Summary
The purpose of this report was to update the 2006 International League Against Epilepsy (ILAE) report and identify the level of evidence for long‐term efficacy or effectiveness for ...antiepileptic drugs (AEDs) as initial monotherapy for patients with newly diagnosed or untreated epilepsy. All applicable articles from July 2005 until March 2012 were identified, evaluated, and combined with the previous analysis (Glauser et al., 2006) to provide a comprehensive update. The prior analysis methodology was utilized with three modifications: (1) the detectable noninferiority boundary approach was dropped and both failed superiority studies and prespecified noninferiority studies were analyzed using a noninferiority approach, (2) the definition of an adequate comparator was clarified and now includes an absolute minimum point estimate for efficacy/effectiveness, and (3) the relationship table between clinical trial ratings, level of evidence, and conclusions no longer includes a recommendation column to reinforce that this review of efficacy/evidence for specific seizure types does not imply treatment recommendations. This evidence review contains one clarification: The commission has determined that class I superiority studies can be designed to detect up to a 20% absolute (rather than relative) difference in the point estimate of efficacy/effectiveness between study treatment and comparator using an intent‐to‐treat analysis. Since July, 2005, three class I randomized controlled trials (RCT) and 11 class III RCTs have been published. The combined analysis (1940–2012) now includes a total of 64 RCTs (7 with class I evidence, 2 with class II evidence) and 11 meta‐analyses. New efficacy/effectiveness findings include the following: levetiracetam and zonisamide have level A evidence in adults with partial onset seizures and both ethosuximide and valproic acid have level A evidence in children with childhood absence epilepsy. There are no major changes in the level of evidence for any other subgroup. Levetiracetam and zonisamide join carbamazepine and phenytoin with level A efficacy/effectiveness evidence as initial monotherapy for adults with partial onset seizures. Although ethosuximide and valproic acid now have level A efficacy/effectiveness evidence as initial monotherapy for children with absence seizures, there continues to be an alarming lack of well designed, properly conducted epilepsy RCTs for patients with generalized seizures/epilepsies and in children in general. These findings reinforce the need for multicenter, multinational efforts to design, conduct, and analyze future clinically relevant adequately designed RCTs. When selecting a patient's AED, all relevant variables and not just efficacy and effectiveness should be considered.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Objective
We studied the effects of LTBP4 and SPP1 polymorphisms on age at loss of ambulation (LoA) in a multiethnic Duchenne muscular dystrophy (DMD) cohort.
Methods
We genotyped SPP1 rs28357094 and ...LTBP4 haplotype in 283 of 340 participants in the Cooperative International Neuromuscular Research Group Duchenne Natural History Study (CINRG‐DNHS). Median ages at LoA were compared by Kaplan–Meier analysis and log‐rank test. We controlled polymorphism analyses for concurrent effects of glucocorticoid corticosteroid (GC) treatment (time‐varying Cox regression) and for population stratification (multidimensional scaling of genome‐wide markers).
Results
Hispanic and South Asian participants (n = 18, 41) lost ambulation 2.7 and 2 years earlier than Caucasian subjects (p = 0.003, <0.001). The TG/GG genotype at SPP1 rs28357094 was associated to 1.2‐year‐earlier median LoA (p = 0.048). This difference was greater (1.9 years, p = 0.038) in GC‐treated participants, whereas no difference was observed in untreated subjects. Cox regression confirmed a significant effect of SPP1 genotype in GC‐treated participants (hazard ratio = 1.61, p = 0.016). LTBP4 genotype showed a direction of association with age at LoA as previously reported, but it was not statistically significant. After controlling for population stratification, we confirmed a strong effect of LTBP4 genotype in Caucasians (2.4 years, p = 0.024). Median age at LoA with the protective LTBP4 genotype in this cohort was 15.0 years, 16.0 for those who were treated with GC.
Interpretation
SPP1 rs28357094 acts as a pharmacodynamic biomarker of GC response, and LTBP4 haplotype modifies age at LoA in the CINRG‐DNHS cohort. Adjustment for GC treatment and population stratification appears crucial in assessing genetic modifiers in DMD. Ann Neurol 2015;77:684–696
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Purpose: To assess which antiepileptic medications (AEDs) have the best evidence for long‐term efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated ...epilepsy.
Methods: A 10‐member subcommission of the Commission on Therapeutic Strategies of The International League Against Epilepsy (ILAE), including adult and pediatric epileptologists, clinical pharmacologists, clinical trialists, and a statistician evaluated available evidence found through a structured literature review including MEDLINE, Current Contents and the Cochrane Library for all applicable articles from 1940 until July 2005. Articles dealing with different seizure types (for different age groups) and two epilepsy syndromes were assessed for quality of evidence (four classes) based on predefined criteria. Criteria for class I classification were a double‐blind randomized controlled trial (RCT) design, ≥48‐week treatment duration without forced exit criteria, information on ≥24‐week seizure freedom data (efficacy) or ≥48‐week retention data (effectiveness), demonstration of superiority or 80% power to detect a ≤20% relative difference in efficacy/effectiveness versus an adequate comparator, and appropriate statistical analysis. Class II studies met all class I criteria except for having either treatment duration of 24 to 47 weeks or, for noninferiority analysis, a power to only exclude a 21–30% relative difference. Class III studies included other randomized double‐blind and open‐label trials, and class IV included other forms of evidence (e.g., expert opinion, case reports). Quality of clinical trial evidence was used to determine the strength of the level of recommendation.
Results: A total of 50 RCTs and seven meta‐analyses contributed to the analysis. Only four RCTs had class I evidence, whereas two had class II evidence; the remainder were evaluated as class III evidence. Three seizure types had AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy: adults with partial‐onset seizures (level A, carbamazepine and phenytoin; level B, valproic acid), children with partial‐onset seizures (level A, oxcarbazepine; level B, None), and elderly adults with partial‐onset seizures (level A, gabapentin and lamotrigine; level B, None). One adult seizure type adults with generalized‐onset tonic–clonic (GTC) seizures, two pediatric seizure types (GTC seizures and absence seizures), and two epilepsy syndromes (benign epilepsy with centrotemporal spikes and juvenile myoclonic epilepsy) had no AEDs with level A or level B efficacy and effectiveness evidence as initial monotherapy.
Conclusions: This evidence‐based guideline focused on AED efficacy or effectiveness as initial monotherapy for patients with newly diagnosed or untreated epilepsy. The absence of rigorous comprehensive adverse effects data makes it impossible to develop an evidence‐based guideline aimed at identifying the overall optimal recommended initial‐monotherapy AED. There is an especially alarming lack of well‐designed, properly conducted RCTs for patients with generalized seizures/epilepsies and for children in general. The majority of relevant existing RCTs have significant methodologic problems that limit their applicability to this guideline's clinically relevant main question. Multicenter, multinational efforts are needed to design, conduct and analyze future clinically relevant RCTs that can answer the many outstanding questions identified in this guideline. The ultimate choice of an AED for any individual patient with newly diagnosed or untreated epilepsy should include consideration of the strength of the efficacy and effectiveness evidence for each AED along with other variables such as the AED safety and tolerability profile, pharmacokinetic properties, formulations, and expense. When selecting a patient's AED, physicians and patients should consider all relevant variables and not just efficacy and effectiveness.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Ethosuximide was identified as the optimal option for new‐onset childhood absence epilepsy (CAE) in a randomized, two‐phase dose escalation comparative effectiveness trial of ethosuximide, ...lamotrigine, and valproic acid. However, 47% of ethosuximide initial monotherapy participants experienced short‐term treatment failure. This study aimed to characterize the initial monotherapy ethosuximide exposure‐response relationship and to propose model‐informed precision dosing guidance. Dose titration occurred over a 16–20‐week period until patients experienced seizure freedom or intolerable side effects. Subjects with initial monotherapy failure were randomized to one of the other two medications and dose escalation was repeated. A population pharmacokinetic model was created using plasma concentration data (n = 1,320), collected at 4‐week intervals from 211 unique participants during both the initial and second monotherapy phases. A logistic regression analysis was performed on the initial monotherapy cohort (n = 103) with complete exposure‐response data. Eighty‐four participants achieved seizure freedom with a wide range of ethosuximide area under the curves (AUC) ranging from 420 to 2,420 μg·h/mL. AUC exposure estimates for achieving a 50% and 75% probability of seizure freedom were 1,027 and 1,489 μg·h/mL, respectively, whereas the corresponding cumulative frequency of intolerable adverse events was 11% and 16%. Monte Carlo Simulation indicated a daily dose of 40 and 55 mg/kg to achieve 50% and 75% probability of seizure freedom in the overall population, respectively. We identified the need for adjusted mg/kg dosing in different body weight cohorts. This ethosuximide proposed model‐informed precision dosing guidance to achieve seizure freedom carries promise to optimize initial monotherapy success for patients with CAE.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
In this multicenter, randomized trial of preterm newborns with a birth weight of 1250 g or less who required ventilatory support, the initiation of inhaled nitric oxide between days 7 and 21 of life ...significantly reduced the risk of death or chronic lung disease and the duration of both hospitalization and supplemental oxygen therapy. Using a regimen of inhaled nitric oxide therapy different from that in the companion report by Kinsella et al., this group also found inhaled nitric oxide to be beneficial in preterm infants with respiratory failure.
In preterm newborns with a birth weight of 1250 g or less who required ventilatory support, the initiation of inhaled nitric oxide between days 7 and 21 of life significantly reduced the risk of death or chronic lung disease and the duration of both hospitalization and supplemental oxygen therapy.
Survival among preterm infants has improved markedly in recent decades, in large part because of the ability to enhance fetal-lung maturation with antenatal corticosteroids and manage the respiratory distress syndrome. Chronic lung disease, or bronchopulmonary dysplasia,
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is now the most important long-term pulmonary complication in these infants and is associated with prolonged hospitalization and long-term pulmonary and neurodevelopmental problems.
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Severe bronchopulmonary dysplasia is associated with inflammation,
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pulmonary hypertension,
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and increased airway resistance,
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as well as abnormalities of lung growth, including disturbed angiogenesis and alveolarization.
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Inhaled nitric oxide is an effective treatment for pulmonary hypertension . . .
Diarrhea-associated hemolytic uremic syndrome (D+HUS) causes acute renal failure. Neutrophil gelatinase-associated lipocalcin (NGAL) is an early indicator of kidney injury.
To determine if urinary ...NGAL excretion is a biomarker of severe renal injury and predicts the need for dialysis in D+HUS.
Patients were randomly selected from among participants in the SYNSORB Pk trial. Urine samples were collected daily if available during the first week of hospitalization. NGAL levels were determined by ELISA.
34 children, age 5.9+/-3.9 yr, were studied; ten (29%) required dialysis. Patients were categorized based on urinary NGAL concentration within five days of hospitalization - <200 ng/ml and >or=200 ng/ml. Twenty patients (58%) had increased urinary NGAL excretion. The severity of D+HUS at enrollment was similar in the two groups. However, children with increased urinary NGAL levels had higher peak BUN and creatinine concentrations (P<0.01) and required dialysis more often, 9/20 versus 1/14 (P=0.024) compared to children with normal excretion.
The majority of patients with D+HUS have renal tubular epithelial injury, as evidenced by elevated urinary NGAL excretion. Urinary NGAL levels below 200 ng/ml within five days of hospitalization may be an adjunctive marker that defines less severe renal involvement.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
We sought to determine whether maternal Medicaid retention influences child Medicaid retention because caregivers play a critical role in assuring children's health access.
We conducted a ...longitudinal prospective cohort study of a convenience sample of 604 Medicaid-eligible mother-child dyads followed from the infant's birth through 24 months of age with parent surveys. Individual enrollment status was abstracted from administrative Medicaid eligibility files. Generalized estimating equations quantified the effect of maternal Medicaid enrollment status on child Medicaid retention, adjusting for relevant covariates. Because varying lengths of gaps may have different effects on child health outcomes, Medicaid enrollment status was further categorized by length of gap: any gap, > 14-days, and > 60-days.
This cohort consists primarily of African-American (94%), unmarried mothers (88%), with a mean age of 23.2 years. In multivariable analysis, children whose mothers experienced any gaps in coverage had 12.6 times greater odds of experiencing gaps when compared to children whose mothers were continuously enrolled. Use of varying thresholds to define coverage gaps resulted in similar odds ratios (> 14-day gap = 11.8, > 60-day gap = 16.8). Cash assistance receipt and maternal knowledge of differences between Temporary Assistance to Needy Families and Medicaid eligibility criteria demonstrated strong protective effects against child Medicaid disenrollment.
Medicaid disenrollment remains a significant policy problem and maternal Medicaid retention patterns show strong effects on child Medicaid retention. Policymakers need to invest in effective outreach strategies, including family-friendly application processes, to reduce enrollment barriers so that all eligible families can take advantage of these coverage opportunities.
Cardiac disease is a major cause of death in patients with muscular dystrophies. The use of feasible and reproducible echocardiographic measures of cardiac function is critical to advance the field ...of therapeutics for dystrophic cardiomyopathy.
Participants aged 8 to 18 years with genetically confirmed Duchenne muscular dystrophy (DMD), Becker muscular dystrophy, or limb-girdle muscular dystrophy were enrolled at five centers, and standardized echocardiographic examinations were performed. Measures of systolic and diastolic function and speckle-tracking echocardiography-derived cardiac strain were reviewed independently by two central readers. Furthermore, echocardiographic measures from participants with DMD were compared with those from retrospective age-matched control subjects from a single site to assess measures of myocardial function.
Forty-eight participants (mean age, 13.3 ± 2.7 years) were enrolled. Shortening fraction had a greater interobserver correlation (intraclass correlation coefficient ICC = 0.63) compared with ejection fraction (ICC = 0.49). One reader could measure ejection fraction in only 53% of participants. Myocardial performance index measured by pulse-wave Doppler and Doppler tissue imaging showed similar ICCs (0.55 and 0.54). Speckle-tracking echocardiography showed a high ICC (0.96). Focusing on participants with DMD (n = 33), significantly increased mitral A-wave velocities, lower E/A ratios, and lower Doppler tissue imaging mitral lateral E' velocities were observed compared with age-matched control subjects. Speckle-tracking echocardiography demonstrated subclinical myocardial dysfunction with decreased average circumferential and longitudinal strain in three distinct subgroups: participants with DMD with normal shortening fractions, participants with DMD aged < 13 years, and participants with DMD with myocardial performance index scores < 0.40 compared with control subjects.
In a muscular dystrophy cohort, assessment of cardiac function is feasible and reproducible using shortening fraction, diastolic measures, and myocardial performance index. Cardiac strain measures identified early myocardial disease in patients with DMD.
Purpose: The ketogenic diet (KD) is a 90% fat diet that is an effective treatment for intractable epilepsy. Rapid initiation of the KD requires hospital admission because of the complexity of the ...protocol and frequent mild and moderate adverse events. The purpose of the study was to compare the efficacy of a gradual KD initiation with the standard KD initiation preceded by a 24‐ to 48‐h fast.
Methods: Children ages 1 to 14 years with intractable epilepsy were randomized to a fasting initiation (FAST‐KD) or gradual initiation (GRAD‐KD). Baseline seizure activity was recorded daily for 28 days before admission and continued for the 3‐month duration of the study. Effectiveness was measured in two ways: (a) the proportion of subjects with >50% reduction in target seizure type from baseline to 3‐month evaluation, and (b) percentage reduction in the frequency of the target seizure type from baseline to 3‐month evaluation. Blood glucose was assessed q4 to 6h, and weights, electrolytes, hydration status, vomiting, acid balance, need for interventions (citric acid and sodium citrates (Bicitra) and IV fluids) were assessed daily. Fisher's exact tests were used to examine the association between protocol and occurrence of adverse events, and longitudinal mixed‐effects models were used to look for trends in tolerability data over time.
Results: Forty‐eight subjects, 24 in each arm, were randomized. In the FAST‐KD protocol, 58% of the children had >50% reduction in the target seizure type at 3 months, and 21% were seizure free. In the GRAD‐KD protocol, 67% had a >50% reduction at 3 months, and 21% were seizure free. The two protocols were equivalent in efficacy (p = 0.033). At 3 months, the FAST‐KD median percentage seizure reduction rate was 78% (ranging from 100% reduction to 73% increase in seizures per week) and was 94% (ranging from 100% reduction to 161% increase in seizures per week) for the GRAD‐KD protocol. By using a logarithmic transformed percentage reduction rate and an equivalence limit difference of 20%, the efficacy of the two protocols was equivalent (p = 0.0002). Children in the GRAD protocol lost significantly less weight (p = 0.006), and had fewer and less‐severe episodes of hypoglycemia (p < 0.001), fewer treatments for acidosis (citric acid and sodium citrates) (p < 0.04) and dehydration (IV fluids) (p < 0.04), but no difference in vomiting was noted.
Conclusions: These data suggest that in children with intractable epilepsy, a gradual initiation results in fewer adverse events and is tolerated better overall while maintaining the efficacy of the KD.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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