Results of phase II levetiracetam trial following acute head injury in children at risk for posttraumatic epilepsy.

Posttraumatic seizures develop in up to 20% of children following severe traumatic brain injury (TBI). Children ages 6-17 years with one or more risk factors for the development of posttraumatic epilepsy, including presence of intracranial hemorrhage, depressed skull fracture, penetrating injury, or occurrence of posttraumatic seizure were recruited into this phase II study. Treatment subjects received levetiracetam 55 mg/kg/day, b.i.d., for 30 days, starting within 8 h postinjury. The recruitment goal was 20 treated patients. Twenty patients who presented within 8-24 h post-TBI and otherwise met eligibility criteria were recruited for observation. Follow-up was for 2 years. Forty-five patients screened within 8 h of head injury met eligibility criteria and 20 were recruited into the treatment arm. The most common risk factor present for pediatric inclusion following TBI was an immediate seizure. Medication compliance was 95%. No patients died; 19 of 20 treatment patients were retained and one observation patient was lost to follow-up. The most common severe adverse events in treatment subjects were headache, fatigue, drowsiness, and irritability. There was no higher incidence of infection, mood changes, or behavior problems among treatment subjects compared to observation subjects. Only 1 (2.5%) of 40 subjects developed posttraumatic epilepsy (defined as seizures >7 days after trauma). This study demonstrates the feasibility of a pediatric posttraumatic epilepsy prevention study in an at-risk traumatic brain injury population. Levetiracetam was safe and well tolerated in this population. This study sets the stage for implementation of a prospective study to prevent posttraumatic epilepsy in an at-risk population.

Cerebral MRI abnormalities associated with vigabatrin therapy.

PURPOSE: Investigate whether patients on vigabatrin demonstrated new-onset and reversible T(2)-weighted magnetic resonance imaging (MRI) abnormalities. METHODS: MRI of patients treated during vigabatrin therapy was reviewed, following detection of new basal ganglia, thalamus, and corpus callosum hyperintensities in an infant treated for infantile spasms. Patients were assessed for age at time of MRI, diagnosis, duration, and dose, MRI findings pre-, on, and postvigabatrin, concomitant medications, and clinical correlation. These findings were compared to MRI in patients with infantile spasms who did not receive vigabatrin. RESULTS: Twenty-three patients were identified as having MRI during the course of vigabatrin therapy. After excluding the index case, we detected new and reversible basal ganglia, thalamic, brainstem, or dentate nucleus abnormalities in 7 of 22 (32%) patients treated with vigabatrin. All findings were reversible following discontinuation of therapy. Diffusion-weighted imaging (DWI) was positive with apparent diffusion coefficient (ADC) maps demonstrating restricted diffusion. Affected versus unaffected patients, respectively, had a median age of 11 months versus 5 years, therapy duration 3 months versus 12 months, and dosage 170 mg/kg/day versus 87 mg/kg/day. All affected patients were treated for infantile spasms; none of 56 patients with infantile spasms who were not treated with vigabatrin showed the same abnormalities. DISCUSSION: MRI abnormalities attributable to vigabatrin, characterized by new-onset and reversible T(2)-weighted hyperintensities and restricted diffusion in thalami, globus pallidus, dentate nuclei, brainstem, or corpus callosum were identified in 8 of 23 patients. Young age and relatively high dose appear to be risk factors.

Use of Gabapentin in Posterior Spinal Fusion is Associated With Decreased Postoperative Pain and Opioid Use in Children and Adolescents.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The objective of this study was to examine associations of gabapentin use with inpatient postoperative daily pain scores and opioid use in children undergoing PSF for AIS. SUMMARY OF BACKGROUND DATA: Gabapentin use in posterior spinal fusion (PSF) postoperative pain management for adolescent idiopathic scoliosis (AIS) is increasingly common in order to decrease opioid use and improve pain control, though there is conflicting data on dosing and effectiveness to support this practice in real world settings. METHODS: Retrospective cohort study of children aged 10 to 21 years undergoing PSF for AIS between January 2013 and June 2016 at an urban academic tertiary care center. Adjuvant gabapentin exposure was defined as at least 15 mg/kg/d by postoperative day (POD) 1 with an initial loading dose of 10 mg/kg on day of surgery. Primary outcomes were daily postoperative mean pain score and opioid use [morphine milligram equivalents/kg/day(mme/kg/d)]. Secondary outcomes were short and long-term complications. RESULTS: Among 129 subjects (mean age, 14.6 y, 74% female, mean coronal cobb, 55.2 degrees), 24 (19%) received gabapentin. Unadjusted GABA exposure was associated with significantly lower opioid use on POD1 and 2 (49% and 31%mme/kg/d, respectively) and lower pain scores (14%) on POD2. Adjusting for preexisting back pain, preoperative coronal Cobb angle, and site, GABA use was associated with significantly lower mean pain scores on POD1 through POD3 (-0.68, P=0.01; -0.86, P=0.002; -0.63, P=0.04). Gabapentin use was also associated with decreased opioid use on POD1 and POD2 (-0.39mme/kg/d, P<0.001; -0.27, P=0.02). There was no difference in complications by gabapentin exposure. CONCLUSIONS: Addition of gabapentin as adjuvant therapy for adolescent PSF, beginning on day of surgery, is associated with improved pain scores and decreased opioid use in the first 48 to 72 hours postoperatively. LEVEL OF EVIDENCE: This is a retrospective cohort study, classified as Level III under "Therapeutic Studies Investigating the Results of a Treatment."

The pediatric neurotransmitter disorders.

The pediatric neurotransmitter disorders represent an enlarging group of neurological syndromes characterized by abnormalities of neurotransmitter synthesis and breakdown. The disorders of dopamine and serotonin synthesis are aromatic amino acid decarboxylase deficiency, tyrosine hydroxylase deficiency, and disorders of tetrahydrobiopterin synthesis. Amino acid decarboxylase, tyrosine hydroxylase, sepiapterin reductase, and guanosine triphosphate cyclohydrolase (Segawa disease) deficiencies do not feature elevated serum phenylalanine and require cerebrospinal fluid analysis for diagnosis. Segawa disease is characterized by dramatic and lifelong responsiveness to levodopa. Glycine encephalopathy is typically manifested by refractory neonatal seizures secondary to a defect of the glycine degradative pathway. gamma-amino butyric acid (GABA) metabolism is associated with several disorders, including glutamic acid decarboxylase deficiency with nonsyndromic cleft lip/ palate, GABA-transaminase deficiency, and succinic semialdehyde dehydrogenase deficiency. The latter is characterized by elevated gamma-hydroxybutyric acid and includes a wide range of neuropsychiatric symptoms as well as epilepsy. Pyridoxine-dependent seizures have now been associated with deficiency of alpha-aminoadipic semialdehyde dehydrogenase, as well as a new variant requiring therapy with pyridoxal-5-phosphate, the biologically active form of pyridoxine.

The Association Between Adjuvant Pain Medication Use and Outcomes Following Pediatric Spinal Fusion.

STUDY DESIGN: A comparative effectiveness database study. OBJECTIVE: The aim of this study was to describe variation in use of adjuvant therapies for managing postoperative pain in in patients undergoing posterior spinal fusion (PSF) for adolescent idiopathic scoliosis (AIS) and determine association between use of these therapies and patient outcomes. SUMMARY OF BACKGROUND DATA: Variation in postoperative pain management for children undergoing PSF for AIS likely impacts outcomes. Minimal evidence exists to support strategies that most effectively minimize prolonged intravenous (IV) opioids and hospitalizations. METHODS: We included patients aged 10 to 18 years discharged from one of 38 freestanding children's hospitals participating in a national database from December 1, 2012, to January 5, 2015, with ICD9 codes indicating scoliosis and PSF procedure. Use of ketorolac, gamma aminobutyric acid (GABA) analogues (GABAa), and benzodiazepines was compared across hospitals. Hierarchical logistic regression adjusting for confounders and accounting for clustering of patients within hospitals was used to estimate association between these therapies and odds of prolonged duration of IV opioids, prolonged length of stay (LOS), and early readmissions. RESULTS: Across hospitals, use of ketorolac and GABAa was highly variable and increased over time among 7349 subjects. Use of ketorolac was independently associated with significantly lower odds of prolonged LOS [odds ratio (OR) 0.75, 95% confidence interval (95% CI) 0.64-0.89] and prolonged duration of IV opioid (OR 0.84, 95% CI 0.73-0.98). GABAa use was significantly associated with decreased odds of prolonged IV opioid use (OR 0.63, 95% CI 0.53-0.75). Readmission rate at 30 days was 1.6% and most strongly associated with prolonged LOS. CONCLUSION: In this national cohort of children with AIS undergoing PSF, patients who received postoperative ketorolac or GABAa were less likely to have prolonged IV opioid exposure. Given the rapid increase in use of adjuvant therapies without strong evidence, resources should be devoted to multicenter trials in order to optimize effectiveness and outcomes. LEVEL OF EVIDENCE: 3.

Results of phase 2 safety and feasibility study of treatment with levetiracetam for prevention of posttraumatic epilepsy.

OBJECTIVES: To evaluate the safety and tolerability of treatment with levetiracetam and determine the trough levels of levetiracetam in patients with traumatic brain injury (TBI) who are at high risk for posttraumatic epilepsy (PTE). DESIGN: Open-label, nonrandomized phase 2 study with 2 arms comparing levetiracetam treatment vs observation. SETTING: Two level 1 trauma centers. PATIENTS: A total of 422 participants 6 years or older with TBI who have a 20% risk for PTE were screened. Of these participants, 205 (48.6%) were eligible. A total of 126 participants were enrolled: 86 adults and 40 children. A total of 66 participants were in the treatment group (46 adults and 20 children), and a total of 60 participants were in the observation group (40 adults and 20 children). Participants presenting within 8 hours after TBI received treatment, and those presenting more than 8 to 24 hours after TBI did not. INTERVENTION: Treatment with levetiracetam (55 mg/kg/d) for 30 days starting within 8 hours after injury. MAIN OUTCOME MEASURES: Number of adverse events, mood score, number of infections, trough level of levetiracetam, and PTE. RESULTS: Of the 66 participants treated with levetiracetam, 2 (3%) stopped treatment owing to toxicity (somnolence). The most common adverse events were fatigue, headache, and somnolence. Mood scores and number of infections did not differ between the treatment and observation groups. Mean trough levels of levetiracetam on days 2 to 30 ranged from 19.6 to 26.7 µg/mL. At 2 years, 13 of 86 adults (15.1%) and 1 of 40 children (2.5%) developed PTE. At 2 years, 5 of 46 treated adults (10.9%) and 8 of 40 untreated adults (20.0%) developed PTE (relative risk, 0.47; P=.18). CONCLUSION: Treatment with 55 mg/kg/d of levetiracetam (a dose with an antiepileptogenic effect on animals) for patients with TBI at risk for PTE is safe and well tolerated, with plasma levels similar to those in animal studies. The findings support further evaluation of levetiracetam treatment for the prevention of PTE. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01463033.