Lessons learned after 20 years of real-world experience with natalizumab.

BACKGROUND: While natalizumab (NTZ) is an effective therapy for multiple sclerosis (MS), it is associated with an increased risk of progressive multifocal leukoencephalopathy (PML). After 20 years (2002-2022) of experience with NTZ at our center, we observed no cases of PML. OBJECTIVES: We evaluated the likelihood of experiencing PML in a subset of our treatment cohort, as well as reviewed treatment practices at our center that may mitigate PML risk. METHODS: For this retrospective study, we reviewed patient characteristics, treatment practices, and clinical and MRI findings in patients receiving NTZ from 2006 to 2020. Observation of no PML cases was compared to the global and US PML incidences, and to the expected incidence based on published risk estimates. RESULTS: 766 patients were evaluated. The number of NTZ infusions received ranged from 1 to 126, with a mean of 28. Patients received neurological examination prior to each infusion, which sometimes resulted in a pause in therapy to rule out PML if clinical worsening occurred. Extended interval dosing (EID) was the overall dosing schedule for 31% of patients. EID did not result in higher rates of radiological disease worsening than standard interval dosing (SID) patients. Depending on the analysis conducted, the finding of 0 PML cases in our cohort ranged from slightly unexpected to slightly expected. CONCLUSIONS: The utilization of EID as well as regular clinical monitoring of patients may have lowered PML risk while still maintaining NTZ efficacy.

Risk of natalizumab-associated PML in patients with MS is reduced with extended interval dosing.

OBJECTIVE: To use the large dataset from the Tysabri Outreach: Unified Commitment to Health (TOUCH) program to compare progressive multifocal leukoencephalopathy (PML) risk with natalizumab extended interval dosing (EID) vs standard interval dosing (SID) in patients with multiple sclerosis (MS). METHODS: This retrospective cohort study included anti-JC virus antibody-positive patients (n = 35,521) in the TOUCH database as of June 1, 2017. The effect of EID on PML risk was evaluated with 3 planned analyses using Kaplan-Meier methods stratified by prior immunosuppressant use. Risk of PML was analyzed by Cox regression adjusted for age, sex, prior immunosuppressants, time since natalizumab initiation, and cumulative number of infusions. RESULTS: This study included 35,521 patients (primary analysis: 1,988 EID, 13,132 SID; secondary analysis: 3,331 EID, 15,424 SID; tertiary analysis: 815 EID, 23,168 SID). Mean average dosing intervals were 35.0 to 43.0 and 29.8 to 30.5 days for the EID and SID cohorts, respectively. Hazard ratios (95% confidence intervals) of PML risk for EID vs SID were 0.06 (0.01-0.22, p < 0.001) and 0.12 (0.05-0.29, p < 0.001) for the primary and secondary analyses, respectively. Relative risk reductions were 94% and 88% in favor of EID for the primary and secondary analyses, respectively. The tertiary analysis included no cases of PML with EID. CONCLUSION: Natalizumab EID is associated with clinically and statistically significantly lower PML risk than SID. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with MS, natalizumab EID is associated with a lower PML risk than SID.

Preventable transfers in pediatric trauma: A 10-year experience at a level I pediatric trauma center.

BACKGROUND: Injured children are often treated at one facility then transferred to another that specializes in pediatric trauma care. The purpose of this study was to identify and characterize potentially preventable transfers (PT) to a freestanding level-I pediatric trauma center. METHODS: Children with traumatic injuries transferred between 2003 and 2013 were retrospectively analyzed. A PT was defined as a child who was discharged within 36hours of arrival without surgical intervention or advanced imaging studies. RESULTS: During this period, 6380 children were transferred, with head injury being the most common injury. 61% had CT imaging performed before transfer. The mean age was 6.9years, mean injury severity score (ISS) 10.4, and median transfer distance 37miles. 27% of these transfers were classified as PT. Air transport was used in 15% at mean charge of $18,574. 29% were discharged from the emergency department. When compared, PTs were younger (6.0 vs. 7.2years, p<0.001), with lower median ISS (5 vs. 9, p<0.001), shorter median LOS (15 vs. 43.6hours, p<0.001), and less PICU admissions (6% vs. 34%, p<0.001). CONCLUSION: A significant number of pediatric trauma transfers can be classified as preventable. Reducing preventable transfers could offer opportunities for improving value in a trauma care system.

Risk factors for traumatic blunt cerebrovascular injury diagnosed by computed tomography angiography in the pediatric population: a retrospective cohort study.

OBJECT Computed tomography angiography (CTA) is frequently used to examine patients for blunt cerebrovascular injury (BCVI) after cranial trauma, but the pediatric population at risk for BCVI is poorly defined. Although CTA is effective for BCVI screening in adults, the increased lifetime risk for malignant tumors associated with this screening modality warrants efforts to reduce its use in children. The authors' objective was to evaluate the incidence of BCVI diagnosed by CTA in a pediatric patient cohort and to create a prediction model to identify children at high risk for BCVI. METHODS Demographic, clinical, and radiographic data were collected retrospectively for pediatric patients who underwent CTA during examination for traumatic cranial injury from 2003 through 2013. The primary outcome was injury to the carotid or vertebral artery diagnosed by CTA. RESULTS The authors identified 234 patients (mean age 8.3 years, range 0.04-17 years, 150 [64%] boys) who underwent CTA screening for BCVI. Of these, 24 (10.3%) had a focal neurological deficit, and 153 (65.4%) had intracranial hemorrhage on a head CTA. Thirty-seven BCVIs were observed in 36 patients (15.4%), and 16 patients (6.8%) died. Multivariate regression analysis identified fracture through the carotid canal, petrous temporal bone fracture, Glasgow Coma Scale (GCS) score of < 8, focal neurological deficit, and stroke on initial CT scan as independent risk factors for BCVI. A prediction model for identifying children at high risk for BCVI was created. A score of ≤ 2 yielded a 7.9% probability of BCVI and a score of ≥ 3 a risk of 39.3% for BCVI. CONCLUSIONS For cranial trauma in children, fracture of the petrous temporal bone or through the carotid canal, focal neurological deficit, stroke, and a GCS score of < 8 are independent risk factors for BCVI.

Helicopter versus ground emergency medical services for the transportation of traumatically injured children.

BACKGROUND: Helicopter emergency medical services (HEMS) are a common mode of transportation for pediatric trauma patients. We hypothesized that HEMS improve outcomes for traumatically injured children compared to ground emergency medical services (GEMS). METHODS: We queried trauma registries of two level 1 pediatric trauma centers for children 0-17 years, treated from 2003 to 2013, transported by HEMS or GEMS, with known transport starting location and outcome. A geocoding service estimated travel distance and time. Multivariate regression analyses were performed to adjust for injury severity variables and travel distance/time. RESULTS: We identified 14,405 traumatically injured children; 3870 (26.9%) transported by HEMS and 10,535 (73.1%) transported by GEMS. Transport type was not significantly associated with survival, ICU length of stay, or discharge disposition. Transport by GEMS was associated with a 68.6%-53.1% decrease in hospital length of stay, depending on adjustment for distance/time. Results were similar for children with severe injuries, and with propensity score matched cohorts. Of note, 862/3850 (22.3%) of HEMS transports had an ISS<10 and hospitalization<1 day. CONCLUSIONS: HEMS do not independently improve outcomes for traumatically injured children, and 22.3% of children transported by HEMS are not significantly injured. These factors should be considered when requesting HEMS for transport of traumatically injured children.

Impact of newly adopted guidelines for management of children with isolated skull fracture.

PURPOSE: In an effort to standardize practices and reduce unnecessary hospital resource utilization, we implemented guidelines for management of patients with isolated skull fractures (ISF). We sought to examine the impact of these guidelines. METHODS: Patients with nondisplaced/depressed fracture of the skull vault without intracranial hemorrhage were prospectively enrolled from February 2010 to February 2014. RESULTS: Eighty-eight patients (median age=10months) were enrolled. Fall was the most common mechanism of injury (87%). The overall admission rate was 57%, representing an 18% decrease from that reported prior to guideline implementation (2003-2008; p=0.001). Guideline criteria for admission included vomiting, abnormal neurologic exam, concern for abuse, and others. Forty-two percent of patients were admitted outside of the guideline, primarily because of young age (20%). Patients transferred from another hospital (36%) were more likely to be admitted, though the majority (63%) did not meet admission criteria. No ED-discharged patient returned for neurologic symptoms, and none reported significant ongoing symptoms on follow-up phone call. CONCLUSIONS: Implementation of a new guideline for management of ISF resulted in a reduction of admissions without compromising patient safety. Young age remains a common concern for practitioners despite not being a criterion for admission. Interhospital transfer may be unnecessary in many cases.

Alpha II Spectrin breakdown products in immature Sprague Dawley rat hippocampus and cortex after traumatic brain injury.

After traumatic brain injury (TBI), proteolysis of Alpha II Spectrin by Calpain 1 produces 145 Spectrin breakdown products (SBDPs) while proteolysis by Caspase 3 produces 120 SBDPs. 145 and 120 SBDP immunoblotting reflects the relative importance of caspase-dependent apoptosis or calpain-dependent excitotoxic/necrotoxic cell death in brain regions over time. In the adult rat, controlled cortical impact (CCI) increased 120 SBDPs in the first hours, lasting a few days, and increased 145 SBDPs within the first few days lasting up to 14 days after injury. Little is known about SBDPs in the immature brain after TBI. Since development affects susceptibility to apoptosis after TBI, we hypothesized that CCI would increase 145 and 120 SBDPs in the immature rat brain relative to SHAM during the first 3 and 5 days, respectively. SBDPs were measured in hippocampi and cortices at post injury days (PID) 1, 2, 3, 5, 7 and 14 after CCI or SHAM surgery in the 17 day old Sprague Dawley rat. 145 SBDPs increased in both brain tissues ipsilateral to injury during the first 3 days, while changes in contralateral tissues were limited to PID2 cortex. 145 SBDPs elevations were more marked and enduring in hippocampus than in cortex. Against expectations, 120 SBDPs only increased in PID1 hippocampus and PID2 cortex. 145 SBDPs elevations occurred early after CCI, similar to previous studies in the adult rat, but resolved more quickly. The minimal changes in 120 SBDPs suggest that calpain-dependent, but not caspase-dependent, cell death predominates in the 17 day old rat after CCI.

Cervical spine computed tomography utilization in pediatric trauma patients.

BACKGROUND: Guidelines for evaluating the cervical spine in pediatric trauma patients recommend cervical spine CT (CSCT) when plain radiographs suggest an injury. Our objective was to compare usage of CSCT between a pediatric trauma center (PTC) and referral general emergency departments (GEDs). METHODS: Patient data from a pediatric trauma registry from 2002 to 2011 were analyzed. Rates of CSI and CSCT of patients presenting to the PTC and GED were compared. Factors associated with use of CSCT were assessed using multivariate logistic regression. RESULTS: 5148 patients were evaluated, 2142 (41.6%) at the PTC and 3006 (58.4%) at the GED. Groups were similar with regard to age, gender, GCS, and triage category. GED patients had a higher median ISS (14 vs. 9, p<0.05) and more frequent ICU admissions (44.3% vs. 26.1% p<0.05). CSI rate was 2.1% (107/5148) and remained stable. CSCT use increased from 3.5% to 16.1% over time at the PTC (mean 9.6% 95% CI=8.3, 10.9) and increased from 6.8% to 42.0% (mean 26.9%, CI=25.4, 28.4) at the GED. Initial care at a GED remained strongly associated with CSCT. CONCLUSIONS: Despite a stable rate of CSI, rate of CSCT increased significantly over time, especially among patients initially evaluated at a GED.

Fecal continence following complex anorectal trauma in children.

BACKGROUND: Complex injuries involving the anus and rectum are uncommon in children. We sought to examine long-term fecal continence following repair of these injuries. METHODS: We conducted a retrospective review using our trauma registry from 2003 to 2012 of children with traumatic injuries to the anus or rectum at a level I pediatric trauma center. Patients with an injury requiring surgical repair that involved the anal sphincters and/or rectum were selected for a detailed review. RESULTS: Twenty-one patients (21/13,149 activations, 0.2%) who had an injury to the anus (n=9), rectum (n=8), or destructive injury to both the anus and rectum (n=4) were identified. Eleven (52%) patients were male, and the median age at time of injury was 9 (range 1-14) years. Penetrating trauma accounted for 48% of injuries. Three (14%) patients had accompanying injury to the urinary tract, and 6 (60%) females had vaginal injuries. All patients with an injury involving the rectum and destructive anal injuries were managed with fecal diversion. No patient with an isolated anal injury underwent fecal diversion. Four (19%) patients developed wound infections. The majority (90%) of patients were continent at last follow-up. One patient who sustained a gunshot injury to the pelvis with sacral nerve involvement is incontinent, but remains artificially clean on an intense bowel management program with enemas, and one patient with a destructive crush injury still has a colostomy. CONCLUSIONS: With anatomic reconstruction of the anal sphincter mechanism, most patients with traumatic anorectal injuries will experience long-term fecal continence. Follow-up is needed as occasionally these patients, specifically those with nerve or crush injury, may require a formal bowel management program.

The role of focused abdominal sonography for trauma (FAST) in pediatric trauma evaluation.

PURPOSE: With increasing concerns about radiation exposure, we questioned whether a structured program of FAST might decrease CT use. METHODS: All pediatric trauma surgeons in our level 1 pediatric trauma center underwent formal FAST training. Children with potential abdominal trauma and no prior imaging were prospectively evaluated from 10/2/09 to 7/31/11. After physical exam and FAST, the surgeon declared whether the CT could be eliminated. RESULTS: Of 536 children who arrived without imaging, 183 had potential abdominal trauma. FAST was performed in 128 cases and recorded completely in 88. In 48% (42/88) the surgeon would have elected to cancel the CT based on the FAST and physical exam. One of the 42 cases had a positive FAST and required emergent laparotomy; the others were negative. The sensitivity of FAST for injuries requiring operation or blood transfusion was 87.5%. The sensitivity, specificity, PPV, and NPV in detecting pathologic free fluid were 50%, 85%, 53.8%, and 87.9%. CONCLUSIONS: True positive FAST exams are uncommon and would rarely direct management. While the negative FAST would have potentially reduced CT use due to practitioner reassurance, this reassurance may be unwarranted given the test's sensitivity.

Neurologically intact children with an isolated skull fracture may be safely discharged after brief observation.

PURPOSE: The management of children presenting with an isolated skull fracture (ISF) posttrauma is highly variable. We sought to estimate the risk of neurologic deterioration in children with a Glasgow coma score (GCS) 15 and ISF to reduce unnecessary hospital admissions. METHODS: A retrospective review at a level I pediatric trauma referral center was conducted for patients with ISF on head computed tomography from 2003 to 2008. Patients were excluded for injury greater than 24 hours prior, GCS less than 15, intracranial pathology, significant fracture depression, or complex fractures involving facial bones or skull base. RESULTS: A total of 235 patients were identified with an ISF. The median age was 11 months, with falls accounting for 87% of the injuries. One hundred seventy-seven patients were admitted, and 58 patients were discharged from the emergency department after a period of observation (median, 3.3 hours). Median length of stay for those admitted to the hospital was 18.2 hours. One patient developed vomiting following overnight observation and a repeat computed tomography scan demonstrated a small extra-axial hematoma that required no intervention. The mean total costs for patients discharged from the emergency department were $291 vs $1447 for those admitted for observation (P < .001). CONCLUSION: Patients with a presenting GCS of 15 and an ISF can be safely discharged from the emergency department after a short period of observation if they are asymptomatic and have a reliable social environment. This could result in significant savings by eliminating inpatient costs.

Use of focused abdominal sonography for trauma at pediatric and adult trauma centers: a survey.

PURPOSE: Focused abdominal sonography for trauma (FAST) has been popularized for the initial evaluation of trauma patients. We sought to understand the scope of practice on a national level with specific attention to its use in the pediatric age group. METHODS: An electronic survey was sent to all American College of Surgeons level I trauma centers and the National Association of Children's Hospitals and Related Institutions that were freestanding children's hospitals. RESULTS: The survey was emailed to 124 centers, and 98 (79%) completed the survey. Of the surveyed centers, 23% cared for adults only, 28% were freestanding children's hospitals, and 49% managed both. At adults-only institutions, 96% use FAST and at children's hospitals, only 15%; it is used at 85% of centers that care for both. For the centers that use FAST on children, 88% have no age limit. Of all the institutions that typically use FAST, the individual performing the examination could be a surgeon (73%), an emergency department doctor (48%), or a radiologist (3%). Of the centers that perform FAST, 51% bill for the FAST examination. CONCLUSIONS: Adult hospitals are much more likely to perform FAST examinations in the trauma patient, and many adult centers routinely use FAST to examine pediatric patients.

Clinical clearance of the cervical spine in blunt trauma patients younger than 3 years: a multi-center study of the american association for the surgery of trauma.

BACKGROUND: Cervical spine clearance in the very young child is challenging. Radiographic imaging to diagnose cervical spine injuries (CSI) even in the absence of clinical findings is common, raising concerns about radiation exposure and imaging-related complications. We examined whether simple clinical criteria can be used to safely rule out CSI in patients younger than 3 years. METHODS: The trauma registries from 22 level I or II trauma centers were reviewed for the 10-year period (January 1995 to January 2005). Blunt trauma patients younger than 3 years were identified. The measured outcome was CSI. Independent predictors of CSI were identified by univariate and multivariate analysis. A weighted score was calculated by assigning 1, 2, or 3 points to each independent predictor according to its magnitude of effect. The score was established on two thirds of the population and validated using the remaining one third. RESULTS: Of 12,537 patients younger than 3 years, CSI was identified in 83 patients (0.66%), eight had spinal cord injury. Four independent predictors of CSI were identified: Glasgow Coma Score <14, GCSEYE = 1, motor vehicle crash, and age 2 years or older. A score of <2 had a negative predictive value of 99.93% in ruling out CSI. A total of 8,707 patients (69.5% of all patients) had a score of <2 and were eligible for cervical spine clearance without imaging. There were no missed CSI in this study. CONCLUSIONS: CSI in patients younger than 3 years is uncommon. Four simple clinical predictors can be used in conjunction to the physical examination to substantially reduce the use of radiographic imaging in this patient population.

Inhibitory effect of reserpine on dopamine transporter function.

Previous studies indicate that reserpine may disrupt dopamine transporter activity. Results presented herein reveal that it also inhibits potently synaptosomal [3H]dopamine uptake. In addition, reserpine administration to rats decreased the V(max) of synaptosomal dopamine transport, as assessed ex vivo 12 h after treatment. This decrease appeared, at least in part, dissociated from concurrent inhibition of the vesicular monoamine transporter-2 (VMAT-2). In separate experiments, synaptosomal dopamine uptake did not differ between wild-type and heterozygous VMAT-2 knockout mice, and reserpine treatment did not inhibit [3H]dopamine uptake into cells heterogously expressing the human dopamine transporter. Taken together, these data suggest that reserpine may transiently alter dopamine transporter function in a noncompetitive, indirect manner.