Corrigendum: Off-Label Use of Ataluren in Four Non-ambulatory Patients With Duchenne Muscular Dystrophy: Effects on Cardiac and Pulmonary Function and Muscle Strength.

[This corrects the article DOI: 10.3389/fped.2018.00316.].

Off-Label Use of Ataluren in Four Non-ambulatory Patients With Nonsense Mutation Duchenne Muscular Dystrophy: Effects on Cardiac and Pulmonary Function and Muscle Strength.

About 15% of Duchenne muscular dystrophy (DMD) cases are caused by point mutations leading to premature stop codons and disrupted synthesis of the dystrophin protein. Stop codon read-through therapy is available with the drug Ataluren (Translarna® by PTC Therapeutics). Following positive results in ambulatory nmDMD (non-sense mutation Duchenne muscular dystrophy) patients, Ataluren received conditional approval in ambulant nmDMD patients by the EMA in 2014. However, there are limited data on non-ambulatory nmDMD patients treated with Ataluren. Here, we report our experience in four non-ambulatory nmDMD patients. Routine investigations included cardiac function, pulmonary function tests and muscle strength. We compared changes in left ventricular fractional shorting, forced volume vital capacity and BMI from two defined time periods (18-26-month period prior to and after Ataluren start). Mean age at loss of ambulation was 10.1 ± 0.5 years, mean age when initiating Ataluren treatment 14.1 ± 1.4 years. Serial echocardiography, pulmonary lung function tests, and assessment of muscle strength indicated mild attenuation of disease progression after initiation of Ataluren treatment. A possible side effect of Ataluren was a reduction in BMI. There were no adverse clinical effects or relevant abnormalities in routine laboratory values. We conclude that Ataluren appears to mildly ameliorate the clinical course in our patients with a good safety profile. However, larger clinical trials are required to assess the role of Ataluren and its long-term impact on disease progression in non-ambulant nmDMD patients.

Effect of sulthiame on EEG pathology, behavior and school performance in children with Rolandic epileptiform discharges.

BACKGROUND: Rolandic epileptiform discharges (RED) may be associated with behavioral difficulties and low school performance. The aim of this study was to assess whether sulthiame is effective in improving electroencephalogram (EEG) pathology, and whether these changes are paralleled by improved school performance and behavior. METHODS: In this single-center study at a university hospital, 38 children with RED (27 boys, 11 girls; mean age, 6 years; range, 3-11 years), but no overt seizures, were included. Sixteen of them were treated with sulthiame (3-10 mg/kg). The observational period was 12 months. In both groups serial EEG was performed, and school performance and behavioral skills were assessed by parents and teachers. RESULTS: Children treated with sulthiame showed marked improvement on EEG pathology when compared to the non-treated group (75% vs 44%; P= 0.149). Improvement of EEG pathology was significantly associated with better school performance and normalization of behavioral difficulties (P= 0.016). A significant positive correlation was established between sulthiame treatment and improved intellectual/school performance and behavior (P < 0.05). Side-effects (transient episodes of tachypnea) were rare (four children; 25%). CONCLUSION: EEG pathology can be improved with sulthiame in children with RED. The EEG changes were associated with improved clinical outcome parameters. The present findings need to be confirmed in a larger randomized controlled trial.

The role of EEG recordings in children undergoing cardiac surgery for congenital heart disease.

Neurological dysfunction may occur after corrective cardiac surgery using cardio-pulmonary bypass (CPB) with or without circulatory arrest. Different neurophysiological monitoring systems have been employed to detect neurological complications and possible brain injury in infants and children during and after cardiac surgery. The value of EEG in infants and children at risk for neurological sequelae has not been systematically studied. Sequential performance of 2 EEGs before and after cardiac surgery at a tertiary University Hospital to screen for possible brain injury after cardiac surgery. In addition, a complete neurological examination was performed. In 313 patients (age: 54.2±55.7 months; normal initial EEG) after cardiac surgery CPB (duration of surgery: 146.0±58.9 minutes; aortic cross clamp time: 34.1±19.1 minutes) a 19-channel EEG recording was performed 2.4±1.8 days prior and 11.6±5.3 days after cardiac surgery. An abnormal EEG was detected in only 8 of 313 patients (2.5%; focal slowing(1), generalised slowing (5), epiletiform discharges(2)) after cardiac surgery, while the EEG was normal in the remaining 305 patients (97.5%). In one patient, an intra-cerebral pathology was seen on MRI (ischemic); in 5 patients follow-up EEGs were performed, which revealed normalised findings. None of the 8 patients demonstrated new focal neurological deficits on physical examination, but 33 (9.7%) children demonstrated minor abnormalities (eg, subtle motor asymmetry, increase in muscle tone, etc.), which were unrelated to abnormal EEG findings. According to the used protocol pathological EEG findings were very infrequent in our study cohort. The routine and indiscriminative recording of EEGs in children before and after corrective or palliative cardiac surgery for congenital heart disease using CPB is not recommended. Further intra-operative neuromonitoring methods with immediate intervention should be evaluated.

Melatonin does not influence sleep deprivation electroencephalogram recordings in children.

UNLABELLED: The electroencephalogram (EEG) is an essential diagnostic tool in children with epilepsy. The recording of a sleep EEG can increase the yield of EEG recordings in certain epileptic syndromes. The primary aim of this study was to assess the influence of melatonin on EEG recording (quality, EEG characteristics) and to assess its efficacy to induce sleep. Children with epilepsy or non-epileptic neurological patients requiring sleep deprivation EEG studies were enrolled into this prospective study at a tertiary University Hospital study. Sequential recording of sleep deprivation EEGs both with and without prior administration of melatonin was performed. A total of 50 patients (27 with epilepsy, 23 non-epileptic neurological patients) were included in this study (median age 9.5 years; range 1-18 years; male 28). The quality and EEG characteristics (abnormal findings, depth of sleep) were not affected by the use of melatonin. In total, 92 of 100 EEGs were successfully performed without significant differences between the two groups (six failures with melatonin, two failures without melatonin; p = 0.289). CONCLUSIONS: We conclude that melatonin does not alter the quality of sleep EEG studies in children with epilepsy or suspected epilepsy. Melatonin does not increase the rate of successfully performed EEG studies in sleep-deprived children.

Christianson syndrome in a patient with an interstitial Xq26.3 deletion.

Interstitial deletions of chromosome band Xq26.3 are rare. We report on a 2-year-old boy in whom array comparative genomic hybridization analysis revealed an interstitial 314 kb deletion in Xq26.3 affecting SLC9A6 and FHL1. Mutations in SLC9A6 are associated with Christianson syndrome (OMIM 300243), a syndromic form of X-linked mental retardation (XLMR) characterized by microcephaly, severe global developmental delay, ataxia and seizures. FHL1 mutations cause Emery-Dreifuss muscular dystrophy (OMIM 310300), X-linked myopathy with postural muscle atrophy (XMPMA, OMIM 300696), scapuloperoneal myopathy (OMIM 300695), or reducing body myopathy (OMIM 300717, 300718). The clinical problems of the patient reported here comprised severe intellectual disability, absent speech, ataxia, epilepsy, and gastroesophageal reflux, and could mostly be attributed to SLC9A6 insufficiency. In contrast to the majority of reported Christianson syndrome patients who were microcephalic, this patient was normocephalic, but his head circumference had decelerated from the 50th centile at birth to the 25th centile at the age of 2 ²/¹² years. Muscle problems due to the FHL1 deletion are not to be expected before late childhood, which is the earliest age of onset for FHL1 associated Emery-Dreifuss muscular dystrophy. This patient broadens the spectrum of SLC9A6 mutations and contributes to the clinical delineation of Christianson syndrome. This is also the first patient with a deletion affecting both SLC9A6 and the complete FHL1 gene.

Sudden unexpected death in epilepsy in children.

Sudden unexpected death in epilepsy (SUPEP) is the commonest cause of seizure-related mortality in people with intractable epilepsy. The incidence of SUDEP varies in different epilepsy populations, with lower rates in population-based studies, higher in referral populations and clinical trials of adjunct drugs for complex partial epilepsy, and highest rates for surgical series. Certain risk factors for SUDEP have been identified, with seizure activity being one of the strongest risk factor for SUDEP. Suspected underlying mechanisms include cardiac dysrhythmias, seizure-related apnoea and postictal respiratory arrest. Prevention of SUDEP has centred on seizure control, and SUDEP incidence has been reduced by epilepsy surgery in some studies. In this review, we present epidemiological data, and discuss risk factors and underlying pathophysiological mechanisms that are associated with SUDEP in children.

A novel missense mutation in a neonate with nonketotic hyperglycinemia.

Nonketotic hyperglycinemia (OMIM #605899), also known as glycine encephalopathy, is an autosomal recessive disorder of glycine metabolism caused by a defect in the glycine cleavage system. A term neonate developed progressive lethargy, muscular hypotonia, and respiratory insufficiency on day 2 after birth, but no overt clinical seizures. Amplitude-integrated electroencephalography indicated a continuous burst-suppression pattern. The diagnosis of nonketotic hyperglycinemia was made biochemically and was confirmed by genetic studies, which revealed two missense mutations (one not previously described) within the glycine decarboxylase gene, GLDC. Nonketotic hyperglycinemia should be incorporated into the differential diagnosis of neonatal hypotonia, to avoid an erroneous diagnosis of sepsis or hypoxic ischemic injury. Amplitude-integrated electroencephalography may be helpful in the initial assessment of severely sick and hypotonic neonates without overt clinical seizures, and may direct further diagnostic evaluation.

New mechanical recanalization devices - the future in pediatric stroke treatment?

OBJECTIVE: To evaluate the recanalization rate and clinical outcome in children with acute ischemic stroke following treatment with innovative mechanical thrombectomy devices. PATIENTS AND METHODS: Three subjects aged 7-16 years presenting with acute cerebral vascular occlusions (thrombolysis in myocardial infarction [TIMI] 0) were treated with either the Penumbra System, operating on an aspiration platform, or the Phenox clot retriever device, a flexible wire compound with perpendicularly-oriented polyamid microfilaments. Target vessels were the internal carotid artery, the middle cerebral artery and the basilar artery. RESULTS: Successful recanalization (TIMI 3) was attained in all cases. No device-related complications or intracranial hemorrhage occurred. Follow up was conducted for up to 30 days. A 10- to 26-point improvement in the National Institutes of Health Stroke Scale (NIHSS) score was achieved. CONCLUSIONS: Mechanical thrombectomy devices possess a dual advantage whereby they can achieve instant recanalization as well as minimize the number of bleeds that customarily accompany intravenous and intra-arterial therapy. These new devices could contribute greatly to treatment decisions in a field not yet clearly defined by current guidelines.

Simultaneous tuberculous meningoencephalitis in two siblings.

UNLABELLED: The high morbidity and mortality of tuberculous meningoencephalitis (TBM) warrants an early diagnosis and treatment. BCG vaccine has been proven to reduce the incidence of disseminated disease in children. We report on two siblings (2-year-old boy and 4-year-old girl) with simultaneous TBM, whose parents originated from Kosovo, Albania, but presently reside in Germany. Early diagnosis of TBM was delayed, and at first the misdiagnosis of viral meningoencephalitis was made. Antituberculosis treatment was not initiated despite profound hyponatremia, hydrocephalus, and signs of inflammatory cerebral disease. After establishing the diagnosis of TBM, the boy died from antituberculosis, drug-induced hepatic failure; the sister survived with severe neurological deficits. Contact tracing revealed that TB had been transmitted by a household contact person with proven pulmonary TB who had refused antituberculosis treatment. A thorough contact investigation including tuberculin skin testing to identify children at risk for TB in the vicinity of this patient was not carried out. These case reports demonstrate an unusual simultaneous occurrence of TBM in a brother and sister. It draws attention to the importance of TBM as a differential diagnosis in children with suspected viral meningoencephalitis. CONCLUSIONS: To prevent severe neurological sequelae, early antituberculosis therapy should be considered in infants and children with a clinical impression of meningitis in the context of cerebrospinal fluid white blood cell count of less than 500 cells/microl and lymphocytic predominance, hyponatremia, and possible hydrocephalus. This notion is especially true for children originating from high-endemicity countries for TB. A rigid implementation of antituberculosis treatment of infected individuals and contact tracing is mandatory in order to prevent dissemination of TB in the community. The use of BCG vaccine should be considered in children at high risk for TB infection because of its potential to reduce disseminated TB.