Jetan H. Badhiwala

Endovascular Thrombectomy for Acute Ischemic Stroke: A Meta-analysis

IMPORTANCE Endovascular intervention for acute ischemic stroke improves revascularization. But trials examining endovascular therapy yielded variable functional outcomes, and the effect of endovascular intervention among subgroups needs better definition. OBJECTIVE To examine the association between endovascular mechanical thrombectomy and clinical outcomes among patients with acute ischemic stroke. DATA SOURCES We systematically searched MEDLINE, EMBASE, CINAHL, Google Scholar, and the Cochrane Library without language restriction through August 2015. STUDY SELECTION Eligible studies were randomized clinical trials of endovascular therapy with mechanical thrombectomy vs standard medical care, which includes the use of intravenous tissue plasminogen activator (tPA). DATA EXTRACTION AND SYNTHESIS Independent reviewers evaluated the quality of studies and abstracted the data. We calculated odds ratios (ORs) and 95% CIs for all outcomes using random-effects meta-analyses and performed subgroup and sensitivity analyses to examine whether certain imaging, patient, treatment, or study characteristics were associated with improved functional outcome. The strength of the evidence was examined for all outcomes using the GRADE method. MAIN OUTCOMES AND MEASURES Ordinal improvement across modified Rankin scale (mRS) scores at 90 days, functional independence (mRS score, 0-2), angiographic revascularization at 24 hours, symptomatic intracranial hemorrhage within 90 days, and all-cause mortality at 90 days. RESULTS Data were included from 8 trials involving 2423 patients (mean [SD] age, 67.4 [14.4] years; 1131 [46.7%] women), including 1313 who underwent endovascular thrombectomy and 1110 who received standard medical care with tPA. In a meta-analysis of these trials, endovascular therapy was associated with a significant proportional treatment benefit across mRS scores (OR, 1.56; 95% CI, 1.14-2.13; P = .005). Functional independence at 90 days (mRS score, 0-2) occurred among 557 of 1293 patients (44.6%; 95% CI, 36.6%-52.8%) in the endovascular therapy group vs 351 of 1094 patients (31.8%; 95% CI, 24.6%-40.0%) in the standard medical care group (risk difference, 12%; 95% CI, 3.8%-20.3%; OR, 1.71; 95% CI, 1.18-2.49; P = .005). Compared with standard medical care, endovascular thrombectomy was associated with significantly higher rates of angiographic revascularization at 24 hours (75.8% vs 34.1%; OR, 6.49; 95% CI, 4.79-8.79; P < .001) but no significant difference in rates of symptomatic intracranial hemorrhage within 90 days (70 events [5.7%] vs 53 events [5.1%]; OR, 1.12; 95% CI, 0.77-1.63; P = .56) or all-cause mortality at 90 days (218 deaths [15.8%] vs 201 deaths [17.8%]; OR, 0.87; 95% CI, 0.68-1.12; P = .27). CONCLUSIONS AND RELEVANCE Among patients with acute ischemic stroke, endovascular therapy with mechanical thrombectomy vs standard medical care with tPA was associated with improved functional outcomes and higher rates of angiographic revascularization, but no significant difference in symptomatic intracranial hemorrhage or all-cause mortality at 90 days.

Biopsy versus partial versus gross total resection in older patients with high-grade glioma: a systematic review and meta-analysis

BACKGROUND Optimal extent of surgical resection (EOR) of high-grade gliomas (HGGs) remains uncertain in the elderly given the unclear benefits and potentially higher rates of mortality and morbidity associated with more extensive degrees of resection. METHODS We undertook a meta-analysis according to a predefined protocol and systematically searched literature databases for reports about HGG EOR. Elderly patients (≥60 y) undergoing biopsy, subtotal resection (STR), and gross total resection (GTR) were compared for the outcome measures of overall survival (OS), postoperative karnofsky performance status (KPS), progression-free survival (PFS), mortality, and morbidity. Treatment effects as pooled estimates, mean differences (MDs), or risk ratios (RRs) with corresponding 95% confidence intervals (CIs) were determined using random effects modeling. RESULTS A total of 12 607 participants from 34 studies met eligibility criteria, including our current cohort of 211 patients. When comparing overall resection (of any extent) with biopsy, in favor of the resection group were OS (MD 3.88 mo, 95% CI: 2.14-5.62, P < .001), postoperative KPS (MD 10.4, 95% CI: 6.58-14.22, P < .001), PFS (MD 2.44 mo, 95% CI: 1.45-3.43, P < .001), mortality (RR = 0.27, 95% CI: 0.12-0.61, P = .002), and morbidity (RR = 0.82, 95% CI: 0.46-1.46, P = .514) . GTR was significantly superior to STR in terms of OS (MD 3.77 mo, 95% CI: 2.26-5.29, P < .001), postoperative KPS (MD 4.91, 95% CI: 0.91-8.92, P = .016), and PFS (MD 2.21 mo, 95% CI: 1.13-3.3, P < .001) with no difference in mortality (RR = 0.53, 95% CI: 0.05-5.71, P = .600) or morbidity (RR = 0.52, 95% CI: 0.18-1.49, P = .223). CONCLUSIONS Our findings suggest an upward improvement in survival time, functional recovery, and tumor recurrence rate associated with increasing extents of safe resection. These benefits did not result in higher rates of mortality or morbidity if considered in conjunction with known established safety measures when managing elderly patients harboring HGGs.

Treatment of posthemorrhagic ventricular dilation in preterm infants: a systematic review and meta-analysis of outcomes and complications

OBJECT The optimal clinical management of intraventricular hemorrhage (IVH) and posthemorrhagic ventricular dilation (PHVD)/posthemorrhagic hydrocephalus (PHH) in premature infants remains unclear. A common approach involves temporary treatment of hydrocephalus in these patients with a ventriculosubgaleal shunt (VSGS), ventricular access device (VAD), or external ventricular drain (EVD) until it becomes evident that the patient needs and can tolerate permanent CSF diversion (i.e., ventriculoperitoneal shunt). The present systematic review and meta-analysis aimed to provide a robust and comprehensive summary of the published literature regarding the clinical outcomes and complications of these 3 techniques as temporizing measures in the management of prematurity-related PHVD/PHH. METHODS The authors searched MEDLINE, EMBASE, CINAHL, Google Scholar, and the Cochrane Library for studies published through December 2013 on the use of VSGSs, VADs, and/or EVDs as temporizing devices for the treatment of hydrocephalus following IVH in the premature neonate. Data pertaining to patient demographic data, study methods, interventions, and outcomes were extracted from eligible articles. For each of the 3 types of temporizing device, the authors performed meta-analyses examining 6 outcomes of interest, which were rates of 1) obstruction; 2) infection; 3) arrest of hydrocephalus (i.e., permanent shunt independence); 4) mortality; 5) good neurodevelopmental outcome; and 6) revision. RESULTS Thirty-nine studies, representing 1502 patients, met eligibility criteria. All of the included articles were observational studies; 36 were retrospective and 3 were prospective designs. Nine studies (n = 295) examined VSGSs, 24 (n = 962) VADs, and 9 (n = 245) EVDs. Pooled rates of outcome for VSGS, VAD, and EVD, respectively, were 9.6%, 7.3%, and 6.8% for obstruction; 9.2%, 9.5%, and 6.7% for infection; 12.2%, 10.8%, and 47.3% for revision; 13.9%, 17.5%, and 31.8% for arrest of hydrocephalus; 12.1%, 15.3%, and 19.1% for death; and 58.7%, 50.1%, and 56.1% for good neurodevelopmental outcome. CONCLUSIONS This study provides robust estimates of outcomes for the most common temporizing treatments for IVH in premature infants. With few exceptions, the range of outcomes was similar for VSGS, VAD, and EVD.

Cervical Spine Clearance in Obtunded Patients After Blunt Traumatic Injury: A Systematic Review

Cervical spine trauma is a major public health problem and a common reason for admission to trauma wards and intensive care units. The cervical spine is injured in 2.3% to 4.3% (14) of blunt traumas. Resultant neurologic impairment is encountered in 33% to 54% (57) of patients with cervical spine trauma. In fact, more than 50% of all acute spinal cord injuries affect the cervical spine (8, 9). Unfortunately, these injuries have poor functional outcomes. Mortality after traumatic cervical spinal cord injury may exceed 20% (1013), and survivors often face lifelong physical disability, along with the associated emotional, psychological, and social burdens (6, 8, 14, 15). The economic costs of spinal cord injury are enormous. In the United States, the total annual direct cost of spinal cord injuries approaches

Diagnostic Yield, Morbidity, and Mortality of Intraventricular Neuroendoscopic Biopsy: Systematic Review and Meta-Analysis

8 billion (16). These factors make diligent and efficient cervical spine clearance protocols a critical priority. The exclusion of cervical spine injury in obtunded patients with trauma poses a significant challenge given the lack of a reliable clinical examination. Common practices at many trauma centers include routine acquisition of cervical spine magnetic resonance imaging (MRI), dynamic radiography (flexion and extension), or continued cervical immobilization until patients are awake and asymptomatic after a negative computed tomography (CT) scan (17, 18). These protocols may increase health care costs unduly, place critically ill patients at risk for deterioration during transportation, and prolong cervical collar immobilization and its associated illnesses. On the other hand, the consequences of missing an injury can be devastating and may include loss of functional ability, independence, and possibly life (1921). The primary aim of this study was to elucidate the role for further routine imaging or prolonged cervical immobilization in excluding significant cervical spine injury after negative CT results in obtunded patients who had blunt traumatic injury. Methods This systematic review was done according to a predefined protocol (Supplement) in accordance with MOOSE (Meta-analysis Of Observational Studies in Epidemiology) guidelines (22) and the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) Statement (23). Supplement. Study Protocol Search Strategy We searched MEDLINE (PubMed and Ovid), EMBASE, CINAHL, Google Scholar, and the Cochrane Library from January 2000 through November 2014 for studies on the role of CT followed by a validating test in evaluating the cervical spine of obtunded trauma patients. We used, in various combinations, keywords and Medical Subject Headings terms pertinent to the patient population (altered, comatose, intensive care, intubated, mental status, obtunded, unconscious, unevaluable, unexaminable, unreliable, or unresponsive), medical condition (fracture, injury, instability, or trauma), anatomical site of interest (cervical-spine or cervical), and relevant radiological imaging methods (clearance, computed tomography, CT, dynamic, extension, flexion, fluoroscopy, imaging, magnetic resonance, MDCT, MR, MRI, plain film, radiograph, or X-ray). We also manually searched the references of relevant studies to identify additional studies for consideration. Selection Criteria Three investigators independently evaluated the studies for eligibility. Selection criteria included a study of any design (randomized, controlled trial; prospective cohort study; or retrospective cohort study). Studies were eligible if the diagnostic protocol of interest included a negative finding on a helical CT scan of the entire cervical spine followed by a confirmatory test. We included only the population of obtunded patients with blunt trauma (Glasgow Coma Scale [GCS] score 14, unreliable clinical examination, or intubation). Only English-language studies documenting the outcome measures of missed cervical spine injury or intervention after a negative CT result and additional findings of a validating test were included. We excluded studies with a sample size of fewer than 10 patients and studies in which partial cervical spine CT scans were used. For studies reporting data on overlapping cohorts from the same institution, we included only the study with the most inclusive cohort to prevent duplication. Studies evaluating only the pediatric population were excluded. Studies that examined awake and obtunded patients were included only if the outcomes of unreliable patients were analyzed separately. Abstracts from meeting proceedings were excluded if the data were not published in full-text articles in a peer-reviewed journal. Disagreements among the 3 reviewers about the decision to include or exclude a study were resolved by consensus and, if necessary, consultation with a fourth reviewer. Data Extraction and Quality Assessment Data from eligible studies were independently extracted by the 3 primary reviewers and verified for accuracy by the fourth reviewer. Discrepancies were resolved by discussion and consensus. We used data collection forms that included the following fields: title, author, year and country of publication, study design, sample size, patient demographic characteristics, Injury Severity Score, GCS score, definition of obtunded, mechanism of injury, CT specifications, further imaging or follow-up of patients with negative CT scans, image interpreter, missed acute cervical spine injuries, and changes in management. The 3 primary reviewers performed quality assessment independently. We used the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies-2) tool (24) and examined patient selection, the index test and reference standard used, and flow and timing to determine whether the risk of bias and concerns about applicability to the review question were low, unclear, or high among eligible studies. Definition of Variables Our primary outcome of interest was clinically significant cervical spine injury missed by CT and detected by the confirmatory test. A clinically significant injury was defined as one resulting in mechanical instability or requiring intervention or change in management. We excluded soft tissue signal changes that did not affect spine stability. The definition of cervical spine instability varied among included studies and was assessed by using many classification systems. Most eligible studies defined instability in accordance with the work of White and Panjabi (25) on biomechanics of the spine. Previous studies defined unstable and purely ligamentous injuries as those involving all 3 columns (26). We adopted and documented cervical spine instability outcomes as reported by the authors of included studies, regardless of the classification used. Changes in management after negative CT results and positive findings on a validating test included prolonged external immobilization or operative stabilization. An obtunded patient was defined as someone who was not fully awake and had an altered level of consciousness (GCS 14). These patients lacked a reliable neurologic examination that could aid in the diagnosis of spinal injury. High-quality CT scans were defined as those protocolled with narrow slice width (1 to 3 mm) and reconstruction in multiple planes. A well-interpreted CT study was defined as an image read by a health professional with special training and expertise in reading such images (that is, a consultant radiologist) rather than an on-call physician or radiology resident. Data Synthesis and Analysis Studies were grouped on the basis of how further evaluation of obtunded trauma patients with negative results from cervical spine CT was handled. The first group included studies that routinely performed MRI after a CT scan that was interpreted as normal. The second group comprised studies in which patients were routinely evaluated with dynamic radiography after negative CT results. The third group included studies in which patients were followed with serial physical examination after a normal CT result, with further imaging obtained as guided by clinical indications (for example, neurologic deficit). For each group, we examined mechanical cervical spine instability, need for operative stabilization, and collar use after negative CT results and additional findings on the confirmatory test. We examined high-quality studies separately. These reports fulfilled 4 criteria: prospective study design, low risk of bias and low concerns about applicability in all domains on the QUADAS-2 tool, well-interpreted CT images, and use of high-quality CT specifications. Given the small number of events (if any), formal meta-analysis was not possible. Data from individual studies are displayed in forest plots with 95% CIs. Exact binominal 1-sided 95% CIs were calculated for each proportion obtained from eligible studies (27). We used R, version 3.1.2 (R Foundation for Statistical Computing), to generate all forest plots. Role of the Funding Source This study received no funding. Results Characteristics of Included Studies Our search yielded 2112 results, of which 1959 were excluded after title and abstract screening. Another 125 were excluded after full-text review (Appendix Figure). The remaining 28 studies (2855) were included, and they reported on a total of 3627 obtunded blunt trauma patients with negative results from cervical spine CT and a validating test. Twenty studies (28, 29, 32, 34, 35, 37, 4044, 46, 4855) were retrospective cohort studies, and 8 (30, 31, 33, 36, 38, 39, 45, 47) were prospective cohort studies. Descriptions of eligible studies are provided in Appendix Tables 1 and 2. Details of methodological assessment of included studies with the QUADAS-2 tool are presented in Appendix Table 3. Appendix Figure. Summary of evidence search and selection. CT = computed tomography. Appendix Table 1. Characteristics of Included Studies Appendix Table 2. Outcomes of Eligible Studies Appendix Table 3. Quality Assessment of Eligible Studies Wit

Clinical trials in cellular immunotherapy for brain/CNS tumors

OBJECTIVE Neuroendoscopic techniques for biopsy of intraventricular tumors are increasingly used, although published data have demonstrated a wide range of outcomes. We performed a systematic review and meta-analysis to investigate the diagnostic yield, morbidity, and mortality of neuroendoscopic biopsy. METHODS Medline and Embase were searched for original data on outcomes of neuroendoscopic biopsy. Summary estimates were achieved by applying a random effects model as per DerSimonian-Laird. Measures of heterogeneity and publication bias were also assessed. Meta-regression was used to assess the relative effect of rigid versus flexible endoscopy on the outcomes of interest. Data on study demographics, operative variables, histopathologies of identified lesions, and clinical features of intraventricular tumors were also collected. RESULTS A total of 30 studies with 2069 total biopsies were included. Neuroendoscopic biopsies were performed concurrently with at least 1 other procedure in 82.7% (n = 1252/1513) of procedures. Germ cell tumors, astrocytomas, and non-neoplastic lesions accounted for most of reported intraventricular lesions at 26.6% (n = 423), 25.5% (n = 406), and 12.4% (n = 198), respectively. The combined diagnostic yield of 28 studies reporting 1995 total biopsies was 87.9% (95% confidence interval [CI] 84.1%-90.9%) with moderate heterogeneity (I(2) = 68.0%). The combined major morbidity of 17 studies reporting 592 total biopsies was 3.1% (95% CI 1.9%-5.1%). The combined mortality of 22 studies reporting 991 total biopsies was 2.2% (95% CI 1.3%-3.6%). There was no significant heterogeneity for major morbidity and mortality (both I(2) = 0). Among included studies, 50% (n = 14) reported using a rigid endoscope exclusively. The results of meta-regression demonstrated no significant differences in diagnostic yield when comparing studies using rigid versus flexible endoscopes exclusively. CONCLUSIONS These results indicate that neuroendoscopic biopsy has a very good diagnostic yield and reasonably low complication rate. The procedure seems most advantageous for diagnosis of intraventricular lesions where cerebrospinal fluid diversion is an additional therapeutic requirement.

Deep brain stimulation for Parkinson’s disease: meta-analysis of results of randomized trials at varying lengths of follow-up

High-grade gliomas are the most common type of primary malignant brain/CNS tumor. There have been only modest advances in surgical techniques, radiotherapy and chemotherapy for high-grade gliomas over the past several decades. None of these have provided a major improvement in survival for patients. Recently, immunotherapy has been explored for the treatment of high-grade gliomas. Immunotherapy capitalizes on the specificity of the host immune system to selectively target tumor cells for destruction, while sparing normal brain parenchyma, thus making it a particularly attractive option. This article provides a comprehensive review of published clinical trials evaluating cellular immunotherapy in primary brain/CNS tumors.

Atraumatic versus conventional lumbar puncture needles: a systematic review and meta-analysis

OBJECTIVE Deep brain stimulation (DBS) is effective in the management of patients with advanced Parkinsons disease (PD). While both the globus pallidus pars interna (GPi) and the subthalamic nucleus (STN) are accepted targets, their relative efficacy in randomized controlled trials (RCTs) has not been established beyond 12 months. The objective of this study was to conduct a meta-analysis of RCTs to compare outcomes among adults with PD undergoing DBS of GPi or STN at various time points, including 36 months of follow-up. METHODS The MEDLINE, Embase, CENTRAL, Web of Science, and CINAHL databases were searched. Registries for clinical trials, selected conference proceedings, and the table of contents for selected journals were also searched. Screens were conducted independently and in duplicate. Among the 623 studies initially identified (615 through database search, 7 through manual review of bibliographies, and 1 through a repeat screen of literature prior to submission), 19 underwent full-text review; 13 of these were included in the quantitative meta-analysis. Data were extracted independently and in duplicate. The Cochrane Collaboration tool was used to assess the risk of bias. The GRADE evidence profile tool was used to assess the quality of the evidence. Motor scores, medication dosage reduction, activities of daily living, depression, dyskinesias, and adverse events were compared. The influence of disease duration (a priori) and the proportion of male patients within a study (post hoc) were explored as potential subgroups. RESULTS Thirteen studies (6 original cohorts) were identified. No difference in motor scores or activities of daily living was identified at 36 months. Medications were significantly reduced with STN stimulation (5 studies, weighted mean difference [WMD] -365.46, 95% CI -599.48 to -131.44, p = 0.002). Beck Depression Inventory scores were significantly better with GPi stimulation (3 studies; WMD 2.53, 95% CI 0.99-4.06 p = 0.001). The motor benefits of GPi and STN DBS for PD are similar. CONCLUSIONS The motor benefits achieved with GPi and STN DBS for PD are similar. DBS of STN allows for a greater reduction of medication, but not as significant an advantage as DBS of GPi with respect to mood. This difference is sustained at 36 months. Further long-term studies are necessary.

The development of thromboembolism may increase the risk of osteonecrosis in children with acute lymphoblastic leukemia.

BACKGROUND Atraumatic needles have been proposed to lower complication rates after lumbar puncture. However, several surveys indicate that clinical adoption of these needles remains poor. We did a systematic review and meta-analysis to compare patient outcomes after lumbar puncture with atraumatic needles and conventional needles. METHODS In this systematic review and meta-analysis, we independently searched 13 databases with no language restrictions from inception to Aug 15, 2017, for randomised controlled trials comparing the use of atraumatic needles and conventional needles for any lumbar puncture indication. Randomised trials comparing atraumatic and conventional needles in which no dural puncture was done (epidural injections) or without a conventional needle control group were excluded. We screened studies and extracted data from published reports independently. The primary outcome of postdural-puncture headache incidence and additional safety and efficacy outcomes were assessed by random-effects and fixed-effects meta-analysis. This study is registered with the International Prospective Register of Systematic Reviews, number CRD42016047546. FINDINGS We identified 20 241 reports; after exclusions, 110 trials done between 1989 and 2017 from 29 countries, including a total of 31 412 participants, were eligible for analysis. The incidence of postdural-puncture headache was significantly reduced from 11·0% (95% CI 9·1-13·3) in the conventional needle group to 4·2% (3·3-5·2) in the atraumatic group (relative risk 0·40, 95% CI 0·34-0·47, p<0·0001; I2=45·4%). Atraumatic needles were also associated with significant reductions in the need for intravenous fluid or controlled analgesia (0·44, 95% CI 0·29-0·64; p<0·0001), need for epidural blood patch (0·50, 0·33-0·75; p=0·001), any headache (0·50, 0·43-0·57; p<0·0001), mild headache (0·52, 0·38-0·70; p<0·0001), severe headache (0·41, 0·28-0·59; p<0·0001), nerve root irritation (0·71, 0·54-0·92; p=0·011), and hearing disturbance (0·25, 0·11-0·60; p=0·002). Success of lumbar puncture on first attempt, failure rate, mean number of attempts, and the incidence of traumatic tap and backache did not differ significantly between the two needle groups. Prespecified subgroup analyses of postdural-puncture headache revealed no interactions between needle type and patient age, sex, use of prophylactic intravenous fluid, needle gauge, patient position, indication for lumbar puncture, bed rest after puncture, or clinician specialty. These results were rated high-quality evidence as examined using the grading of recommendations assessment, development, and evaluation. INTERPRETATION Among patients who had lumbar puncture, atraumatic needles were associated with a decrease in the incidence of postdural-puncture headache and in the need for patients to return to hospital for additional therapy, and had similar efficacy to conventional needles. These findings offer clinicians and stakeholders a comprehensive assessment and high-quality evidence for the safety and efficacy of atraumatic needles as a superior option for patients who require lumbar puncture. FUNDING None.

Exploring the expectation-actuality discrepancy: a systematic review of the impact of preoperative expectations on satisfaction and patient reported outcomes in spinal surgery.

Previous studies indicate pathophysiological and epidemiological parallels between osteonecrosis (ON) and thromboembolism (TE), two common treatment‐related morbidities in acute lymphoblastic leukemia (ALL). To elucidate risk factors for ON and explore the relationship between ON and TE, we undertook a retrospective study of children (n = 208) with ALL. Twenty‐one (10.1%) children developed ON and 42 (20.2%) TE on therapy. Thromboembolism was a significant predictor of ON on univariate (OR 8.85) and multivariate analysis, along with older age and PEGylated asparaginase. This observation supports a role for hypercoagulability in the pathogenesis of ON. Larger prospective studies are needed to further test these findings. Pediatr Blood Cancer 2015;62:1851–1854.