I read with interest "The Fifteen-minute consultation on the infant with a large head" published recently by Arnab Seal. Clinicians should also be aware of 'Benign Enlargement of Subarachnoid Space (BESS)'. It is described under various names in literature including benign extra-axial collections of infancy, external hydrocephalus, subdural effusions, etc (1). It presents in infancy with rapid enlarged of head circumference on the background of normal development. It should be differentiated from isolated or familial macrocephaly as the head circumference is normal at birth followed by rapid growth in infancy crossing more than 2 centiles. Hence although it would fall in category E (figure 2) neuroimaging (Computed tomography (CT)/Magnetic resonance imaging (MRI) head) would be required to rule out any intracranial pathology and establish the diagnosis. In the majority of cases there is a positive family history of macrocephaly, thus can be misdiagnosed as familial macrocephaly if neuroimaging is not undertaken. The anterior fontanelle is enlarged along with enlargement of fronto- parietal subarachnoid space. There is no associated brain atrophy or signs of raised intracranial pressure. As the name indicates it is completely benign condition and no surgical intervention is required. This condition is self-limiting with spontaneous resolution usually by 2 years of age. Although the macrocephaly may persist it plateaus by 2 years of age and associated with resolution of subarachnoid space as the child grow older (1). It is important to monitor the head growth and developmental progress. If there is any deviation from normal in neuro-development or there is persistence of rapid head growth beyond 2 years of age further evaluation is required to exclude other intracranial pathologies (2). In summary, clinicians should consider BESS in any infant presenting with rapid head growth and normal development. This is a benign self-limiting condition and no surgical intervention is required.

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The reservations exepressed about the interpretation of interferon gamma release assays(IGRAs)(1)are underpinned by the following observations:- IGRAs do not reliably identify subjects with active tuberculosis(even in the context of culture positive disease)(2), as shown by a study where 45 subjects received a diagnosis of active tuberculosis characterised, in 37 of those subjects, by positive cultures for mycobacterium tuberculosis(MTB). Nevertheless, in 17 of the 45 patients with a final diagnosis of active tuberculosis the IGRA test was negative(2). This means that, in that study,the spectrum of 17 negative IGRA tests included, at a bare minimum, at least eight patients with culture positive tuberculosis. The suboptimal sensitivity of IGRAs is compounded by apparently spontaneous reversion from positive to negative test status(3)(4), and also by apparently spontaneous by conversion from negative to positive test status(3)(4). This state of affairs has implications for recognition and management of latent tuberculosis, not only in the context of low disease prevalence(3), but also in the context of high disease prevalence(4). In the former context, an American study utilised IGRAs to screen 3,234 individuals considered to be at low risk of mycobacterium tuberculosis infection, including low risk of infection in the remote past. Of these, 2,819 tested unequivocally negative, 218 tested unequivocally positive, and 177 yielded indeterminate tests per manufaturer's criteria. On retesting 13(9%) of initially negative tests converted to positive, and 15(7%) of initially positive tests reverted to negative test status using the manufacturer's cut-off value(3). In the context of high disease prevalence a review was published which included evaluation of in-subject variability of IGRAs in India and in South Africa. In the Indian context, over a 2 weeks period, 2 of 14 health care workers experienced reversion from positive to negative test status. In the South African study, over a 3 week period, 7 of 26 helth care workers experienced either a conversion or a reversion. In both the Indian and the South African studies subjects who experienced either reversion or conversion had initial values close to the cut-off point(4). These observations(2)(3)(4) should serve as fundamental caveats to the use of IGRAs in clinical practice. References (1) Pollock L., Roy RB., Kampmann B How to use: interferon gamma release assays for tuberculosis Education and Practice 2013;98:99-105 (2)Dewan PK., Grinsdale J., Kawamura M Low sensitivity of a whole blood interferon gamma release assay for detection of active tuberculosis Clinical Infectious Diseases 2007;44:69-73 (3) Metcalfe JZ., Cattamanchi A., McCulloch CE et al Test variability of the QuabtiFERON-TB-Gold in-Tube assay in clinical practice Am J Respir Crit Care Med 2013;187:206-2011 (4) van Zyl Smit RN., Zwerling A., Dheda K., Pai M Within-subject variability of interferon-gamma assay results for tuberculosis and boosting effect of tuberculin skin testing: A systematic review PLoS ONE 2009;4:e8517

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Carter and colleagues have done a superb job in summarising the theory and practice of tools used in assessing children for autism. Unfortunately their paper is marred by a mathematical error which, if left unchallenged, could undermine trust in the use of one such tool, the ADOS.

According to the paper, the positive predictive value (ppv, i.e. the proportion of those who test positive who actually have the condition) of the ADOS is 80.4% in a neurodevelopmental clinic population, whilst the negative predictive value (npv, proportion of those who test negative who do not have the condition) in the same population is only 11.9%. If this were true it would mean that the proportion of those in the test negative group who have the condition would actually be higher than in the test positive group- 88.1% against 80.4%. Fortunately it is not true.

Using the population prevalence of 53% quoted, and the figures of 91% sensitivity and 75% specificity the true figure for ppv is as given, but the npv is actually 87.5%. Carter et al's conclusion, therefore, that tests should be interpreted in the light of history and information from other sources stands, but the ADOS is not as hopeless as their paper might have suggested.

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.Dear Sir, We read with great interest the accurate paper by Sen et al. regarding the indications for testing lupus anticoagulants (LA) in pediatric patients1. We believe that two further considerations might provide a complete overview on this issue. First, it has to be underlined the important contribution given by Boffa MC concerning either the laboratory methods for the detection of LA2 or the association between antiphospholipid syndrome (APS) and obstetrical complications in women3. Second, in the article by Sen et al. the authors do not take into consideration infants born to mothers with APS. To date, it is still unclear how neonates born to mothers with APS should be evaluated and which is the true clinical relevance of neonatal antiphospholipid antibodies (APL). Concerning the indications to LA testing, the authors suggested two main indications: the presence of thrombosis and/or of unexplained prolonged aPTT. We agree with the authors concerning the first indication, i.e. APL testing in all infants with thrombosis even in neonates born to mothers with negative APL4. Concerning the second indication, it should be specified that the activated partial thromboplastin time (aPTT) in neonates is intrinsically longer than in adults and changes according to postnatal age5. Boffa et al. suggested that APL should be sistematically tested at birth in neonates born to mothers with APS6 since unpredictable transplacental passage occurs in about 30% of cases. The low rate and the unpredictable entity of APL crossing through the placenta could depend on the absorption of antibodies by trophoblast cells and by their binding to heparin, administered to mothers with APS during pregnancy. Interesting data have been recently provided by the European registry of babies born to mothers with APS7. First, maternal APL crossing over the placental barrier was confirmed. Second, the kind of neonatal APL correlated with the same mother's isotype before 6 months of life and mostly disappeared thereafter. Third, 10% of children showed persistent APL at 24 months of life. Fourth, de-novo production of antibodies was reported; in particular, de-novo anti-beta2 glycoprotein-I antibodies synthesis occurred in 16% and LA in 4% of cases. It was suggested that prolonged APS exposure could represent an immunological trigger, as well as vaccinations or infections, for de-novo synthesis of APL. Nevertheless, the exact clinical relevance of neonatal APL positivity is still poorly understood. Although only few case reports of thrombosis have been described among children born to mothers with APS6, this increased prothrombotic risk should not be underestimated. In addition, the European registry of babies born to mothers with primary APS reported four cases of neurodevelopmental anomalies during the 5-year follow-up7. According to the current knowledge on this topic, APL screening should be performed at birth only in case of thrombosis, and after 6 months of life in asymptomatic neonates to investigate the eventual persistence of APL. In this case, a long lasting follow-up is required to verify the true clinical significance of persisting APL.

References 1. Sen ES, Beresford MW, Avcin T, Ramanan AV. How to use lupus anticoagulants. Arch Dis Child Educ Pract Ed. 2012 Oct 6. 2. Lambert M, Ferrard-Sasson G, Dubucquoi S, Hachulla Eet al. Diluted Russell viper- venom time improves identification of antiphospholipid syndrome in a lupus anticoagulant-positive patient population. Thromb Haemost 2009;101(3):577- 81. 3. Soulier JP, Boffa MC: Avortements a repetition, thromboses et anticoagulant circulant anti-thromboplastine: trois observations. Nouv Presse Med 1980;9:859. 4 De Carolis MP, Salvi S, Bersani I, De Carolis S. Isolated cerebral sinovenous thrombosis: a rare case of neonatal antiphospholipid syndrome. Indian Pediatr. 2012 May;49(5):411-2. 5. Andrew M, Paes B, Milner R, et al. Development of the human coagulation system in the full-term infant. Blood 1987;70(1):165-72. 6. Boffa MC, Lachassinne E. Infant perinatal thrombosis and antiphospholipid antibodies: a review. Lupus 2007;16(8):634-41. Review. 7. Mekinian A, Lachassinne E, Nicaise- Roland P, et al. European registry of babies born to mothers with antiphospholipid syndrome. Ann Rheum Dis. 2012 May 15.

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