Person:

Alexander, Mark

Rett syndrome (RTT) is a severe X-linked neurodevelopmental disorder mainly affecting females and is associated with mutations in MECP2, the gene encoding methyl CpG-binding protein 2. Mouse models suggest that recombinant human insulin-like growth factor 1 (IGF-1) (rhIGF1) (mecasermin) may improve many clinical features. We evaluated the safety, tolerability, and pharmacokinetic profiles of IGF-1 in 12 girls with MECP2 mutations (9 with RTT). In addition, we performed a preliminary assessment of efficacy using automated cardiorespiratory measures, EEG, a set of RTT-oriented clinical assessments, and two standardized behavioral questionnaires. This phase 1 trial included a 4-wk multiple ascending dose (MAD) (40–120 μg/kg twice daily) period and a 20-wk open-label extension (OLE) at the maximum dose. Twelve subjects completed the MAD and 10 the entire study, without evidence of hypoglycemia or serious adverse events. Mecasermin reached the CNS compartment as evidenced by the increase in cerebrospinal fluid IGF-1 levels at the end of the MAD. The drug followed nonlinear kinetics, with greater distribution in the peripheral compartment. Cardiorespiratory measures showed that apnea improved during the OLE. Some neurobehavioral parameters, specifically measures of anxiety and mood also improved during the OLE. These improvements in mood and anxiety scores were supported by reversal of right frontal alpha band asymmetry on EEG, an index of anxiety and depression. Our data indicate that IGF-1 is safe and well tolerated in girls with RTT and, as demonstrated in preclinical studies, ameliorates certain breathing and behavioral abnormalities.

Background: Pediatric syncope is common. Cardiac causes are rarely found. We describe and assess a pragmatic approach to these patients first seen by a pediatric cardiologist in the New England region, using Standardized Clinical Assessment and Management Plans (SCAMPs). Methods and Results: Ambulatory patients aged 7 to 21 years initially seen for syncope at participating New England Congenital Cardiology Association practices over a 2.5‐year period were evaluated using a SCAMP. Findings were iteratively analyzed and the care pathway was revised. The vast majority (85%) of the 1254 patients had typical syncope. A minority had exercise‐related or more problematic symptoms. Guideline‐defined testing identified one patient with cardiac syncope. Syncope Severity Scores correlated well between physician and patient perceived symptoms. Orthostatic vital signs were of limited use. Largely incidental findings were seen in 10% of ECGs and 11% of echocardiograms. The 10% returning for follow‐up, by design, reported more significant symptoms, but did not have newly recognized cardiac disease. Iterative analysis helped refine the approach. Conclusions: SCAMP methodology confirmed that the vast majority of children referred to the outpatient pediatric cardiology setting had typical low‐severity neurally mediated syncope that could be effectively evaluated in a single visit using minimal resources. A simple scoring system can help triage patients into treatment categories. Prespecified criteria permitted the effective diagnosis of the single patient with a clear cardiac etiology. Patients with higher syncope scores still have a very low risk of cardiac disease, but may warrant attention.

BACKGROUND: Neosaxitoxin (NeoSTX) is a site-1 sodium channel blocker that produces prolonged local anesthesia in animals and humans. Under a Food and Drug Administration-approved phase 1 Investigational New Drug trial, the authors evaluated safety and efficacy of NeoSTX alone and combined with 0.2% bupivacaine (Bup) with and without epinephrine. METHODS: The authors conducted a double-blind, randomized, controlled trial involving healthy male volunteers aged 18 to 35 yr receiving two 10-ml subcutaneous injections. Control sites received Bup. In part 1, active sites received (1) 5 to 40 μg NeoSTX+Saline (NeoSTX-Saline), (2) 5 to 40 μg NeoSTX+Bup (NeoSTX-Bup), or (3) placebo (Saline). In part 2, active sites received 10 or 30 μg NeoSTX+Bup+Epinephrine (NeoSTX-Bup-Epi) or placebo. Primary outcome measures were safety and adverse events associated with NeoSTX. Secondary outcomes included clinical biochemistry, NeoSTX pharmacokinetics, and cutaneous hypoesthesia. RESULTS: A total of 84 subjects were randomized and completed the two-part trial with no serious adverse events or clinically significant physiologic impairments. Perioral numbness and tingling increased with NeoSTX dose for NeoSTX-Saline and NeoSTX-Bup. All symptoms resolved without intervention. NeoSTX-Bup-Epi dramatically reduced symptoms compared with other NeoSTX combinations (tingling: 0 vs. 70%, P = 0.004; numbness: 0 vs. 60%, P = 0.013) at the same dose. Mean peak plasma NeoSTX concentration for NeoSTX-Bup-Epi was reduced at least two-fold compared with NeoSTX-Saline and NeoSTX-Bup (67 ± 14, 134 ± 63, and 164 ± 81 pg/ml, respectively; P = 0.016). NeoSTX-Bup showed prolonged cutaneous block duration compared with Bup, NeoSTX-Saline, or placebo, at all doses. Median time to near-complete recovery for 10 μg NeoSTX-Bup-Epi was almost five-fold longer compared with Bup (50 vs. 10 h, P = 0.007). CONCLUSION: NeoSTX combinations have a tolerable side effect profile and appear promising for prolonged local anesthesia.

The predictability of pain makes surgery an ideal model for the study of pain and the development of strategies for analgesia and reduction of perioperative pain. As functional near-infrared spectroscopy reproduces the known functional magnetic resonance imaging activations in response to a painful stimulus, we evaluated the feasibility of functional near-infrared spectroscopy to measure cortical responses to noxious stimulation during general anesthesia. A multichannel continuous wave near-infrared imager was used to measure somatosensory and frontal cortical activation in patients undergoing catheter ablation of arrhythmias under general anesthesia. Anesthetic technique was standardized and intraoperative NIRS signals recorded continuously with markers placed in the data set for the timing and duration of each cardiac ablation event. Frontal cortical signals only were suitable for analysis in five of eight patients studied (mean age 14 ± 1 years, weight 66.7 ± 17.6 kg, 2 males). Thirty ablative lesions were recorded for the five patients. Radiofrequency or cryoablation was temporally associated with a hemodynamic response function in the frontal cortex characterized by a significant decrease in oxyhemoglobin concentration (paired t-test, p<0.05) with the nadir occurring in the period 4 to 6 seconds after application of the ablative lesion. Cortical signals produced by catheter ablation of arrhythmias in patients under general anesthesia mirrored those seen with noxious stimulation in awake, healthy volunteers, during sedation for colonoscopy, and functional Magnetic Resonance Imaging activations in response to pain. This study demonstrates the feasibility and potential utility of functional near-infrared spectroscopy as an objective measure of cortical activation under general anesthesia.

Background: The 2005 Bethesda Conference Guidelines advise patients with long QT syndrome against competitive sports. We assessed cardiac event rates during competitive and recreational sports, and daily activities among treated long QT syndrome patients. Methods and Results: Long QT syndrome patients aged ≥4 years treated with anti‐adrenergic therapy were included. Demographics included mechanism of presentation, corrected QT interval pretreatment, symptom history, medication compliance, and administration of QT‐prolonging medications. Corrected QT interval ≥550 ms or prior cardiac arrest defined high risk. Sports were categorized by cardiovascular demand per the 2005 Bethesda Conference Guidelines. Each was classified as recreational or competitive. One hundred seventy‐two patients (90; 52% female) with median age 15.2 years (interquartile range 11.4, 19.4) were included. Evaluation was performed for family history (102; 59%), incidental finding (34; 20%), and symptoms (36; 21%). Median corrected QT interval was 474 ms (interquartile range 446, 496) and 14 patients (8%) were deemed high risk. Treatment included β‐blockers (171; 99%), implantable cardioverter‐defibrillator (27; 16%), left cardiac sympathetic denervation (7; 4%), and pacemaker (3; 2%). Sports participation was recreational (66; 38%) or competitive (106; 62%), with 92 (53%) exercising against the Bethesda Conference Guidelines. There were no cardiac events in competitive athletes and no deaths. There were 13 cardiac events in 9 previously symptomatic patients during either recreational exercise or activities of daily life. Conclusions: In this cohort of appropriately managed children with long QT syndrome, cardiac event rates were low and occurred during recreational but not competitive activities. This study further supports the need for increased assessment of arrhythmia risk during exercise in this patient population.

Abstract Objective: To measure the efficacy of mecasermin (recombinant human insulin‐like growth factor 1, rhIGF‐1), for treating symptoms of Rett syndrome (RTT) in a pediatric population using a double‐blind crossover study design. Methods: Thirty girls with classic RTT in postregression stage were randomly assigned to placebo or rhIGF‐1 in treatment period 1 and crossed over to the opposite assignment for period 2 (both 20 weeks), separated by a 28‐week washout period. The primary endpoints were as follows: Anxiety Depression and Mood Scale (ADAMS) Social Avoidance subscale, Rett Syndrome Behaviour Questionnaire (RSBQ) Fear/Anxiety subscale, Parent Target Symptom Visual Analog Scale (PTSVAS) top three concerns, Clinical Global Impression (CGI), Parent Global Impression (PGI), and the Kerr severity scale. Cardiorespiratory‐ and electroencephalography (EEG)‐based biomarkers were also analyzed. Results: There were no significant differences between randomization groups. The majority of AEs were mild to moderate, although 12 episodes of serious AEs occurred. The Kerr severity scale, ADAMS Depressed Mood subscale, Visual Analog Scale Hyperventilation, and delta average power change scores significantly increased, implying worsening of symptoms. Electroencephalography (EEG) parameters also deteriorated. A secondary analysis of subjects who were not involved in a placebo recall confirmed most of these findings. However, it also revealed improvements on a measure of stereotypic behavior and another of social communication. Interpretation As in the phase 1 trial, rhIGF‐1 was safe; however, the drug did not reveal significant improvement, and some parameters worsened.