The results of the landmark major multi-center randomized clinical trial "Management of Myelomeningocele Study (MOMS)" report on fetal surgery for spina bifida has been published in the 9 February issue of the New England Journal of Medicine, NEJM. The results indicate that prenatal surgery for spina bifida has greatly improved benefits over postnatal repair, by reducing the need for shunting and improving motor outcomes.
The randomized clinical trial is the first that systematically evaluated the best treatment for myelomeningocele. The eight-year trial was stopped early since the results suggested that fetal surgery greatly reduced the need for postnatal intervention. The early intervention in utero also resulted in improved motor development.The early success of the trial has been cause for celebration at UCSF, who carried out the first human fetal surgery some thirty years ago.The surgical procedures evaluated in this trial, known as the Management of Myelomeningocele Study (MOMS), were developed at UCSF's Fetal Treatment Center, under the direction of Michael Harrison, UCSF professor emeritus of clinical surgery, pediatrics, obstetrics and gynecology.Harrison, often referred to as the "Father of Fetal Surgery", performed the world's first open fetal surgery 30 years ago at UCSF, and the institution has also trained most of the current leaders in the field.
The study originally planned to enroll 200 pregnant women carrying a child with myelomeningocele, but was stopped early, with only 183 participants enrolled, because of the significant benefits shown in the children who underwent fetal surgery. The pregnant women were randomly assigned to one of two groups: a prenatal surgery group and a postnatal surgery group. The prenatal group underwent surgery to close the spinal defect in the fetus before the 26th week of pregnancy. The babies born in the postnatal group had the standard surgery in the usual time frame. The children underwent independent evaluation at 12 months and 30 months. At 12 months of age only 39.7% of children in the prenatal surgery group needed csf shunt surgery compared to 82.5% in the postnatal surgery group. Standardized motor and cognitive outcome assessments performed at 30 months saw the prenatal surgery group scoring significantly higher than the postnatal surgery group. 41.9% of the children in the fetal surgery group were able to walk unaided compared to only 20.9% in the postnatal group.
It should however be noted that there are risks to the mother and fetus associated with early intervention and this option might not be suitable in all cases.
A Randomized Trial of Prenatal versus Postnatal Repair of Myelomeningocele. N. Scott Adzick, Elizabeth A. Thom, Catherine Y. Spong, John W. Brock, Pamela K. Burrows, Mark P. Johnson, Lori J. Howell, Jody A. Farrell, Mary E. Dabrowiak, Leslie N. Sutton, Nalin Gupta, Noel B. Tulipan, Mary E. D'Alton, Diana L. Farmer (2011)
New England Journal of Medicine p. 110209140307019
http://www.nejm.org/doi/abs/10.1056/NEJMoa1014379
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American Academy of Pediatrics (AAP) publishes updated practice guidelines on simple febrile seizures, in the January 31 issue of Pediatrics. Following a comprehensive review of the evidence based literature from 1996 to February 2009, the AAP have published updated guidelines on simple febrile seizures which replaces the 1996 practice statndards.
The recommendations stresses the importance of identifying the etiology in children presenting with fever. A lumbar puncutre should be performed if there are any signs or symptoms concerning meningitis. In infants between 6 and 12 months, who are unimmunized or in whose vaccination status is unclear, a lumbar puncture should be considered. The guidelines also suggest that a lumbar puncture should be considered where the child had already received antibiotics. Simple febrile seizures do not normally require any further investigations particularly EEG or neuroimaging.
Subcommittee on Febrile Seizures. Neurodiagnostic evaluation of the child with a simple febrile seizure. Pediatrics. 2011 Feb;127(2):389-94. PubMed PMID:
21285335. [ Free Full Text]
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Red ear syndrome (RES) in children is a highly specific sign for migraine, according to the results of a study published by Raieli et al in Cephalalgia on December 2010
.Previous studies have suggested a relationship between ‘red ear syndrome’ (RES) and pediatric migraine and a crossover between RES and other other primary headaches, such as trigeminal autonomic cephalalgias (TACs) have also been proposed. The red ear syndrome is a rare syndrome originally described by Lance in 1994. It involves pain in and around the ear and associated autonomic phenomena, the most significant of which is cutaneous erythema of the ear ipsilateral to the pain and obvious to the patient and examiner during the attack.
In this retrospective study, 226 children (aged 4-17yrs) suffering from headache were studied to assess the frequency, specificity and sensitivity of RES in a population of pediatric migraineurs and to establish the pathophysiological mechanisms of Red Ear Syndrome associated with migraine. The authors found that Red Ear Syndrome was followed significantly more frequently by migraine (23.3%; p .0001), and was characterized by high specificity and positive predictive value (96.3 and 95.3%, respectively). RES showed a statistically significant association with male sex, throbbing quality of the pain and vomiting. However the authors did not undertake a systematic analysis of local autonomic symptoms and the findings cannot be generalized to adult patients with migraine.
The authors also suggest that evidence of an association of RES with some migraine features partially provoked by the parasympathetic system supports the hypothesis of a shared pathophysiological background (e.g. via the activation of the trigeminal-autonomic reflex).
The study results suggest RES as a very useful clinical marker in the pediatric age group, along with other symptoms including vomiting, localization of pain or behavior of the child during the attack.
Reference
Raieli V, Compagno A, Brighina F, La Franca G, Puma D, Ragusa D et al. (2010) Prevalence of red ear syndrome in juvenile primary headaches. Cephalalgia ():. DOI: 10.1177/0333102410388437 PMID: 21123628.
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In pioneering research published in the Jan 18 issue of Neurology Pegoraro et al reports the identification of genetic modifiers of muscular dystrophy in humans for the first time.
Duchenne muscular dystrophy is a severe X-linked disease caused by mutations in the DMD gene that lead to nearly complete loss of dystrophin in skeletal and cardiac muscle.
In pioneering research published in the Jan 18 issue of Neurology Pegoraro et al reports the identification of genetic modifiers of muscular dystrophy in humans for the first time.The authors used informatics approaches, based on their earlier studies in normal subjects and from comparisons of rapid vs slow progression in DMD, to select a limited set of 29 candidate polymorphisms for analysis. One of the polymorphisms is a previously known single base variant in the promoter region of SPP1, and the authors provide evidence that the G allele of rs28357094 (observed in 35% of cases) is associated with more severe disease, as measured by either time to continuous wheelchair use or grip strength in 2 independent cohorts. The severe allele is present in about a third of all people, so this single allele could account for a substantial portion of the variability in disease progression.
In an accompanying editorial Drs Stanley F. Nelson and Robert C. Griggs point out that the presence of the G allele may provide a basis for stratifying patients entering clinical trials according to the anticipated rate of disease progression. This may improve the power of the trial by reducing interindividual heterogeneity, thereby permitting clinicians to select the relatively rapidly progressing subjects who may respond better to therapy.
In addition, the SPP1 variants associated with disease severity in DMD suggest the possibility of osteopontin as a rational therapeutic target.Osteopontin is a cytokine that promotes immune cell migration and survival; high tissue and circulating levels of osteopontin have been identified in a variety of muscular dystrophies, various inflammatory disorders, and cancer.
Studies of osteopontin knockout models have shown lessened severity and fibrosis in the mdx mouse. Interestingly however the G allele, associated with low osteopontin expression in mice and less disease seems to be associated with more severe disease in humans as shown by Pegoraro et al.
While hailing the findings of this study Drs Stanley F. Nelson and Robert C. Griggs also point out the importance of replicating these findings in larger cohort of DMD boys.It is indeed likely that all observed variations in DMD disease severity were not due to SPP1 variants.
With relatively inexpensive comprehensive sequencing of the human genome now made possible, this study should pave the way for more genome wide searches of disease modifiers as in the case of the recent identification of the IFRD1 variant in cystic fibrosis.
- SPP1 genotype is a determinant of disease severity in Duchenne muscular dystrophy E. Pegoraro, E.P. Hoffman, L. Piva, B.F. Gavassini, S. Cagnin, M. Ermani, L. Bello, G. Soraru, B. Pacchioni, M.D. Bonifati, G. Lanfranchi, C. Angelini, A. Kesari, I. Lee, H. Gordish-Dressman, J.M. Devaney, C.M. McDonald On behalf of the Cooperative International Neuromuscular Research Group Neurology 2011;76 219-226
- Predicting the severity of Duchenne muscular dystrophy: Implications for treatment Stanley F. Nelson and Robert C. Griggs Neurology 2011;76 208-20
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Fever-induced refractory epileptic encephalopathy in school-age children (FIRES) is a recently described epileptic entity whose etiology remains unknown. Brain abnormalities shown by MRI are usually limited to mesial-temporal structures and do not account for the catastrophic neuropsychologic findings.
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