232 www.thelancet.com/neurology Vol 12 March 2013

In Context

News in briefHeadache in childrenTwo studies have aimed to provide a clearer picture of which treatments are most useful for children and adolescents with head ache and to investigate why the results of many trials have been negative. In a meta-analysis of randomised trials of prophylactic treatments in patients under 18 years of age (JAMA Pediatr 2013; published online Jan 28. DOI:10.1001/ jama pediatrics. 2013.508), only two drugs were more eff ective than placebo for episodic migraine (weighted mean diff erences in headaches per month –0·71, 95% CI –1·19 to –0·24, for two trials of topiramate; –0·60, –1·09 to –0·11, for one trial of trazodone). The other study was a systematic review of data submitted to the US Food and Drug Administration from trials of triptans for acute treatment of children with migraine (JAMA Pediatr 2013; published online Jan 28. DOI:10.1001/jamapediatrics.2013.872). The authors of both studies reported signifi cant placebo response rates and conclude that future trial designs should take this placebo response into account.

New monoamine disorderRilstone and colleagues describe a brain dopamine–serotonin vesicular transport disease inherited in an auto-somal-recessive manner in children from an extended consanguineous Saudi Arabian family (N Engl J Med 2013; published online Jan 30. DOI:10.1056/ NEJMoa1207281). Clinical symptoms included infantile-onset movement disorder, mood disturbance, auto-nomic instability, and developmental delay. Abnormalities in the levels of monoamines and their metabolites were detected in urine but not in CSF. Genome studies identifi ed a mutation in the gene SLC18A2, that encodes vesicular monoamine transporter 2 (VMAT2), which translocates dopamine and serotonin into synaptic vesicles. In COS-7 cells, Pro387Leu-mutant

human VMAT2 showed markedly decreased activity compared with wild-type VMAT2, although not a complete loss of function. Treatment with levodopa–carbidopa resulted in severe deterioration of symptoms, with intense chorea and worsened dystonia, whereas direct dopamine agonists led to rapid and sustained improvements in parkinsonism and other symptoms.

Statin promise for FXSLovastatin might be useful as a disease-modifying therapy in fragile X syndrome (FXS), according to a recent study. In Fmr1–/y knockout mice, an animal model of FXS that recapitulates some clinical features of patients with the disease, lovastatin reduced excitability in the visual cortex and inhibited the expression of audiogenic seizures. These eff ects on cortical hyperexcitability seemed to stem from the ability of the drug to correct the excessive protein synthesis that characterises the pathogenesis of the disease, which suggests that lovastatin might also improve sensory and cognitive symptoms (Neuron 2013; 77: 243–50). Remarkably, in previous studies in a mouse model of neurofi bromatosis, lovastatin treatment improved cognitive defi cits.

Outcome after cardiac arrestThe benefi t of prehospital advanced airway management (using endo-tracheal intubation or supra glottic airway devices compared with conventional bag–valve–mask vent-il ation) for improving neurological outcome and survival after out-of-hospital cardiac arrest was in vestigated in a prospective, nation-wide, population-based study of 649 359 consecutive patients in Japan (JAMA 2013; 309: 257–86). The primary endpoint was a favourable neurological outcome at 1 month, defi ned as a Glasgow–Pittsburgh cerebral perfor-mance category of 1 or 2. The rate of a favourable neurological outcome

was lower for the 281 522 patients (43%) in the advanced airway group than for the 367 837 patients (57%) who received bag–valve–mask ventil-ation (odds ratio [OR] 0·38; 95% CI 0·36–0·39). In multivariable logistic re gression analyses, advanced air-way management had an OR for favourable neurological outcome of 0·38 (0·37–0·40). Both methods of advanced airway management were similarly associated with decreased odds of neurologically favourable survival. These fi ndings contradict assumptions about aggressive air way intervention and call for recon sideration of the approach to pre hospital airway management in this patient group.

C9orf72 and membrane traffi ckingThe most common single mutation in families with overlapping amyo-trophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) has been mapped to a non-coding repeat expansion in the uncharacterised gene C9orf72. Using online bioinformatic engines, sensitive searches of homology to proteins of known function identifi ed strong structural homology between the product of C9orf72 and the full-length Rab-specifi c guanine nucleotide exchange factor (GEF) domains in the DENN-like superfamily of proteins (Bioinformatics 2013; published online Jan 16. DOI: 10.1093/bioinformatics/bts725). Fine-tuning of membrane traffi cking by modulation of Rab activity is known to be important for neuronal function, and several DENN-domain-containing proteins have been linked to neurodegeneration, also through their eff ects on membrane traffi cking. Therefore, a potential role for the product of C9orf72 in membrane traffi cking, particularly in endosomal and lysosomal function, points to to a new avenue to investigate the underlying pathology of ALS–FTD.

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