2010 Round-up

www.thelancet.com/neurology Vol 10 January 2011 15

Paediatric neurology: understanding risk and improving therapeutic choices

Monogenic or polygenic genetic predisposition is clinically relevant for many neurological disorders of childhood, and has implications for outcome, risk, and treatment options in epilepsy of infancy, stroke, and lysosomal disorders.

A 2006 study1 reported that 12 of 14 patients with suspected vaccine encephalopathy—a poorly defi ned disorder that causes seizures and intellectual impairment in infants with onset after vaccination—had clinical features of Dravet syndrome, a severe epileptic encephalopathy. 11 of these 12 patients had de-novo mutations of the sodium channel gene SCN1A. Although this study suggested that this genetic condition had been misattributed to pertussis vaccination, it also raised the question of whether there was a genuine temporal association of seizure onset with vaccination, or whether the patients who had onset of Dravet syndrome shortly after vaccination had any specifi c molecular or outcome diff erences compared with other patients with Dravet syndrome.

These researchers have reported a further study of 40 patients with Dravet syndrome and SCN1A mutations whose fi rst seizure was a convulsion.2 The study examined associations between proximity of vaccination to seizure onset, mutation type, and intellectual and seizure outcomes. They found that age at seizure onset was lower in those whose seizure onset was within 2 days of vaccination than in those in the vaccination-distant group (18·4 weeks vs 26·2 weeks; diff erence 7·8 weeks, 95% CI 2·6–13·1); however, there were no diff erences in intellectual outcome, subsequent seizure type, or mutation type between the two groups. Furthermore, intellectual outcome did not diff er between patients who received vaccination after seizure onset and those who did not. Because the investigators found no evidence that vaccination aff ected outcome, they recommend that vaccination should not be withheld from children with SCN1A mutations. This fi nding fi nally provides a satisfying resolution to the debate in the 1960s and 1970s about pertussis immunisation that led to the subsequent public response to concerns (now shown to be unfounded) about the measles, mumps, and rubella vaccine.

Kenet and colleagues3 assessed the eff ect of thrombophilia on the risk of fi rst arterial ischaemic stroke and on fi rst cerebral sinovenous thrombosis in infants and

children by reviewing reports that compared individuals aff ected by such strokes and controls. Such comparative studies, with adequate reporting of laboratory methods and reference ranges, accounted for just 22 of 185 reports identifi ed in this systematic review of studies published since 1970. Surprisingly, none of the included studies had been published before 1998, but the investigators reported no signifi cant association between year of publication and eff ect size, and cite symmetrical standard errors as evidence against publication bias. Their meta-analysis of the entire cohort of 1764 patients suggests a statistically signifi cant association with stroke for each thrombophilia trait assessed. Summary odds ratios for the presence of traits in patients with stroke ranged from 1·58 for the methylenetetrahydrofolate reductase (MTHFR) T677T genotype to 9·31 for patients with protein C defi ciency. The investigators state that most children in the included studies were white, and their fi ndings might not apply to other ethnic groups. The odds ratios of thrombophilic traits did not diff er signifi cantly between perinatal and childhood arterial ischaemic stroke (although the neonatal data were relatively sparse) or, despite their distinct pathophysiologies, between arterial ischaemic stroke and cerebral sinovenous thrombosis. The data for the meta-analysis do not address recurrence risk or outcome after fi rst stroke, both of which would be relevant to clinicians making decisions about therapeutic intervention in a child presenting with a stroke.

As the accompanying editorial4 points out, the reliability of the reported odds ratios depends crucially on the quality of the control groups of the individual studies, and also on the timing of the blood sample relative to the stroke because thrombosis can cause transient acquired low levels of antithrombin, protein C, or protein S. The investigators also add methodological caveats to the reported abnormalities of MTHFR, lipoprotein(a), and antiphospholipid antibodies. The meta-analysis does not establish the clinical value, economic eff ectiveness, or psychological implications of thrombophilia testing in this setting; therefore, debates about who to investigate for thrombophilia, when, and for what reason will continue. Despite this continued uncertainty about the clinical implications of the identifi ed association between

2010 Round-up

16 www.thelancet.com/neurology Vol 10 January 2011

thrombophilia and childhood stroke, there will soon be intervention trials for childhood stroke.

Moharir and colleagues5 published a very useful report of safety and outcome of anticoagulation for cerebral sinovenous thrombosis given to 29 of 83 neonates and 56 of 79 children. In the whole study group, clinical outcome was unfavourable (defi cit or death) in 59% of neonates and 37% of children. Of those receiving anticoagulants, major haemorrhage occurred in 14% of those with and 2% of those without pretreatment intracranial haemorrhage, compared with 1% of those not receiving anticoagulants. Of patients who had anticoagulation-related haemorrhage, 50% had a favourable outcome. Rates of thrombus propagation decreased from 28% and 37% without anticoagulants to 4% and 7% with anticoagulants in infants and children, respectively. This fi nding is an important step forward in building the platform for a randomised trial of anticoagulation.

Chaperone therapy might be a new avenue for lysosomal storage disorders. A study by Kirkegaard and colleagues6 shows that heat-shock protein 70 (Hsp70)—a molecular chaperone that supports the folding of newly formed

polypeptides—enters the lysosome by endocytosis and inhibits lysosomal breakdown. Once within the lysosomes, the affi nity of Hsp70 to bismonoacylglycerophosphate (BMP), associated with the lysosomal inner membrane, is enhanced by the acidic environment within the lysosome. Interaction between Hsp70 and BMP stabilises the membrane by enhancing the interaction between BMP and acid sphingomyelinase (ASM)—the enzyme responsible for breakdown of sphingomyelin that is defi cient in Niemann-Pick disease. This membrane stabilisation promotes cell survival. Normal cells in which ASM is depleted, and cells from patients with Niemann-Pick disease, are sensitive to lysosomal damage when exposed to oxidative stress but the investigators showed that addition of Hsp70 increased activity of ASM, enhanced lysosomal stability, and normalised the abnormally enlarged lysosomes of cells from patients with Niemann-Pick disease. Thus, Hsp70, or other BPM modulators yet to be elucidated, might provide an exciting new family of therapeutic agents in lysosomal storage disorders.

Colin KennedyDivision of Clinical Neurosciences, School of Medicine, University of Southampton, Southampton S017 1BJ, UKcrk1@soton.ac.uk

I declare that I have no confl icts of interest.

1 Berkovic SF, Harkin L, McMahon JM, et al. De-novo mutations of the sodium channel gene SCN1A in alleged vaccine encephalopathy: a retrospective study. Lancet Neurol 2006; 5: 488–92.

2 McIntosh AM, McMahon J, Dibbens LM, et al. Eff ects of vaccination on onset and outcome of Dravet syndrome: a retrospective study. Lancet Neurol 2010; 9: 592–98.

3 Kenet G, Lütkhoff MA, Albisetti M, et al. Impact of thrombophilia on risk of arterial ischemic stroke or cerebral sinovenous thrombosis in neonates and children: a systematic review and meta-analysis of observational studies. Circulation 2010; 121: 1838–47.

4 Trenor CC 3rd, Michelson AD. Thrombophilia and pediatric stroke. Circulation 2010; 121: 1795–97.

5 Moharir MD, Shroff M, Stephens D, et al. Anticoagulants in pediatric cerebral sinovenous thrombosis: a safety and outcome study. Ann Neurol 2010; 67: 590–99.

6 Kirkegaard T, Roth AG, Petersen NH, et al. Hsp70 stabilizes lysosomes and reverts Niemann-Pick disease-associated lysosomal pathology. Nature 2010; 463: 549–53.

Neurological infections: infl uenza in the spotlightInfl uenza, both 2009 H1N1 and seasonal infl uenza virus, continued to dominate the attention of doctors and the public during 2010. The medical community breathed a collective sigh of relief when the pandemic of infl uenza 2009 H1N1 virus, which, although undoubtedly

associated with striking morbidity and mortality, was of a smaller magnitude than was initially feared. However, articles about pandemic and seasonal infl uenza were frequent in the published work on neuroinfectious disease in 2010, with at least 12 published case reports

Sam

uel A

shfi e

ld/S

cienc

e Ph

oto

Libr

ary

DTP vaccination