Outcome Reporting Bias in Clinical Trials Researching Disease-Modifying Therapy in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Outcome reporting bias occurs when publication of trial results is dependent on clinical significance, thereby threatening the validity of trial results. Research on immunomodulatory drugs in multiple sclerosis has thrived in recent years. We aim to comprehensively examine to what extent outcome reporting bias is present in these trials and the possible underlying factors. METHODS: We identified clinical trials evaluating the efficacy and safety of immunomodulatory drugs in patients with multiple sclerosis (MS) registered in ClinicalTrials.gov after September 2007 and completed before the end of 2018. Information about study design, type of funding, and primary and secondary outcome measures was extracted from the registry. Timing of registration in relation to study initiation and subsequent amendments to the planned outcomes were reviewed. Publications related to these trials were identified in several bibliographic databases using the trial registration number. Registered primary and secondary outcomes were recorded for each trial and compared with outcomes in the publication describing the main outcomes of the trial. RESULTS: A search of ClinicalTrials.gov identified 535 eligible registered clinical trials; of these, 101 had a matching publication. Discrepancies between registered and published primary and secondary outcomes were found in 95% of the trials, including discrepancies between the registered and published primary outcomes in 26 publications. Forty-four percent of the published secondary outcomes were not included in the registry. A similar proportion of registered and nonregistered reported primary efficacy outcomes were positive (favoring the intervention). Nonindustry-funded and open-label trials in MS were more prone to selective primary outcome reporting, although these findings did not reach statistical significance. Only two-thirds of the trials were registered in ClinicalTrials.gov before the trial start date, and 62% of trials made amendments in registered outcomes during or after the trial period. DISCUSSION: Selective outcome reporting is prevalent in trials of disease-modifying drugs in people with MS. We propose methods to diminish the occurrence of this bias in future research.

The Value of Cranial CT Imaging in Patients With Headache at the Emergency Department.

Background: Headache is among the most prevalent complaints in patients presenting to the emergency department (ED). Clinicians are faced with the difficult task to differentiate primary (benign) from secondary headache disorders, since no international guidelines currently exist of clinical indicators for neuroimaging in headache patients. Methods: We performed a retrospective review of 501 patients who presented at the ED with headache as a primary complaint between April 2018 and December 2018. Primary outcomes included the amount of diagnostic imaging, the different conclusions provided by diagnostic imaging, and the clinical factors associated with abnormal imaging results. Results: About half of the patients were diagnosed with a primary headache disorder. Cranial CT imaging at the ED was performed regularly (61% of the patients) and led to the diagnosis of underlying pathology in 1 in 7.6 patients. In a multivariate model, factors significantly associated with abnormal cranial CT results were age 50 years or older, presentation within 1 h after headache onset, clinical history of aphasia, and focal neurological deficit at examination. Conclusions: As separate clinical characteristics have limited value in detecting severe underlying headache disorders, cranial imaging is regularly performed in the ED. Clinical prediction model tools applied to headache patients may identify patients at risk of intracranial pathology prior to diagnostic imaging and reduce cranial imaging in the future.

The association of patient age with postoperative morbidity and mortality following resection of intracranial tumors.

Introduction: The postoperative functional status of patients with intracranial tumors is influenced by patient-specific factors, including age. Research question: This study aimed to elucidate the association between age and postoperative morbidity or mortality following the resection of brain tumors. Material and methods: A multicenter database was retrospectively reviewed. Functional status was assessed before and 3-6 months after tumor resection by the Karnofsky Performance Scale (KPS). Uni- and multivariable linear regression were used to estimate the association of age with postoperative change in KPS. Logistic regression models for a ≥10-point decline in KPS or mortality were built for patients ≥75 years. Results: The total sample of 4864 patients had a mean age of 56.4 â€‹± â€‹14.4 years. The mean change in pre-to postoperative KPS was -1.43. For each 1-year increase in patient age, the adjusted change in postoperative KPS was -0.11 (95% CI -0.14 - - 0.07). In multivariable analysis, patients ≥75 years had an odds ratio of 1.51 to experience postoperative functional decline (95%CI 1.21-1.88) and an odds ratio of 2.04 to die (95%CI 1.33-3.13), compared to younger patients. Discussion: Patients with intracranial tumors treated surgically showed a minor decline in their postoperative functional status. Age was associated with this decline in function, but only to a small extent. Conclusion: Patients ≥75 years were more likely to experience a clinically meaningful decline in function and about two times as likely to die within the first 6 months after surgery, compared to younger patients.

Development and external validation of a clinical prediction model for functional impairment after intracranial tumor surgery.

OBJECTIVE: Decision-making for intracranial tumor surgery requires balancing the oncological benefit against the risk for resection-related impairment. Risk estimates are commonly based on subjective experience and generalized numbers from the literature, but even experienced surgeons overestimate functional outcome after surgery. Today, there is no reliable and objective way to preoperatively predict an individual patient's risk of experiencing any functional impairment. METHODS: The authors developed a prediction model for functional impairment at 3 to 6 months after microsurgical resection, defined as a decrease in Karnofsky Performance Status of ≥ 10 points. Two prospective registries in Switzerland and Italy were used for development. External validation was performed in 7 cohorts from Sweden, Norway, Germany, Austria, and the Netherlands. Age, sex, prior surgery, tumor histology and maximum diameter, expected major brain vessel or cranial nerve manipulation, resection in eloquent areas and the posterior fossa, and surgical approach were recorded. Discrimination and calibration metrics were evaluated. RESULTS: In the development (2437 patients, 48.2% male; mean age ± SD: 55 ± 15 years) and external validation (2427 patients, 42.4% male; mean age ± SD: 58 ± 13 years) cohorts, functional impairment rates were 21.5% and 28.5%, respectively. In the development cohort, area under the curve (AUC) values of 0.72 (95% CI 0.69-0.74) were observed. In the pooled external validation cohort, the AUC was 0.72 (95% CI 0.69-0.74), confirming generalizability. Calibration plots indicated fair calibration in both cohorts. The tool has been incorporated into a web-based application available at https://neurosurgery.shinyapps.io/impairment/. CONCLUSIONS: Functional impairment after intracranial tumor surgery remains extraordinarily difficult to predict, although machine learning can help quantify risk. This externally validated prediction tool can serve as the basis for case-by-case discussions and risk-to-benefit estimation of surgical treatment in the individual patient.

[Headache in puerperium]. / Een kraamvrouw met hoofdpijn.

BACKGROUND: Sheehan's syndrome is a rare complication of excessive postpartum hemorrhage with impaired function of the pituitary gland (hypopituitarism). Clinical presentation includes headache, fatigue, nausea, symptoms due to electrolyte imbalance and pituitary hormone insufficiency. Cranial imaging can support the diagnosis if pituitary gland ischemia or empty sella sign is detected. Therapy is based on correction of hypovolemia in the acute setting, symptom reduction and chronic hormone replacement treatment. CASE: We report a case of a patient who developed Sheehan's syndrome as a result of severe blood loss during cesarean section. Brain imaging in this case was initially performed with an alternative differential diagnosis in mind. CONCLUSION: Differential diagnosis of headache in puerperium is comprised of a spectrum of syndromes, in which attention for medical and patient history are key. In Sheehan's syndrome early diagnosis is of crucial prognostic importance.

Cranial Imaging and Lumbar Puncture in Patients With Suspected Central Nervous System Infection.

BACKGROUND: Performing cranial imaging prior to lumbar punctures (LPs) in patients with suspected central nervous system (CNS) infections has been associated with delayed treatments and poor outcomes. Various guidelines provide different criteria for cranial imaging prior to LP. METHODS: We describe the use of cranial imaging in a cohort of adult patients with suspected CNS infections, and evaluated adherence to the recommendations made in the Infectious Disease Society of America (IDSA), European Society of Clinical Microbiology and Infectious Diseases (ESCMID), Swedish, and Dutch guidelines. We also analyzed the association between cranial imaging and the time between emergency department entrance and intravenous antibiotic administration. RESULTS: From 2012-2015, 203 patients with suspected CNS infections were included, of whom 56 (27%) were diagnosed with CNS infections and 16 were diagnosed with bacterial meningitis (8%). Cranial imaging, in all cases computed tomography (CT), was performed in 130 patients (64%) and led to the deferral of LPs in 7 (5%). Criteria by the IDSA, ESCMID, Swedish, and Dutch guidelines showed indications for imaging in 64%, 39%, 39%, and 40% of patients, respectively. The times between emergency department arrivals and the start of antibiotic therapy between patients with and without CT before LP were similar (median 134 [interquartile range (IQR) 58-292] vs. 141 minutes [IQR 52-227], respectively; Mann-Whitney U P = .74). CONCLUSIONS: A cranial CT prior to LP was done in the majority of patients with a suspected CNS infection, irrespective of guideline indications. The ESCMID, Swedish, and Dutch guidelines were more restrictive in advising imaging, compared to the IDSA guidelines. Performing cranial imaging prior to LP was not associated with treatment delays in this Dutch cohort study.

Implications of genetic diagnostics in epilepsy surgery candidates: A single-center cohort study.

OBJECTIVE: Genetic causes are increasingly identified in patients with focal epilepsy. These genetic causes may be related to the effectiveness of epilepsy surgery. We aimed to assess the use and yield of genetic testing in a large cohort of patients who were evaluated for epilepsy surgery. METHODS: We performed a retrospective single-center consecutive cohort study of patients who were evaluated for surgery between 1990 and 2016. Within this cohort, we assessed the use of genetic testing-either before or after presurgical decision-making. We evaluated genetic results as well as the outcome of presurgical decision-making and surgery, and compared these end points for different subgroups-especially MRI-positive vs MRI-negative patients. Patients with tuberous sclerosis (TSC) and KRIT1 mutations were excluded from analysis. RESULTS: Of the 2385 epilepsy patients who were evaluated for surgery, 1280 (54%) received surgical treatment in our center. Of the entire cohort, 325 (14%) underwent genetic testing, comprising 156 of 450 MRI-negative patients (35%) vs 169 of 1935 MRI-positive patients (9%). A genetic cause of epilepsy was found in 40 of the 325 patients (12%, 2% of the entire cohort), mainly consisting of mutations in ion channel function and synaptic transmission genes, and mTOR pathway gene mutations. Three of the seven patients with mTOR pathway gene mutations underwent surgery; two achieved complete seizure freedom. One of the 17 patients with germline mutations in ion channel function and synaptic transmission genes received resective surgery but was not rendered seizure-free; two other patients underwent invasive intracranial EEG-monitoring before being rejected. SIGNIFICANCE: This study shows that genetic testing is increasingly applied in focal epilepsy patients who are considered for epilepsy surgery. The diagnostic yield of genetic testing is highest in next generation sequencing techniques, and the outcome of genetic testing assists selecting eligible patients for invasive intracranial monitoring and resective surgery.