A Pragmatic Randomized Trial Comparing Surgical Clipping and Endovascular Treatment of Unruptured Intracranial Aneurysms.

BACKGROUND AND PURPOSE: Surgical clipping and endovascular treatment are commonly used in patients with unruptured intracranial aneurysms. We compared the safety and efficacy of the 2 treatments in a randomized trial. MATERIALS AND METHODS: Clipping or endovascular treatments were randomly allocated to patients with one or more 3- to 25-mm unruptured intracranial aneurysms judged treatable both ways by participating physicians. The study hypothesized that clipping would decrease the incidence of treatment failure from 13% to 4%, a composite primary outcome defined as failure of aneurysm occlusion, intracranial hemorrhage during follow-up, or residual aneurysms at 1 year, as adjudicated by a core lab. Safety outcomes included new neurologic deficits following treatment, hospitalization of >5 days, and overall morbidity and mortality (mRS > 2) at 1 year. There was no blinding. RESULTS: Two hundred ninety-one patients were enrolled from 2010 to 2020 in 7 centers. The 1-year primary outcome, ascertainable in 290/291 (99%) patients, was reached in 13/142 (9%; 95% CI, 5%-15%) patients allocated to surgery and in 28/148 (19%; 95% CI, 13%-26%) patients allocated to endovascular treatments (relative risk: 2.07; 95% CI, 1.12-3.83; P = .021). Morbidity and mortality (mRS >2) at 1 year occurred in 3/143 and 3/148 (2%; 95% CI, 1%-6%) patients allocated to surgery and endovascular treatments, respectively. Neurologic deficits (32/143, 22%; 95% CI, 16%-30% versus 19/148, 12%; 95% CI, 8%-19%; relative risk: 1.74; 95% CI, 1.04-2.92; P = .04) and hospitalizations beyond 5 days (69/143, 48%; 95% CI, 40%-56% versus 12/148, 8%; 95% CI, 5%-14%; relative risk: 0.18; 95% CI, 0.11-0.31; P < .001) were more frequent after surgery. CONCLUSIONS: Surgical clipping is more effective than endovascular treatment of unruptured intracranial aneurysms in terms of the frequency of the primary outcome of treatment failure. Results were mainly driven by angiographic results at 1 year.

Surgical or Endovascular Treatment of MCA Aneurysms: An Agreement Study.

BACKGROUND AND PURPOSE: MCA aneurysms are still commonly clipped surgically despite the recent development of a number of endovascular tools and techniques. We measured clinical uncertainty by studying the reliability of decisions made for patients with middle cerebral artery (MCA) aneurysms. MATERIALS AND METHODS: A portfolio of 60 MCA aneurysms was presented to surgical and endovascular specialists who were asked whether they considered surgery or endovascular treatment to be an option, whether they would consider recruitment of the patient in a randomized trial, and whether they would provide their final management recommendation. Agreement was studied using κ statistics. Intrarater reliability was assessed with the same, permuted portfolio of cases of MCA aneurysm sent to the same specialists 1 month later. RESULTS: Surgical management was the preferred option for neurosurgeons (n = 844/1320; [64%] responses/22 raters), while endovascular treatment was more commonly chosen by interventional neuroradiologists (1149/1500 [76.6%] responses/25 raters). Interrater agreement was only "slight" for all cases and all judges (κ = 0.094; 95% CI, 0.068-0.130). Agreement was no better within specialties or with more experience. On delayed requestioning, 11 of 35 raters (31%) disagreed with themselves on at least 20% of cases. Surgical management and endovascular treatment were always judged to be a treatment option, for all patients. Trial participation was offered to patients 65% of the time. CONCLUSIONS: Individual clinicians did not agree regarding the best management of patients with MCA aneurysms. A randomized trial comparing endovascular with surgical management of patients with MCA aneurysms is in order.

Understanding burden of proof and equipoise in the design of pragmatic clinical trials: An example from a trial on brain arteriovenous malformations.

BACKGROUND AND PURPOSE: The burden of proof principle is rarely discussed and poorly understood, but central to the proper design of pragmatic clinical trials. A better understanding of the principle could play an important role in the re-introduction of scientific methods within practice and in revising fundamental problems with the current research-care separation. METHODS: We analyze the design of the ARUBA trial on the management of unruptured brain arteriovenous malformations. We also review how the concept of clinical equipoise was introduced to address a misconceived problem of research ethics. RESULTS: The ARUBA trial hypothesis in favour of conservative management of brain arteriovenous malformations failed to take into account the fact that the burden of proof was on surgery, endovascular treatment or radiation therapy. Thus, results remained inconclusive and other trials are needed. The equipoise notion fails to take into account that the burden of proof is on unvalidated medical or surgical interventions, if we want to provide outcome-based medical care that patients can trust. CONCLUSION: The burden of proof principle is essential to properly design pragmatic trials. This principle also explains why in certain circumstances optimal care is a randomized care trial.

Results of a French pilot database of standard of care of chronic subdural hematoma.

BACKGROUND: A registry of chronic subdural hematoma does not exist in France yet. OBJECTIVE: To present a monocentric pilot project of a French registry of surgical management of chronic subdural hematoma. METHOD: A monocentric pseudonymized formal database was created. From May 2020 to May 2021, all patients undergoing surgical evacuation of chronic subdural hematoma were entered into the database. RESULTS: One hundred and twenty four surgeries from 113 patients were entered in the database. Patients' demographic and surgical data as well as follow-up are described. CONCLUSION: A local database is easy to implement. We propose a national registry of chronic subdural hematoma management.

What is the role of neurosurgeons in the current management of intracranial aneurysm in France? An analysis of professional practices.

STUDY DESIGN: Retrospective observational survey-based study. INTRODUCTION: In France, intracranial aneurysm (IA) patients are managed by neurosurgeons and by interventional neuroradiologists. The growth of endovascular treatment led us to reflect on the role of neurosurgeons in the management of patients with IA. The present study aimed to highlight the current organization of IA management in France. METHOD: A 60-question survey was sent to the neurosurgeons in 34 hospitals managing IA patients. Thirty-three questions dealt with standards of care, follow-up procedures and the involvement of the specific specialist. RESULTS: Twenty-seven centers (79.4%) responded to the survey. A Vascular Multidisciplinary Discussion Team was organized, including both surgeons and neuroradiologists, in 92% of responding centers. There were department protocols in 66% of centers, a local registry in 33% and clinical trials in IA in 60%. Patients with unruptured IA were first seen by a neurosurgeon or by an interventional neuroradiologist, with different practices. For ruptured IA, the neurosurgeons were contacted first in 93% of cases, and were systematically involved in initial intensive care unit management. The patients were hospitalized in the neurosurgery department in 89% of the centers. The neurosurgeons took care of initial follow-up in 85% of the centers, and of lifetime follow-up in 36%. In most centers, radiological monitoring of IA was based on MRI angiography for patients who were embolized or under surveillance, and on CT angiography after microsurgery. CONCLUSION: Despite the growth of endovascular treatments, the present survey and the literature highlight a major role of neurosurgeons in treatment, follow-up and care coordination.

Noninvasive Angiographic Results of Clipped or Coiled Intracranial Aneurysms: An Inter- and Intraobserver Reliability Study.

BACKGROUND AND PURPOSE: Noninvasive angiography is commonly used to assess the outcome of surgical or endovascular treatment of intracranial aneurysms in clinical series or randomized trials. We sought to assess whether a standardized 3-grade classification system could be reliably used to compare the CTA and MRA results of both treatments. MATERIALS AND METHODS: An electronic portfolio composed of CTAs of 30 clipped and MRAs of 30 coiled aneurysms was independently evaluated by 24 raters of diverse experience and training backgrounds. Twenty raters performed a second evaluation 1 month later. Raters were asked which angiographic grade and management decision (retreatment; close or long-term follow-up) would be most appropriate for each case. Agreement was analyzed using the Krippendorff α (αK) statistic, and the relationship between angiographic grade and clinical management choice, using the Fisher exact and Cramer V tests. RESULTS: Interrater agreement was substantial (αK = 0.63; 95% CI, 0.55-0.70); results were slightly better for MRA results of coiling (αK = 0.69; 95% CI, 0.56-0.76) than for CTA results of clipping (αK = 0.58; 95% CI, 0.44-0.69). Intrarater agreement was substantial to almost perfect. Interrater agreement regarding clinical management was moderate for both clipped (αK = 0.49; 95% CI, 0.32-0.61) and coiled subgroups (αK = 0.47; 95% CI, 0.34-0.54). The choice of clinical management was strongly associated with the size of the residuum (mean Cramer V = 0.77 [SD, 0.14]), but complete occlusions (grade 1) were followed more closely after coiling than after clipping (P = .01). CONCLUSIONS: A standardized 3-grade scale was found to be a reliable and clinically meaningful tool to compare the results of clipping and coiling of aneurysms using CTA or MRA.

Management of intracranial aneurysms in France: Place of microsurgery and demography of vascular neurosurgeons.

STUDY DESIGN: Observational retrospective survey-based study. INTRODUCTION: Intracranial aneurysms (IA) can be treated with microsurgery or by endovascular treatments (EVT). EVT have taken an increasingly important part in IA management; the ability of neurosurgical teams to perform such surgery as well as the quality of their training is being questioned. We therefore wanted to assess the proportion of IA treated by microsurgery in France, the demography and caseload of surgeons trained in vascular neurosurgery. METHODOLOGY: A 60-question survey was sent to the 34 French neurosurgical centers treating IA. Twenty-seven questions dealt with the demography of neurovascular surgeons and caseload. Descriptive data are reported here. RESULTS: Twenty-seven centers answered, giving us a response rate of 79.4%. A total of 209 neurosurgeons worked in these centers. Forty-six neurosurgeons were designated as referents in vascular neurosurgery, 47% of them were under 45 years old. Among the centers, 96.3% had at least one surgeon that was a referent in neurovascular surgery. A total of 88 surgeons performed IA surgery, but only 11 operated more than 20 IA per year. Two thousand four hundred and thirty seven unruptured IA were treated every year in these centers, 25% of which by microsurgery. A total of 2727 ruptured IA were treated in these centers, of which 15% were treated by microsurgery. The most common indications for microsurgical treatment of IA were: middle cerebral artery aneurysms, wide-neck intracranial aneurysms, and giant intracranial aneurysms, as well as aneurysms associated with a hematoma for the ruptured ones. CONCLUSION: Demography of vascular neurosurgeons remains favorable, with a referent neurosurgeon in most centers, who, in half of the cases, is a young practitioner. The percentage of microsurgery in the treatment of IA is low, especially for ruptured ones. The most frequently operated types of intracranial aneurysm correspond to good practice recommendations.

Functional outcome 1 year after aneurysmal subarachnoid hemorrhage due to ruptured intracranial aneurysm in elderly patients.

BACKGROUND: Population aging raises questions about extending treatment indications in elderly patients with aneurysmal subarachnoid hemorrhage (aSAH). We therefore assessed functional status 1 year after treatment. METHODS: This study involved 310 patients, aged over 70 years, with ruptured brain aneurysm, enrolled between 2008 and 2014 in a prospective multicentre trial (FASHE study: NCT00692744) but considered unsuitable for randomisation and therefore analysed in the observational arms of the study: endovascular occlusion (EV), microsurgical exclusion (MS) and conservative treatment. The aims were to assess independence, cognition, autonomy and quality of life (QOL) at 1 year post-treatment, using questionnaires (MMSE, ADLI, IADL, EORTC-QLQ-C30) filled in by independent nurses after discharge. RESULTS: The 310 patients received the following treatments: 208 underwent EV (67.1%), 54 MS (17.4%) and 48 were conservatively managed (15.5%). At 1 year, independence rates for patients admitted with good clinical status (WFNS I-III) were, according to the aneurysm exclusion procedure (EV, MS or conservative), 58.9%, 50% and 12.1% respectively. MMSE score was pathological in 26 of the 112 EV patients (23.2%), 10 of the 25 MS patients (40%) and 4 of the 9 patients treated conservatively (44%), without any statistically significant difference [Pearson's Chi2 test, F ratio=4.29; P=0.11]. Regarding QoL, overall score was similar between the EV and MS cohorts, but significantly lower with conservative treatment. CONCLUSION: Elderly patients in good clinical condition with aSAH should be treated regardless of associated comorbidities. Curative treatment (EV or MS) reduced mortality without increasing dependence, in comparison with conservative treatment.

A randomized trial of endovascular versus surgical management of ruptured intracranial aneurysms: Interim results from ISAT2.

BACKGROUND AND PURPOSE: Appropriate management of ruptured intracranial aneurysm (RIA) in patients eligible for surgical clipping but under-represented in or excluded from previous randomized trials remains undetermined. METHODS: The International Subarachnoid Aneurysm Trial-2 (ISAT-2) is a randomized care trial comparing surgical versus endovascular treatment (EVT) of RIA. All patients considered for surgical clipping but eligible for endovascular treatment can be included. The primary endpoint is death or dependency on modified Rankin score (mRS>2) at 1 year. Secondary endpoints are 1 year angiographic results and length of hospital stay. RESULTS: An interim analysis was performed after 103 patients were treated from November 2012 to July 2017 in 4 active centers. Fifty-two of the 55 patients allocated to surgery were treated by clipping, and 45 of the 48 allocated to EVT were treated by coiling, with 3 crossovers in each arm. The main endpoint (1 year mRS>2), available for 76 patients, was reached in 16/42 patients allocated to clipping (38%; 95%CI: 25%-53%), and 10/34 patients allocated to coiling (29%; 17%-46%). One year imaging results were available in 54 patients: complete aneurysm occlusion was found in 23/27 patients allocated to clipping (85%; 67%-94%), and 18/27 patients allocated to coiling (67%; 47%-81%). Hospital stay exceeding 20 days was more frequent in surgery (26/55 [47%; 34%-60%]) than EVT (9/48 [19%; 10%-31%]). CONCLUSION: Ruptured aneurysm patients for whom surgical clipping may still be best can be managed in a randomized care trial, which is feasible in some centers. More participating centers are needed.

A randomized controlled study assessing outcome, cognition, autonomy and quality of life in over 70-year-old patients after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Current aging of the population with good physiological status and the increasing incidence of subarachnoid hemorrhage (SAH) in elderly patients has enhanced the benefit of treatment in terms of independence and long-term quality of life (QoL). METHODS: From November 1, 2008 to October 30, 2012, 351 patients aged 70 years or older with aneurysmal SAH underwent adapted treatment: endovascular coiling (EV) for 228 (65%) patients, microsurgical clipping (MS) for 75 (29.3%) or conservative treatment for 48 (13.7%). Forty-one of these were randomized to EV (n=20) or to MS (n=21). The objectives were to determine the proportion of patients with modified Rankin Scale score≤2 (independence) at 1 year, and, secondarily, to compare cognitive function on the Mini-Mental State Examination (MMSE), autonomy on the Activities of Daily Living Index (ADLI) and Instrumental Activities of Daily Living scale (IADL), and QoL, in the prospective and randomized arms, at 1 year. RESULTS: At 1 year, with 1 loss to follow-up in the EV arm, 11 patients (55%) were independent after EV occlusion and 8 (38.1%) after MS exclusion, without significant difference (P=0.29). Mortality was higher after MS during the first 2 postoperative months, and thereafter the difference between MS and EV ceased to be significant. Cognitive function and autonomy scores were similar in both arms. CONCLUSION: In elderly patients treated for aneurysmal SAH, approximately 50% were independent at 1 year, with conserved cognition and autonomy. EV and MS are valid procedures in this population, with similar results at 1 year in terms of independence, cognition, autonomy, and QoL.

Differential growth costs and nitrogen fixation in Cytisus multiflorus (L'Hér.) Sweet and Cytisus scoparius (L.) Link are mediated by sources of inorganic N.

Shrubby legumes in Mediterranean-type ecosystems face strong nutrient limitations that worsen in summer, when water is absent. Nitrogen-fixing legumes are likely to be able to switch between soil N and atmospheric N (N2 ) sources to adjust the C costs of N acquisition in different seasons. We investigated the utilisation of different inorganic N sources by two indigenous shrubby legumes (Cytisus multiflorus and Cytisus scoparius). Plant performance in terms of photosynthesis and biomass production was also analysed. Plants were cultivated in sterile river sand supplied with Hoagland nutrient solution, grown in N-free nutrient solution and inoculated with effective rhizobial strains from nodules of adult plants of the same species. A second treatment consisted of plants given 500 µm NH4 NO3 added into the nutrient solution. In a third treatment, plants were watered with another source of N (500 µm NH4 NO3 ) as well as being inoculated with effective rhizobial strains. The application of NH4 NO3 to the legumes resulted in a larger increase in plant dry matter. Carbon construction costs were higher in plants supplied with mineral and symbiotic N sources and always higher in the endemic C. multiflorus. Differences in photosynthesis rates were only observed between species, regardless of the N source. Non-fertilised inoculated plants had more effective root nodules and a clear dependence on N2 fixation. We propose that the ability of C. scoparius to change N source makes it a plastic species, which would account for its broader distribution in nature.

[Treatment of brain AVMS (TOBAS): A randomized controlled trial and registry]. / Le traitement des MAVS cérébrales (TOBAS) : une étude randomisée controlée avec registre.

OBJECTIVE: The management of unruptured and ruptured brain arteriovenous malformations (AVMs) remains controversial. The Treatment of Brain AVM Study (TOBAS) was designed to assess curative treatments in the management of AVMs. The purpose of our study is to provide a care trial context to brain AVM patients. METHODS: TOBAS is a pragmatic, prospective study including 2 randomized controlled trials and a registry. All AVM patients can be recruited. The preferred management modality will be predetermined prior to randomization by the team based on clinical judgment. Patients eligible for both conservative and interventional management will be randomly allocated conservative or curative treatment. Randomization will be stratified by a treatment modality (surgery, radiosurgery or embolization) and minimized according to a history of previous rupture and Spetzler-Martin grade. A second randomization will allocate eligible patients to embolization/no embolization prior to surgery or radiosurgery. The primary outcome of the study is death (any cause) or disabling stroke (mRS>2) at 10 years. All patients managed according to clinical judgment alone will be included in the registry. The study is registered under: wwwTrials.gov, ID: NCT02098252. EXPECTED RESULTS: A minimum recruitment of 540 patients is required to show that treatment can reduce the primary outcome by 10 % (from 25 to 15 %); 440 patients will be needed to show a 10 % increase in angiographic occlusion for a good clinical outcome with pre-embolization. CONCLUSION: The trial is designed to offer optimal and verifiable care to patients with brain AVMs in spite of the uncertainty. We are currently seeking the participation of multiple centers.

A case of dorsolateral pontine infarct: Description of a new vascular alternating syndrome.

INTRODUCTION: Inferolateral pontine infarcts are well-described lesions of the anterior inferior cerebellar artery territory with a wide variety of clinical presentations. We report the case of isolated unilateral hearing loss and contralateral sensation of coldness due to a dorsolateral lower pontine infarct. CASE DESCRIPTION: We describe the case of a 48-year-old female patient who developed isolated selective high-frequency hearing loss on the left side, and contralateral hemibody sensation of coldness. MRI showed a left-sided dorsolateral lower pontine ischemic lesion. A subsequent angiogram revealed the lesion to result from the spontaneous dissection of a long circumferential branch of the basilar artery. CONCLUSION: To our knowledge, this is the first reported case of a vascular alternating syndrome consisting of isolated ipsilateral hearing loss and contralateral thermal dysesthesia from a dorsolateral lower pontine infarct. Occlusion of a long perforating branch of the basilar artery and consequent posterolateral lower pontine infarct may result in an alternating syndrome with subtle clinical symptoms. Knowledge of this type of syndrome may direct physicians towards the diagnosis of a dorsolateral lower pontine infarct, despite vague clinical complaints.

Atypical IgM multiple myeloma with deletion of c-MAF.

IgM multiple myeloma (MM) is a rare subtype of myeloma that shares clinical and pathological features with Waldenström's macroglobulinaemia. These are two separate entities that differ both in therapy and prognosis. We report a 57-year-old male, who presented with anaemia, hypercalcaemia, acute renal failure and several vertebral fractures that clinically suggested a multiple myeloma. Further investigations revealed a serum monoclonal component of IgM lambda type and a bone marrow infiltrated by small, lymphoplasmocytic cells. IgM MM was finally diagnosed by means of both inmunophenotypic and immunohistochemistry techniques, stressing the importance of inmunophenotypic evaluation when clinical and morphological features are discordant. Fluorescence in situ hybridization (FISH) studies disclosed a particular combination of deletion 13q14, t(11;14) and monoallelic deletion C-MAF without t(14;16). The clinical evolution after a Bortezomib-containing polychemotherapy and autologous stem cell transplantation (ASCT) conditioned with busulphan and melphalan is also presented. This very uncommon case highlights the impact of immunophenotyping on the differential diagnosis between IgM MM and WM, to choose the best treatment and establish an appropriate outcome.

Could ventriculoperitoneal shunt and tracheotomy procedures be realized in the same surgical time?

BACKGROUND: Both tracheotomy and ventriculoperitoneal shunting procedures may be required for the same critically ill patient. However, the risk of surgical site infection (SSI) may be increased if both procedures are performed simultaneously. METHOD: We performed a retrospective analysis of 41 consecutive patients who underwent both procedures simultaneously in our institution between March 2000 and January 2008. RESULTS: Analysis revealed no difference in SSI rate between patients undergoing both procedures simultaneously and in staged procedures. CONCLUSIONS: VP shunting and tracheotomy procedures could be performed simultaneously without increasing the risk of surgical site infection. Such strategy may shorten the length of stay in critical care units.

High prevalence of thyroid dysfunction in pregnant women.

BACKGROUND/AIM: Maternal thyroid dysfunction during pregnancy has been associated with adverse obstetric and neonatal outcomes. This prospective study evaluates the prevalence of these disorders in pregnant women. SUBJECTS AND METHODS: Serum levels of TSH, free T4 (fT4), and thyroperoxidase antibodies (TPO-Ab) were measured in 951 women at different gestational ages of pregnancy. Trimester-specific reference ranges for TSH were used to classify pregnant women into five groups: 1) Overt hypothyroidism (OH); 2) Subclinical hypothyroidism (SCH); 3) Isolated hypothyroxinemia (IH); 4) Low TSH (isolated or associated with high fT4); and 5) Normal. A classification was made also according to the lower and upper ranges provided by the manufacturer for thyroid hormones. Pregnant women who were at a high risk of developing thyroid disease were identified. RESULTS: Altogether, 117 women (12.3%) had hypothyroidism and 25 (2.6%) had low TSH. The prevalence of both OH and SCH was higher in the high-risk group than in the low-risk group, but 17.9% of women with hypothyroidism were classified at low-risk. A family history of thyroid disorders and TPO-Ab positivity increased the risk of SCH. Using non-pregnant reference range for TSH, 10.6% of women were misclassificated. CONCLUSIONS: The high prevalence of hypothyroidism observed in this study suggests that accurate thyroid screening with trimester specific reference ranges should be warranted, particularly in areas with mild to moderate iodine deficiencies.