline group; RR 1·21 [95% CI 0·37-3·91], p=0·771) was similar. INTERPRETATION In patients with intraventricular haemorrhage and a routine extraventricular drain, irrigation with alteplase did not substantially improve functional outcomes at the mRS 3 cutoff compared with irrigation with saline. Protocol-based use of alteplase with extraventricular drain seems safe. Future investigation is needed to determine whether a greater frequency of complete intraventricular haemorrhage removal via alteplase produces gains in functional status. FUNDING National Institute of Neurological Disorders and Stroke.

Safety and efficacy of minimally invasive surgery plus alteplase in intracerebral haemorrhage evacuation (MISTIE): a randomised, controlled, open-label, phase 2 trial

BACKGROUND Craniotomy, according to the results from trials, does not improve functional outcome after intracerebral haemorrhage. Whether minimally invasive catheter evacuation followed by thrombolysis for clot removal is safe and can achieve a good functional outcome is not known. We investigated the safety and efficacy of alteplase, a recombinant tissue plasminogen activator, in combination with minimally invasive surgery (MIS) in patients with intracerebral haemorrhage. METHODS MISTIE was an open-label, phase 2 trial that was done in 26 hospitals in the USA, Canada, the UK, and Germany. We used a computer-generated allocation sequence with a block size of four to centrally randomise patients aged 18-80 years with a non-traumatic (spontaneous) intracerebral haemorrhage of 20 mL or higher to standard medical care or image-guided MIS plus alteplase (0·3 mg or 1·0 mg every 8 h for up to nine doses) to remove clots using surgical aspiration followed by alteplase clot irrigation. Primary outcomes were all safety outcomes: 30 day mortality, 7 day procedure-related mortality, 72 h symptomatic bleeding, and 30 day brain infections. This trial is registered with ClinicalTrials.gov, number NCT00224770. FINDINGS Between Feb 2, 2006, and April 8, 2013, 96 patients were randomly allocated and completed follow-up: 54 (56%) in the MIS plus alteplase group and 42 (44%) in the standard medical care group. The primary outcomes did not differ between the standard medical care and MIS plus alteplase groups: 30 day mortality (four [9·5%, 95% CI 2·7-22.6] vs eight [14·8%, 6·6-27·1], p=0·542), 7 day mortality (zero [0%, 0-8·4] vs one [1·9%, 0·1-9·9], p=0·562), symptomatic bleeding (one [2·4%, 0·1-12·6] vs five [9·3%, 3·1-20·3], p=0·226), and brain bacterial infections (one [2·4%, 0·1-12·6] vs zero [0%, 0-6·6], p=0·438). Asymptomatic haemorrhages were more common in the MIS plus alteplase group than in the standard medical care group (12 [22·2%; 95% CI 12·0-35·6] vs three [7·1%; 1·5-19·5]; p=0·051). INTERPRETATION MIS plus alteplase seems to be safe in patients with intracerebral haemorrhage, but increased asymptomatic bleeding is a major cautionary finding. These results, if replicable, could lead to the addition of surgical management as a therapeutic strategy for intracerebral haemorrhage. FUNDING National Institute of Neurological Disorders and Stroke, Genentech, and Codman.SUMMARY Background Craniotomy, when evaluated in trials, does not improve outcome after intracerebral haemorrhage (ICH). Whether minimally invasive catheter evacuation followed by thrombolysis is safe and can achieve a good functional outcome by removing clot is unknown. We investigated safety and efficacy of alteplase with minimally invasive surgery (MIS) in patients with intracerebral haemorrhage. Methods MISTIE was an international, randomized, open-label study and was done in 26 hospitals in the USA, Canada, the UK, and Germany. Patients (aged 18–80 years), with non-traumatic (spontaneous) ICH ≥20 mL were randomly allocated, centrally, to medical care or image-guided MIS plus rt-PA (0.3 mg or 1.0 mg every 8 hours for up to 9 doses) to remove clot using surgical aspiration followed with alteplase clot irrigation. The primary efficacy outcome was the adjusted dichotomized modified Rankin Scale (mRS) 0–3 vs 4–6 assessed at day 180 after symptom onset. Analysis was by intention to treat. (ClinicalTrials.gov number NCT00224770). Findings Between February 2, 2006 and April 8, 2013, 96 subjects were randomized and completed follow-up: 54 received treatment and 42 medical care. Primary safety outcomes: mortality, symptomatic bleeding, brain infections, as well as withdrawal of care, did not differ between groups. Asymptomatic hemorrhages were more common in the surgical group (3 (7%) vs. 12 (22%) p= 0.05) producing a difference of 15.1% (95% CI: 1.5% to 28.6%). The estimated absolute benefit, i.e., the unadjusted difference in observed proportions of all subjects with mRS 0–3 (33% vs 21%) at 180 days comparing MISPA vs. medical control, is 0.109 [95%CI: −0.088, 0.294; p=0.26], and is 0.162 [95%CI: 0.003, 0.323; p=0.05] after adjustment for potential imbalances in baseline severity between study arms (primary efficacy outcome). Interpretation MIS+rt-PA appears safe with an apparent advantage of better functional outcome at 180 days. Increased asymptomatic bleeding is a major cautionary finding. The MISTIE trial results, if replicable, could produce a meaningful functional benefit adding surgical management as a therapeutic strategy for ICH. Funding National Institute of Neurologic Disorders and Stroke, Genentech, and Codman.

The integral biologically effective dose to predict brain stem toxicity of hypofractionated stereotactic radiotherapy

OBJECTIVE The aim of this work was to develop a parameter for use during fractionated stereotactic radiotherapy treatment planning to aid in the determination of the appropriate treatment volume and fractionation regimen that will minimize risk of late damage to normal tissue. MATERIALS & METHODS We have used the linear quadratic model to assess the biologically effective dose at the periphery of stereotactic radiotherapy treatment volumes that impinge on the brain stem. This paper reports a retrospective study of 77 patients with malignant and benign intracranial lesions, treated between 1987 and 1995, with the dynamic rotation technique in 6 fractions over a period of 2 weeks, to a total dose of 42 Gy prescribed at the 90% isodose surface. From differential dose-volume histograms, we evaluated biologically effective dose-volume histograms and obtained an integral biologically-effective dose (IBED) in each case. RESULTS Of the 77 patients in the study, 36 had target volumes positioned so that the brain stem received more than 1% of the prescribed dose, and 4 of these, all treated for meningioma, developed serious late damage involving the brain stem. Other than type of lesion, the only significant variable was the volume of brain stem exposed. An analysis of the IBEDs received by these 36 patients shows evidence of a threshold value for late damage to the brain stem consistent with similar thresholds that have been determined for external beam radiotherapy. CONCLUSION We have introduced a new parameter, the IBED, that may be used to represent the fractional effective dose to structures such as the brain stem that are partially irradiated with stereotactic dose distributions. The IBED is easily calculated prior to treatment and may be used to determine appropriate treatment volumes and fractionation regimens minimizing possible toxicity to normal tissue.

Early progression of traumatic cerebral contusions: characterization and risk factors.

BACKGROUND Traumatic intracerebral contusions carry a high rate of early progression and are associated with morbidity and mortality. Our objectives were to better characterize the prevalence of progression of traumatic contusions, risk factors, and the association with outcome. METHODS Participants were 46 patients with traumatic intracerebral contusion who underwent a repeat computed tomography (CT) scan within 24 hours of injury. Hemorrhage volume on the CT scan was quantified using the ABC/2 technique. Univarite and multivariate statistics were used to define growth (percentage increase and absolute volume increase), to examine the relationship between the risk factors of interest and hemorrhage expansion, and with neurologic function and discharge destination. RESULTS Sixty-five percent of the patients experienced progression in the size of the lesion in the initial 24 hours postinjury. The international normalized ratio was significantly higher in the group that demonstrated progression. Deterioration on the Glasgow Coma Score was associated with a threefold risk of hemorrhage expansion being found on the CT as defined by percentage increase (odds ratio [OR] = 3.43; 95% confidence interval [CI]: 0.90 to 13.10) and similarly when defined as absolute increase in volume (OR = 3.32; 95% CI: 0.96 to 11.41). Controlling for injury severity, there was an association between hemorrhage growth and death with those displaying progression more likely to die during hospitalization (OR = 1.08; 95% CI: 0.97 to 1.20). CONCLUSION A high proportion of intracerebral contusions evolve in size very early in the postinjury period and are associated with negative outcomes. There is still not a proven therapy for limiting the expansion although the association of an elevated international normalized ratio with expansion suggests that coagulation abnormalities must be actively corrected.

Dynamic stereotactic radiosurgery in the palliative treatment of cerebral metastatic tumors

From October 1988 to April 1990, 9 patients with metastatic brain disease (11 lesions) underwent stereotactic radiosurgery. All patients but two had recurrent metastatic disease after previous brain irradiation. The patients were treated with a single dose of 20 Gy, delivered to spherical target volumes ranging in diameters from 10 mm to 30 mm and prescribed to the 90% isodose surface. All tumors treated showed a favorable response to the treatment, with 4 patients achieving a complete radiological disappearance of the tumor. The majority of the patients experienced a rapid clinical improvement of their symptoms. No complications attributable to the radiosurgical treatment were seen. Stereotactic radiosurgery appears to be an effective and safe treatment for patients with recurrent metastatic brain disease.

Radiosurgery and accelerated radiotherapy for patients with glioblastoma

OBJECTIVE To assess the feasibility, toxicity, and local control of stereotactic radiosurgery followed by accelerated external beam radiotherapy (AEBR) for patients with glioblastoma multiforme. MATERIALS AND METHODS Six males and eight females, with a median age of 67.5 years (range 45-78 years), entered the study. Karnofsky performance status was 90 for five, 80 for six, and 60 for three patients. Following surgery, the patients were left with a residual mass 4 cm. Radiosurgery was delivered with a single dose of 20 Gy to the 90% isodose surface corresponding to the contrast-enhancing edge of the tumour. A total AEBR dose of 60 Gy in 30 fractions was delivered using a concomitant boost technique over four weeks. RESULTS Median survival time was 40 weeks (range 17-80 weeks). Actuarial survivals at 12 and 18 months were 43% and 14%, respectively. The median time to progression was 25 weeks (range 2-77 weeks). One patient developed a seizure on the day of stereotactic radiosurgery. Two patients experienced somnolence at 47 and 67 days post-radiotherapy. Eight patients remained steroid-dependent. Radiological evidence of leukoencephalopathy was observed in one patient, and brain necrosis in two additional patients at 30 and 63 weeks. One of these two patients with brain necrosis developed complete loss of vision in one eye, and decreased vision in the contralateral eye at 63 weeks. CONCLUSION Stereotactic radiosurgery followed by AEBR was feasible but was associated with late complications. The use of such radiosurgical boost for patients with glioblastoma multiforme should be reserved for those patients entering controlled clinical trials.

Tension pneumocephalus after evacuation of chronic subdural hematoma and subsequent treatment with continuous lumbar subarachnoid infusion and craniostomy drainage.

We present a case of tension pneumocephalus after burr hole evacuation of bilateral chronic subdural hematomas. Subsequent treatment was effected with combined twist drill closed system drainage and continuous intrathecal infusion of a physiological solution. The clinical entity, tension pneumocephalus, and the use of continuous subarachnoid infusion and drainage as a method of cerebral reexpansion are discussed.

A halo-ring technique for fractionated stereotactic radiotherapy

Stereotactic radiosurgery has become established as an effective treatment modality for certain non-malignant brain diseases such as arteriovenous malformations. This paper describes an extension of our linear accelerator-based radiosurgical technique to fractionated treatment of intracranial disease. The fractionated stereotactic radiotherapy technique expands the use of the modality by sparing normal cells within the treatment volume thus improving the therapeutic ratio. The first treatment is given using a stereotactic frame both for target localization and patient immobilization. The frame is then removed and subsequent treatments use a standard neurosurgical halo-ring for patient immobilization. The halo-ring is left in place on the skull for the duration of the course of treatment. Thus the physical requirements for fractionation pertain firstly to the patient immobilization and target localization using the halo-ring and secondly to the stringent quality assurance procedures required to maintain spatial accuracy under these new conditions. We describe a sensitive and effective technique for checking the rotational beam parameters and collimator alignment which we use immediately prior to treatment to ensure adequate accuracy of dose delivery to the target volume.

Intensity-modulated radiosurgery for childhood arteriovenous malformations

SummaryPurpose. Presentation of intensity-modulated radiosurgery (IMRS) for the treatment of inoperable, complex shaped pediatric arterio-venous malformations AVM. Method. Between 03/99 and 11/04, IMRS was delivered to seven children aged six to 18 years. Prescribed minimum doses ranged from 17.5 to 20 Gy (median 18 Gy). Radiosurgery planning and delivery used a serial tomotherapeutic IMRT technique (Peacock IMRT, North American Scientific/Nomos, Cranberry Township, PA) over two to four couch angles. A linear accelerator attached binary multi-leaf collimator was used to generate pencil beams of 10 mm by either 8.5 or 4.0 mm. Treatment planning employed an inverse treatment planning optimization algorithm. Parameters submitted to the treatment planning system were: prescription dose (PD), volume of target allowed to receive less dose (standard 3%), minimum dose (0.5 Gy less than PD), and maximum dose (200% of PD). Planning system specific IMRS target and tissue types were selected to prioritize dose conformality over dose homogeneity. The prescription isodose encompassed at least 95% of the target volume. We calculated conformality (CI) and homogeneity indices (HI) to characterize the quality of IMRS plans, and summarized preliminary clinical outcomes. Findings. Target volumes ranged from 0.71 to 63.02 cm3 (median 13.8 cm3, 6/7 AVM larger than 10 cm3). Median CI was 1.07 (range 1.05 to 1.7) according to RTOG criteria. Median HI was 1.12 (range 1.09 to 1.23). During limited follow-up (median 32 months, range 5 to 53 months), two AVM completely obliterated at 19 and 22 months, and partial obliteration (>75%) was observed in three cases. No treatment-related side effects, other than acute nausea and temporary headaches interpreted as being associated with changes in cerebral blood distribution, were observed. Conclusions. IMRS can allow for highly conformal planning and delivery of radiosurgery radiation doses even if pediatric AVM target volumes are large and/or highly complex in shape. This technique has been seen to result in favorable preliminary outcomes, thus supporting future exploration of this technique in pediatric and adult patients.