Serum proteomics reveals hemophagocytic lymphohistiocytosis-like phenotype in a subset of patients with multisystem inflammatory syndrome in children.

Children with Multisystem Inflammatory Syndrome in Children (MIS-C) can present with thrombocytopenia, which is a key feature of hemophagocytic lymphohistiocytosis (HLH). We hypothesized that thrombocytopenic MIS-C patients have more features of HLH. Clinical characteristics and routine laboratory parameters were collected from 228 MIS-C patients, of whom 85 (37%) were thrombocytopenic. Thrombocytopenic patients had increased ferritin levels; reduced leukocyte subsets; and elevated levels of ASAT and ALAT. Soluble IL-2RA was higher in thrombocytopenic children than in non-thrombocytopenic children. T-cell activation, TNF-alpha and IFN-gamma signaling markers were inversely correlated with thrombocyte levels, consistent with a more pronounced cytokine storm syndrome. Thrombocytopenia was not associated with severity of MIS-C and no pathogenic variants were identified in HLH-related genes. This suggests that thrombocytopenia in MIS-C is not a feature of a more severe disease phenotype, but the consequence of a distinct hyperinflammatory immunopathological process in a subset of children.

Adverse effect of lockdowns during the COVID-19 pandemic: increased incidence of pediatric crisis admissions due to eating disorders and adolescent intoxications.

During the COVID-19 pandemic, countries imposed (partial) lockdowns that reduced viral transmission. However, these interventions may have unfavorable effects on emotional and psychological well-being. The aim of this study was to quantify possible adverse effects of the COVID-19 pandemic on psychological wellbeing in children and adolescents. Hospital admission data between January 2017 and September 2021 from eight general hospitals in the Netherlands was collected, comparing the incidences of sub-categorized psychological diagnoses, more specifically eating disorders, intentional intoxications, accidental intoxications, and excessive crying, before (2017-2019) and during the pandemic (2020-2021). Data was summarized per month and per year, and the years 2020 and 2021 were compared to 2017-2019. The relative increase or decrease in diagnoses since the start of the pandemic was calculated. Overall pediatric hospital admissions decreased with 28% since the start of the pandemic. Non-infectious diagnoses showed a decrease of 8%. Of these non-infectious diagnoses, overall psychosocial admissions were increased (+ 9%), mostly caused by an increase in admissions for eating disorders (+ 64%) and intoxications in adolescents (+ 24%). In addition, the proportion of admissions due to psychosocial diagnoses increased post-pandemic (6% vs 4%, p < 0.001). Overall admissions for intoxications in children (- 3%) and excessive crying (- 1%) did not increase, although peaks in incidence were found at the start of the second lockdown. CONCLUSION: During the COVID-19 pandemic, admission rates for eating disorders and intentional intoxications showed a substantial increase, indicating a high burden of pediatric psychiatric diseases. WHAT IS KNOWN: • The COVID-19 pandemic has had an impact on psychosocial wellbeing in children and adolescents. WHAT IS NEW: • There was an increase in admissions due to psychosocial problems in the Netherlands in the period after the pandemic. • This was mainly caused by an increase in crisis admissions due to eating disorders and intoxications in adolescents.

The impact of lockdown on pediatric ED visits and hospital admissions during the COVID19 pandemic: a multicenter analysis and review of the literature.

The coronavirus disease 2019 pandemic has enormous impact on society and healthcare. Countries imposed lockdowns, which were followed by a reduction in care utilization. The aims of this study were to quantify the effects of lockdown on pediatric care in the Netherlands, to elucidate the cause of the observed reduction in pediatric emergency department (ED) visits and hospital admissions, and to summarize the literature regarding the effects of lockdown on pediatric care worldwide. ED visits and hospital admission data of 8 general hospitals in the Netherlands between January 2016 and June 2020 were summarized per diagnosis group (communicable infections, noncommunicable infections, (probable) infection-related, and noninfectious). The effects of lockdown were quantified with a linear mixed effects model. A literature review regarding the effect of lockdowns on pediatric clinical care was performed. In total, 126,198 ED visits and 47,648 admissions were registered in the study period. The estimated reduction in general pediatric care was 59% and 56% for ED visits and admissions, respectively. The largest reduction was observed for communicable infections (ED visits: 76%; admissions: 77%), whereas the reduction in noninfectious diagnoses was smaller (ED visits 36%; admissions: 37%). Similar reductions were reported worldwide, with decreases of 30-89% for ED visits and 19-73% for admissions.Conclusion: Pediatric ED utilization and hospitalization during lockdown were decreased in the Netherlands and other countries, which can largely be attributed to a decrease in communicable infectious diseases. Care utilization for other conditions was decreased as well, which may indicate that care avoidance during a pandemic is significant. What is Known: • The COVID-19 pandemic had enormous impact on society. • Countries imposed lockdowns to curb transmission rates, which were followed by a reduction in care utilization worldwide. What is New: • The Dutch lockdown caused a significant decrease in pediatric ED utilization and hospitalization, especially in ED visits and hospital admissions because of infections that were not caused by SARS-CoV-2. • Care utilization for noninfectious diagnoses was decreased as well, which may indicate that pediatric care avoidance during a pandemic is significant.

Multicentre study found that adherence to national antibiotic recommendations for neonatal early-onset sepsis was low.

AIM: Our aim was to evaluate adherence to the Dutch neonatal early-onset sepsis (EOS) guidelines, adapted from UK guidance. We also looked at the effect on antibiotic recommendations and duration. METHOD: This was a multicentre, prospective observational cross-sectional study carried out in seven hospitals in the Netherlands between 1 September 2018 and 1 November 2019. We enrolled 1024 neonates born at 32 weeks of gestation or later if they demonstrated at least one EOS risk factor or clinical signs of infection. RESULTS: The Dutch guidelines recommended antibiotic treatment for 438/1024 (42.8%) of the neonates designated at risk, but only 186/438 (42.5%) received antibiotics. The guidelines advised withholding antibiotics for 586/1024 (57.2%) of neonates and in 570/586 (97.3%) cases the clinicians adhered to this recommendation. Blood cultures were obtained for 182/186 (97.8%) infants who started antibiotics and only four were positive, for group B streptococci. Antibiotic treatment was continued for more than 3 days in 56/178 (31.5%) neonates, despite a negative blood culture. CONCLUSION: Low adherence to the Dutch guidelines meant that the majority of neonates did not receive the antibiotic treatment that was recommended, while some antibiotic use was prolonged despite negative blood cultures. The guidelines need to be revised.

Seasonal variation of diseases in children: a 6-year prospective cohort study in a general hospital.

UNLABELLED: Seasonal variation in pediatrics has been well described in some infectious diseases, asthma, and diabetes, but data on seasonality for other diseases in children are sparse. To explore the extent of seasonal variation of the entire pediatric field, we analyzed diagnostic codes of all newly referred patients (n = 51,054) to our pediatric department of a large teaching hospital in the Netherlands over a 6-year period (2008-2013). Seasonality was analyzed using simple moving averages, the standard error of the mean (SEM) and the percentage monthly variation. We defined seasonal variation as a visually recognizable periodic pattern in every year in combination with a standard error of the mean > 0.20. Four diseases fulfilled our definition of seasonality: respiratory tract infections (peak in January, +107.0 %), gastroenteritis (peak in February-March, +95.8 % and +112.9 %, respectively), functional complaints (peak in March, +34.0 %, and November, +13.4 %), and asthma (peak in March, +27.8 %, and October, +17.5 %). Together, these four categories comprised 21.2 % of all newly referred patients. CONCLUSION: Seasonal variation occurs in more than one fifth of all patients with pediatric disease. We demonstrated not only seasonal variation for respiratory tract infections, gastroenteritis, and asthma, but also for functional complaints. WHAT IS KNOWN: • Seasonal variation has been described for pediatric diseases such as bronchiolitis, gastroenteritis, asthma, and diabetes. • Information on seasonality in other pediatric fields is sparse but may be helpful in understanding pathophysiology and workforce planning. What is new: • This study confirmed seasonal variation in respiratory infection diseases gastroenteritis and asthma. • Moreover, it showed seasonal variation for functional complaints for example (abdominal pain and headache), which has not been described previously.

Glucosuria as an early marker of late-onset sepsis in preterms: a prospective cohort study.

BACKGROUND: Early and accurate diagnosis of late-onset sepsis (LONS) in preterm infants is difficult since presenting signs are subtle and non-specific. Because neonatal sepsis may be accompanied by glucose intolerance and glucosuria, we hypothesized that glucosuria may be associated with LONS in preterms, in an early stage. We aim to evaluate the association of glucosuria and late-onset neonatal sepsis (LONS) in preterm infants, in an attempt to improve early and accurate diagnosis of LONS. METHODS: We performed a prospective observational cohort study in 316 preterms (<34 weeks). We daily measured glucosuria and followed patients for occurrence of LONS, defined as clinical and blood culture-proven sepsis occurring after 72 h. Attending physicians were blinded to glucosuria results. We assessed the diagnostic value of glucosuria for clinical and blood culture-proven LONS using logistic regression analysis. RESULTS: Glucosuria was found in 65.8% of 316 preterm patients, and sepsis was suspected 157 times in 123 patients. LONS was found in 47.1% of 157 suspected episodes. The presence of glucosuria was associated with LONS (OR 2.59, 95% CI 1.24-5.43, p = 0.012) with sensitivity 69.0% and specificity 53.8% (Likelihoodratio 1.49). After adjustment for gestational age, birth weight, and postnatal age, this association weakened and was no longer significant (adjusted OR 2.16; 95% CI 0.99-1.85, p = 0.055). An increase in glucosuria 48-24 h before onset of symptoms was not associated with LONS. CONCLUSION: In preterms glucosuria is associated with LONS within 24 h, however this association is too weak to be of diagnostic value.

Systematic review: insufficient validation of clinical scores for the assessment of acute dyspnoea in wheezing children.

BACKGROUND: A reliable, valid, and easy-to-use assessment of the degree of wheeze-associated dyspnoea is important to provide individualised treatment for children with acute asthma, wheeze or bronchiolitis. OBJECTIVE: To assess validity, reliability, and utility of all available paediatric dyspnoea scores. METHODS: Systematic review. We searched Pubmed, Cochrane library, National Guideline Clearinghouse, Embase and Cinahl for eligible studies. We included studies describing the development or use of a score, assessing two or more clinical symptoms and signs, for the assessment of severity of dyspnoea in an acute episode of acute asthma, wheeze or bronchiolitis in children aged 0-18 years. We assessed validity, reliability and utility of the retrieved dyspnoea scores using 15 quality criteria. RESULTS: We selected 60 articles describing 36 dyspnoea scores. Fourteen scores were judged unsuitable for clinical use, because of insufficient face validity, use of items unsuitable for children, difficult scoring system or because complex auscultative skills are needed, leaving 22 possibly useful scores. The median number of quality criteria that could be assessed was 7 (range 6-11). The median number of positively rated quality criteria was 3 (range 1-5). Although most scores were easy to use, important deficits were noted in all scores across the three methodological quality domains, in particular relating to reliability and responsiveness. CONCLUSION: None of the many dyspnoea scores has been sufficiently validated to allow for clinically meaningful use in children with acute dyspnoea or wheeze. Proper validation of existing scores is warranted to allow paediatric professionals to make a well balanced decision on the use of the dyspnoea score most suitable for their specific purpose.

Clinical signs to identify late-onset sepsis in preterm infants.

UNLABELLED: Late-onset neonatal sepsis (LOS) in preterm infants is an important cause of morbidity and mortality in preterm infants. Since presenting symptoms may be non-specific and subtle, early and correct diagnosis is challenging. We aimed to develop a nomogram based on clinical signs, to assess the likelihood of LOS in preterms with suspected infection without the use of laboratory investigations. We performed a prospective cohort study in 142 preterm infants <34 weeks admitted to the neonatal intensive care unit with suspected infection. During 187 episodes, 21 clinical signs were assessed. LOS was defined as blood culture-proven and/or clinical sepsis, occurring after 3 days of age. Logistic regression was used to develop a nomogram to estimate the probability of LOS being present in individual patients. LOS was found in 48 % of 187 suspected episodes. Clinical signs associated with LOS were: increased respiratory support (odds ratio (OR) 3.6; 95 % confidence interval (CI) 1.9-7.1), capillary refill (OR 2.2; 95 %CI 1.1-4.5), grey skin (OR 2.7; 95 %CI 1.4-5.5) and central venous catheter (OR 4.6; 95 %CI 2.2-10.0) (area under the curve of the receiver operating characteristic curve 0.828; 95 %CI 0.764-0.892). CONCLUSION: Increased respiratory support, capillary refill, grey skin and central venous catheter are the most important clinical signs suggestive of LOS in preterms. Clinical signs that are too non-specific to be useful in excluding or diagnosing LOS were temperature instability, apnoea, tachycardia, dyspnoea, hyper- and hypothermia, feeding difficulties and irritability.

Usefulness of the fluid balance: a randomised controlled trial in neonates.

AIM: To assess the effects of fluid balance charts in neonates with moderate disease severity on duration of hospitalisation and medical interventions. METHODS: Randomised, controlled trial in a neonatal ward in a general teaching hospital in the Netherlands between June 2009 and March 2010. One hundred seventy neonates with moderate disease severity, requiring continuous monitoring of vital parameters (mean gestational age 36(+2) weeks (standard deviation 2(+5) days), mean birthweight 2782 g (standard deviation 749 g)) participated. In the control group (n = 86), attending physicians could access all fluid balance data, whilst these data were blacked out in the intervention group (n = 84). Primary outcome was length of hospital stay. Secondary outcomes were percentage weight loss, interventions based on the fluid status, unblinding of fluid balance data and incident reporting. RESULTS: Length of hospital stay did not differ significantly between the intervention and the control group (median 9 vs. 8 days, with ratio of geometric mean 1.25, 95% confidence interval 0.99 to 1.57; P = 0.06). We found no significant differences in secondary outcomes. CONCLUSIONS: Routinely keeping fluid balances in neonates with moderate disease severity does not affect duration of hospitalisation or medical treatment.

[Chronic non-infectious osteomyelitis in children]. / Chronische niet-infectieuze osteomyelitis bij kinderen.

Musculoskeletal pain in common and the differential diagnosis is broad. It is important to recognize the harmful and/or treatable pathology, without performing unnecessary diagnostics. Pattern recognition is crucial. One of the differential diagnostic considerations is chronic non-infectious osteomyelitis (CNO). A relatively unknown auto-inflammatory disease. By presenting three cases, we want to draw attention to this condition and contribute to a better recognition of this disease. We emphasize the importance of doing a total body MRI, when CNO is considered.

Transcutaneous Bilirubin Accuracy Before, During, and After Phototherapy: A Meta-Analysis.

CONTEXT: Transcutaneous bilirubinometry (TcB) is used as a valid screening to identify neonates requiring measurement of total serum bilirubin (TSB) before phototherapy. Its use during and after phototherapy is not advised yet because of unknown reliability. OBJECTIVES: To determine the agreement of TcB and TSB measurements before, during, and after phototherapy. DATA SOURCES: PubMed Medline, Cochrane Library, and references of eligible studies were searched. STUDY SELECTION: Prospective and retrospective cohort and cross-sectional studies reporting Bland-Altman statistics of paired TcB and TSB measurements in term and preterm newborns. DATA EXTRACTION: Meta-analysis was performed using the Mantel-Haenszel weighted approach. The agreement between TcB and TSB in µmol/L was described by pooled mean differences (MDs) and limits of agreement (LoA). RESULTS: Fifty-four studies were included. The pooled MD before phototherapy is 2.5 µmol/L (LoA -38.3 to 43.3). The pooled MD during phototherapy is -0.3 µmol/L (LoA -34.8 to 34.2) on covered skin and -28.6 µmol/L (LoA -105.7 to 48.5) on uncovered skin. The pooled MD after phototherapy is -34.3 µmol/L (LoA -86.7 to 18.1) on covered skin and -21.1 µmol/L (LoA -88.6 to 46.4) on uncovered skin. Subgroup analysis revealed the best agreement at the forehead. We did not find any difference in agreement between term and preterm neonates. LIMITATIONS: Language restriction. CONCLUSIONS: TcB measurements before and during phototherapy on covered skin show good agreement compared with TSB in term and preterm newborns. More studies are needed to evaluate the accuracy after phototherapy.

High-flow oxygen therapy in moderate to severe bronchiolitis: a randomised controlled trial.

BACKGROUND AND OBJECTIVE: High-flow (HF) oxygen therapy is being used increasingly in infants with bronchiolitis, despite lack of convincing evidence of its superiority over low flow (LF). We aimed to compare the effect of HF to LF in moderate to severe bronchiolitis. METHODS: Multicentre randomised controlled trial during four winter seasons (2016-2020) including 107 children under 2 years of age admitted with moderate to severe bronchiolitis, oxygen saturation of <92% and severely impaired vital signs. Crossovers were not allowed. HF was administered at flow rates of 2 L/kg for the first 10 kg, plus 0.5 L/kg for every kg >10 kg, LF with a maximum flow rate of 3 L/min. Primary outcome was improvement of vital signs and dyspnoea severity within 24 hours assessed by a composite score. Secondary outcomes were comfort, duration of oxygen therapy, supplemental feedings, hospitalisation duration and intensive care admission for invasive ventilation. RESULTS: Significant improvement within 24 hours occurred in 73% of 55 patients randomised to HF and in 78% of 52 patients with LF (difference 6%, 95% CI -13% to 23%). Intention-to-treat analysis revealed no significant differences in any secondary outcome: duration of oxygen therapy, supplemental feedings, hospitalisation and need for invasive ventilation or intensive care admission, except for comfort (face, legs, activity, cry, consolability), which was one point (out of a scale of 0-10) higher in the LF group. No adverse effects occurred. CONCLUSION: We found no measurable clinically relevant benefit in the use of HF compared with LF in hypoxic children with moderate to severe bronchiolitis. TRIAL REGISTRATION NUMBER: NCT02913040.

Conservative Treatment of Parapneumonic Effusion in Children: Experience From a 10-Year Consecutive Case Series.

BACKGROUND: In children with parapneumonic effusion (PPE), it remains unclear when conservative treatment with antibiotics suffixes or when pleural drainage is needed. In this study we evaluate clinical features and outcomes of children with PPE. METHODS: A retrospective, multicentre cohort study at 4 Dutch pediatric departments was performed, including patients 1-18 years treated for PPE between January 2010 and June 2020. RESULTS: One hundred thirty-six patients were included (mean age 8.3 years, SD 4.8). 117 patients (86%) were treated conservatively and 19 (14%) underwent pleural drainage. Patients undergoing pleural drainage had mediastinal shift more frequently compared with conservatively treated patients (58 vs. 3%, difference 55%; 95% CI: 32%-77%). The same accounted for pleural septations/pockets (58 vs. 11%, difference 47%; 95% CI: 24%-70%), pleural thickening (47 vs. 4%, difference 43%; 95% CI: 20%-66%) and effusion size (median 5.9 vs. 2.7 cm; P = 0.032). Conservative management was successful in 27% of patients (4 of 15) with mediastinal shift, 54% of patients (13 of 24) with septations/pockets, 36% of patients (5 of 14) with pleural thickening, and 9% of patients (3 of 32) with effusions >3 cm, all radiological signs generally warranting pleural drainage. In patients treated conservatively, median duration of hospitalization was 5 days (IQR 4-112) compared with 19 days (IQR 15-24) in the drainage group ( P < 0.001), without significant difference in readmission rate (11 vs. 4%, difference 6%; 95% CI: -8%-21%). CONCLUSION: This study suggests that the greater amount of children with PPE could be treated conservatively with antibiotics only, especially in absence of mediastinal shift, pleural septations/pockets, pleural thickening or extensive effusions.

Effect of lockdowns on the epidemiology of pediatric respiratory disease-A retrospective analysis of the 2021 summer epidemic.

BACKGROUND: The imposition of lockdowns during the severe acute respiratory syndrome coronavirus-2 pandemic led to a significant decrease in pediatric care utilization in 2020. After restrictions were loosened, a surge in pediatric respiratory disease was observed in pediatric wards. The aim of this study was to quantify the effect of the lockdown(s) on the incidence of pediatric respiratory disease. METHODS: For this multicenter retrospective study, emergency department (ED) visit and admission data between January 2017 and September 2021 was collected from eight general hospitals in the Netherlands. Clinical diagnoses were extracted and categorized in groups ("communicable infectious disease," "all respiratory infections," "upper respiratory tract infection," "lower respiratory tract infection," and "asthma/preschool wheezing"). The incidence of admissions and ED visits during 2020 and 2021 was compared to the incidence in 2017-2019. RESULTS: Successive lockdowns resulted in a maximum decrease of 61% and 57% in ED visits and admissions, respectively. After loosening restrictions during the summer of 2021, a 48% overall increase in ED visits and 31% overall increase in admission numbers was observed in July compared to the average July in 2017-2019. This was explained by a 381% increase in ED visits and a 528% increase in ward admissions due to overall respiratory infections, mainly due to lower respiratory tract infections. CONCLUSIONS: Successive lockdowns in the spring and winter of 2020 and 2021 led to a decreased incidence of communicable infections, especially respiratory tract infections. The resulting lack of pediatric immunity resulted in an off-season surge in care utilization at an unexpected moment.

Severe Pediatric COVID-19 and Multisystem Inflammatory Syndrome in Children From Wild-type to Population Immunity: A Prospective Multicenter Cohort Study With Real-time Reporting.

BACKGROUND: SARS-CoV-2 variant evolution and increasing immunity altered the impact of pediatric SARS-CoV-2 infection. Public health decision-making relies on accurate and timely reporting of clinical data. METHODS: This international hospital-based multicenter, prospective cohort study with real-time reporting was active from March 2020 to December 2022. We evaluated longitudinal incident rates and risk factors for disease severity. RESULTS: We included 564 hospitalized children with acute COVID-19 (n = 375) or multisystem inflammatory syndrome in children (n = 189) from the Netherlands, Curaçao and Surinam. In COVID-19, 134/375 patients (36%) needed supplemental oxygen therapy and 35 (9.3%) required intensive care treatment. Age above 12 years and preexisting pulmonary conditions were predictors for severe COVID-19. During omicron, hospitalized children had milder disease. During population immunity, the incidence rate of pediatric COVID-19 infection declined for older children but was stable for children below 1 year. The incidence rate of multisystem inflammatory syndrome in children was highest during the delta wave and has decreased rapidly since omicron emerged. Real-time reporting of our data impacted national pediatric SARS-CoV-2 vaccination- and booster-policies. CONCLUSIONS: Our data supports the notion that similar to adults, prior immunity protects against severe sequelae of SARS-CoV-2 infections in children. Real-time reporting of accurate and high-quality data is feasible and impacts clinical and public health decision-making. The reporting framework of our consortium is readily accessible for future SARS-CoV-2 waves and other emerging infections.

Reliability of the fluid balance in neonates.

AIM: To assess the reliability of fluid balance charts in neonates. METHODS: An observational study in 170 nonbreastfed neonates, requiring continuous monitoring on a high-care unit, but not critically ill. The fluid balance was compared to daily body weight changes using Bland-Altman analysis. Differences more than 20% of daily fluid intake were considered clinically relevant. RESULTS: The mean gestational age was 36 + 2 weeks (SD 18.7 days) and mean birth weight 2782 g (SD 749 g). The mean difference between 394 fluid balances over 24 h (in mL) and daily weight changes (in g) was -12.1 (limits of agreement -128.1 to 103.8). In 40% of comparisons, the difference with daily weight change was more than 20% of daily fluid intake. CONCLUSION: Fluid balance charts both over- and underestimate body weight changes in an unpredictable pattern and are therefore unreliable as a single measure of fluid status in neonates.

Patterns and seasonality in pediatric referrals for functional somatic symptoms.

Functional somatic symptoms (FSS), or medically unexplained physical symptoms, are common in children and it has been suggested that the incidence is increasing. To determine the incidence and pattern of referrals for FSS to pediatricians, we performed a retrospective analysis including newly referred pediatric patients to our secondary pediatric practice in Zwolle, The Netherlands, ultimately diagnosed with FSS between 2013 and 2018. FSS was defined as functional abdominal pain, chronic fatigue, chronic musculoskeletal pain and chronic headache without an underlying medical diagnosis. In the 6-year period, 10.4% of elective referrals were related to FSS without a significant upward trend. We found clear seasonal variation with peaks in incidences in March (+31%) and November (+21%) and a nadir around August (-48%). In conclusion, FSS account for 1 in 10 non-acute pediatric referrals, without an increase in incidence in the past 6 years. The seasonal pattern is remarkable and warrants further analysis.

Glucose transporter-1 deficiency syndrome: the expanding clinical and genetic spectrum of a treatable disorder.

Glucose transporter-1 deficiency syndrome is caused by mutations in the SLC2A1 gene in the majority of patients and results in impaired glucose transport into the brain. From 2004-2008, 132 requests for mutational analysis of the SLC2A1 gene were studied by automated Sanger sequencing and multiplex ligation-dependent probe amplification. Mutations in the SLC2A1 gene were detected in 54 patients (41%) and subsequently in three clinically affected family members. In these 57 patients we identified 49 different mutations, including six multiple exon deletions, six known mutations and 37 novel mutations (13 missense, five nonsense, 13 frame shift, four splice site and two translation initiation mutations). Clinical data were retrospectively collected from referring physicians by means of a questionnaire. Three different phenotypes were recognized: (i) the classical phenotype (84%), subdivided into early-onset (<2 years) (65%) and late-onset (18%); (ii) a non-classical phenotype, with mental retardation and movement disorder, without epilepsy (15%); and (iii) one adult case of glucose transporter-1 deficiency syndrome with minimal symptoms. Recognizing glucose transporter-1 deficiency syndrome is important, since a ketogenic diet was effective in most of the patients with epilepsy (86%) and also reduced movement disorders in 48% of the patients with a classical phenotype and 71% of the patients with a non-classical phenotype. The average delay in diagnosing classical glucose transporter-1 deficiency syndrome was 6.6 years (range 1 month-16 years). Cerebrospinal fluid glucose was below 2.5 mmol/l (range 0.9-2.4 mmol/l) in all patients and cerebrospinal fluid : blood glucose ratio was below 0.50 in all but one patient (range 0.19-0.52). Cerebrospinal fluid lactate was low to normal in all patients. Our relatively large series of 57 patients with glucose transporter-1 deficiency syndrome allowed us to identify correlations between genotype, phenotype and biochemical data. Type of mutation was related to the severity of mental retardation and the presence of complex movement disorders. Cerebrospinal fluid : blood glucose ratio was related to type of mutation and phenotype. In conclusion, a substantial number of the patients with glucose transporter-1 deficiency syndrome do not have epilepsy. Our study demonstrates that a lumbar puncture provides the diagnostic clue to glucose transporter-1 deficiency syndrome and can thereby dramatically reduce diagnostic delay to allow early start of the ketogenic diet.

Validity and interobserver agreement of reagent strips for measurement of glucosuria.

BACKGROUND: Measurement of glucosuria by means of a visually readable reagent test strip is frequently used in a wide variety of clinical settings. The aim of this study was to evaluate the validity and reliability of this semi-quantitative measurement of glucosuria compared to laboratory measurements of glucose concentrations in urine. METHODS: Reagent test strips (Combur³Test® Roche) from 375 artificially supplemented samples of urine, covering a wide range of glucose concentrations, were independently read by three different observers. Scores of the strips were categorized as 0, 1+, 2+, 3+ or 4+, in ascending degree of glucosuria. Results of the test-strips were compared to the quantitative measurement of urinary glucose concentration in the laboratory. RESULTS: 21.7% of reagent strips readings were discordant with the laboratory measurements (p < 0.001). Under- or overestimating the degree of glucosuria occurs predominantly in category 1+ and 2+. In category '0' only 5.1% of the readings were incorrect. The interobserver-agreement was very good with 85% overall agreement and multirater Kappa 0.81. Interobserver-scores of the reagent strips never deviated more than one category from each other. CONCLUSION: The validity as well as the interobserver-agreement for the semi-quantitative measurement of glucosuria using reagent strips is moderate, but sufficient for excluding glucosuria. However it is too imprecise for an accurate quantitative measurement. It might only be valuable in settings where automated readings are not available or suitable.