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Infantile hemangioma (IH) is the most common benign vascular tumor of infancy, affecting about 5% of infants. It has a characteristic growth pattern of early rapid proliferation followed by progressive involution. Although most IH evolve favorably, complications are observed in 10–15% of cases, justifying treatment. For over 10 years now, propranolol has become the first-line therapy for complicated IH, revolutionizing their management and their prognosis. In this article, we review the clinical features, associations, complications/sequelae and therapeutic approaches for IH, focusing on current medical therapy. Indications for treatment and various treatment options, including propranolol and other oral β-blockers, topical timolol, and corticosteroids are presented. Current controversies regarding oral propranolol such as pre-treatment screening, in- vs out-patient initiation of treatment, early and potential long-term side effects and recommended monitoring are discussed.

Pediatric-onset multiple sclerosis (POMS), representing approximately 5% of all MS cases, affects the central nervous system during its ongoing development. POMS is most commonly diagnosed during adolescence but can occur in younger children as well. For pediatric patients with MS, it is critical to manage the full impact of the disease and monitor for any effects on school and social functioning. Disease management includes not only disease-modifying therapies but also strategies to optimize wellbeing. We review the interventions with the highest evidence of ability to improve the disease course and quality of life in POMS. High levels of vitamin D and a diet low in saturated fat are associated with lower relapse rates. Exercise ameliorates fatigue and sleep. Behavioral strategies for sleep hygiene and mood regulation can also improve fatigue and perceived health. POMS management should be addressed holistically, including assessing overall symptom burden as well as the psychological and functional impact of the disease.

The use of ustekinumab in pediatric patients with inflammatory bowel disease (IBD) is off-label and the data are limited. We conducted a systematic review evaluating the efficacy and safety of ustekinumab in pediatric IBD. We systematically searched PubMed, EMBASE and Cochrane databases for studies of ustekinumab in children and adolescents with IBD investigating clinical remission, clinical response, corticosteroid-free (CS-free) remission, endoscopic remission/response, or safety up to March 17, 2023. A random-effects model was used for calculating summary estimates. Eleven studies, comprising 370 patients were included. For Crohn’s disease (CD), the pooled clinical remission rates were 34% (73/204) at 8–16 weeks and 46% (60/129) at 1 year. The pooled CS-free clinical remission rates were 23% (10/44) at 8–16 weeks and 45% (42/96) at 1 year. For ulcerative colitis (UC)/IBD unspecified (IBD-U), the pooled CS-free clinical remission rates were 24% (6/25) at 26 weeks and 46% (16/35) at 1 year. Endoscopic remission was found in 0–37.5% of CD and 63.6% of UC. Serious adverse events were reported in 3.5% of patients. About one half of patients required reduction in dose intervals and 62.75% patients could continue ustekinumab therapy at 1 year or final visit. According to low-quality evidence mainly from cohort studies and case series, approximately one half of patients with CD and UC/IBD-U achieved remission at 1 year. Ustekinumab has a reasonable safety profile and dose optimization is frequently required. Data on the long-term benefit and high-quality evidence are still needed.

The purpose of this review is to summarize existing data on the long-term safety and efficacy of stimulant treatment, and how long-term stimulant treatment of children with attention deficit hyperactivity disorder (ADHD) affects their outcome. Existing controlled studies of children with ADHD treated and untreated with stimulants, as well as long-term prospective follow-up studies, are reviewed. Children with ADHD treated with stimulants for as long as 2 years continue to benefit from the treatment, with improvements observed in ADHD symptoms, comorbid oppositional defiant disorder, and academic and social functioning, with no significant problems of tolerance or adverse effects. Long-term, prospective follow-up studies into adulthood show that stimulant treatment in childhood has slight benefits regarding social skills and self-esteem. Long-term adverse effects from stimulant treatment in childhood regarding adult height or future substance abuse have not been supported by existing studies.

Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) are under-recognized sleep disorders in children and adolescents. Several recent epidemiological studies have shown that RLS and PLMD are common in the pediatric population, and if left untreated, may lead to cardiovascular and neurocognitive consequences. Therefore, early diagnosis and intervention may help preventing long-term consequences. The management of RLS and PLMD in children involves both non-pharmacologic and pharmacologic approaches. Although there is emerging literature supporting medical therapy in children with RLS and PLMD, the overall experiences with these medications remain limited. Most children and adolescents with RLS and PLMD have low iron storage; therefore, iron therapy should be considered as the first line of treatment in children. Currently, there is no FDA-approved medication for RLS and PLMD in children. There is increasing evidence on the effectiveness of dopaminergic medications in children but the data are quite limited. Other medications such as α2δ-1 ligands, benzodiazepine, and clonidine are frequently used, but have not been adequately investigated in children. Further studies are needed to evaluate the safety and efficacy of pharmacologic therapy for RLS and PLMD in children.

Although ethosuximide is one of the oldest antiepileptic drugs (AEDs), little information is available about the cognitive side effects of ethosuximide. The aim of this study was to investigate the cognitive profile of ethosuximide. In this cross-sectional study, we used an extensive neuropsychological test battery in patients with epilepsy aged 6–16 years who were treated with monotherapy ethosuximide. We evaluated the efficacy of the drug by seizure frequency (seizure free or not). We included 61 patients with a mean age of 9.4 years [standard deviation (SD) 2.7] who used on average 686 mg/day (SD 245) ESM as monotherapy. ESM was effective in the majority of the patients (70 % were seizure free for at least 6 months at moment of inclusion). The total study population showed impairments of intelligence, visuomotor, and attentional function including activation/alertness. Comparisons between the well-controlled patients and patients who were not in remission showed significantly lower intelligence values and lower performance on the visual-perceptual and attentional tasks for the group with ongoing seizures. Our results suggested that the higher order cognitive dysfunctions (such as intelligence and visual-perceptual functions) may be regarded as seizure or aetiology effects and that the impaired fluid cognitive functions, such as activation/alertness, sustained auditory attention and attentional control or switching, were due to ESM. This study suggests the attentional dysfunction resulting in psychomotor slowing and alertness deficits may be regarded as effects of ethosuximide. Although no untreated baseline assessment was available, these effects are comparable to those of other AEDs, and ethosuximide may therefore be considered an AED with only mild effects on cognition. As ethosuximide is a first-line therapy for absence seizures in childhood, and drug-induced cognitive impairment may interfere with development, learning, and academic achievement, these findings are of interest to clinicians who prescribe this drug, especially when informing parents.

In adults, the area under the concentration–time curve (AUC) divided by the minimum inhibitory concentration (MIC) is associated with better clinical and bacteriological response to vancomycin in patients with methicillin-resistant Staphylococcus aureus who achieve target AUC/MIC ≥ 400. This target is often extrapolated to pediatric patients despite the lack of similar evidence. The impracticalities of calculating the AUC in practice means vancomycin trough concentrations are used to predict the AUC/MIC. This review aimed to determine the relationship between vancomycin trough concentrations and AUC/MIC in pediatric patients. We searched the MEDLINE and Embase databases, the Cochrane Database of Systematic Reviews, and the Cochrane Central Register of Controlled Trials using the medical subject heading (MeSH) terms vancomycin and AUC and pediatric* or paediatric*. Articles were included if they were published in English and reported a relationship between vancomycin trough concentrations and AUC/MIC. Of 122 articles retrieved, 11 met the inclusion criteria. One trial reported a relationship between vancomycin trough concentrations, AUC/MIC, and clinical outcomes but was likely underpowered. Five studies found troughs 6–10 mg/l were sufficient to attain an AUC/MIC > 400 in most general hospitalized pediatric patients. One study in patients undergoing cardiothoracic surgery found a trough of 18.4 mg/l achieved an AUC/MIC > 400. Two oncology studies reported troughs ≥ 15 mg/l likely attained an AUC/MIC ≥ 400. In critical care patients: one study found a trough of 9 mg/l did not attain the AUC/MIC target; another found 7 mg/l corresponded to an AUC/MIC of 400. Potential vancomycin targets varied based on the population studied but, for general hospitalized pediatric patients, troughs of 6–10 mg/l are likely sufficient to achieve AUC/MIC ≥ 400. For MIC ≥ 2 mg/l, higher troughs are likely necessary to achieve an AUC/MIC ≥ 400. More research is needed to determine the relationships between vancomycin trough concentrations, AUC/MIC, and clinical outcomes.

Topiramate is an antiepileptic drug (AED) which appears to have a broad range of antiseizure activity in humans. A previous overview focused primarily on results of trials of topiramate in adults with epilepsy, and this review highlights the use of topiramate in children. Clinical trials have shown that topiramate is effective when used adjunctively in children with refractory partial-onset seizures and generalised tonic-clonic seizures. The drug significantly reduced seizure frequency compared with placebo in children with partial-onset epilepsy after 16 weeks of double-blind adjunctive treatment (33.1 vs 10.5%); the frequency of secondarily generalised seizures was also markedly reduced. During a nonblind extension of this trial, the mean dosage was titrated from 4.8 to 9 mg/kg/day and further reductions in the frequency of seizures were observed (71% compared with prestudy levels). In 2 mixed adult/paediatric populations with primary generalised tonic-clonic seizures, topiramate (target dosage 5.2 to 9.3 mg/kg/day) reduced the seizure rate compared with those receiving placebo. This difference was significant in one trial (56.7 vs 9%) but not in another (57.1 vs 33.2%). A subanalysis of the paediatric patients found that the favourable effect of topiramate on seizure rates was not age-related. Topiramate (median average dosage 5.1 mg/kg/day) was also found to be useful as adjunctive therapy in the management of Lennox-Gastaut syndrome and significantly reduced the mean frequency of drop attacks by 14.8% compared with an increase of 5.1% with placebo. Further gains in seizure control were made in a nonblind extension of this trial where the mean topiramate dosage was 10 mg/kg/day. Nine of 11 patients in 1 pilot trial of children with otherwise intractable West syndrome, and 5 of 10 in another, achieved a ≥50% reduction in seizure rate with topiramate (target dosage up to 24 mg/kg/day). In an 18-month extension of the former trial (mean dosage 29 mg/kg/day) a ≥50% reduction in seizures was maintained in 7 of 11 children. Adverse events associated with adjunctive topiramate therapy in children were predominantly neuropsychiatric and generally mild to moderate in severity. Behavioural and cognitive problems do occur and are a limiting factor in some children. Also, weight loss can be problematical in some individuals. Withdrawal rates were low in the controlled trials (4.8%), but appear to be more frequent in noncomparative and post-marketing studies. Conclusion: Well controlled studies have demonstrated that topiramate is an effective agent for the adjunctive therapy of partial and generalised tonic-clonic seizures in children. Treatment-limiting adverse events do occur, but these may be managed by slow titration. Although comparative studies with the other newer AEDs used in adjunctive therapy are required, topiramate is an important extension to the range of drugs that may be used to treat refractory epilepsy in children. Topiramate is a structurally novel anticonvulsant derived from the naturally occurring monosaccharide D-fructose and contains a sulfamate moiety essential for pharmacological activity. In vitro experiments have identified several molecular activities that may contribute to its anticonvulsant activity: inhibition of voltage-sensitive sodium and/or calcium channels, potentiation of γ-aminobutyric acid, selective blockade of kainate-activated glutamate receptors, and inhibition of carbonic anhydrase. For many antiepileptic drugs (AEDs) there are strong correlations between results obtained in animal models of epilepsy and efficacy in humans. In vivo animal studies with topiramate have demonstrated the following: suppression of the hindlimb tonic-extensor component of the maximal electro-shock seizure test in rodents; regression of amygdaloid kindled seizures in rats, rabbits and cats; suppression of tonic and absence-like seizures in spontaneously epileptic rats; inhibition of audiogenic tonic convulsions and clonic seizures in rats and lowering of neurodeficit score; control of tonic-clonic seizures in a rat model of global ischaemia-induced epilepsy; inhibition of seizures in hypoxic neonatal rats. Overall, these in vivo studies suggest that topiramate has a broad spectrum of antiseizure activity and supports the clinical findings where topiramate has been found to be effective in both partial and generalised seizures. In a study of 18 children (aged 4 to 17 years) with epilepsy who received oral topiramate for 4 weeks (titrated to a target dose of 9 mg/kg/day) peak plasma topiramate concentration (Cmax) and area under the plasma concentration-time curve (AUC) were linearly related to dose regardless of age. Cmax and AUC were lower, and the time to Cmax shorter, in younger children. Plasma topiramate concentrations in patients receiving the same dosage (on a mg/kg basis) are likely to be about 33% lower in children than in adults because of more rapid clearance, so higher dosages may be required to achieve seizure control in children. The bioavailability of topiramate in adults is ≈80% and is unaffected by food. Paediatric patients frequently receive topiramate as a ‘sprinkle’ formulation with food and the relative bioavailabilities of 2 sprinkle formulations and immediate release tablets has been shown to be equivalent in 9 healthy adult male volunteers. Data obtained in healthy adult male volunteers indicate that topiramate distributes primarily into body water and the volume of distribution was 0.6 to 0.8 L/kg after a single oral dose of 100 to 1200mg. The extent of plasma protein binding of topiramate is 13 to 17%. Topiramate is not extensively metabolised after oral administration. After administration of a single radiolabelled topiramate 100mg dose 78% of the radioactivity in the plasma was unchanged drug while <5% appeared as metabolites. Topiramate is excreted primarily by the kidneys; after 10 days, 80.6% of the radiolabelled dose was recovered from the urine and 0.7% from the faeces. The clearance of topiramate from plasma during haemodialysis is about 9 times faster than in patients with normal renal function. The oral clearance (CL/F) and terminal elimination half-life (t½) of topiramate were both independent of dose in children, but CL/F was somewhat higher in patients ≤7years of age, resulting in lower Cmax and AUC values in this group. However, it is not possible to attribute this observation to age differences because an unequal number of patients in each age group were receiving enzyme-inducing AEDs (which increase clearance of topiramate). Subgroup analysis showed that those patients receiving enzyme-inducing AEDs had a significantly higher CL/F, than those receiving AEDs which do not induce enzymes. Consequently, the t½ was significantly shorter in the former group. A comparison between these results in children and historical data in adults suggests that CL/F in children is approximately 50% higher than in adults. Topiramate interacts with other AEDs and the plasma concentration of topiramate is reduced when it is administered with carbamazepine (↓≈40), phenytoin (↓ 33 to 50%) or valproic acid (sodium valproate) [↓ 15%]. The plasma concentration of phenytoin is increased by 25% when administered with topiramate, while that of valproic acid is decreased by 11% in the presence of topiramate. Three cases of hyperammonaemic encephalopathy have been reported in patients who had topiramate added to previously well-tolerated valproic acid therapy. Serum ethinylestradiol concentrations were reduced by 18 to 30% and CL/F values by 15 to 33% in 12 women with epilepsy taking ethinylestradiol 35µg plus norethisterone (norethindrone) 1mg for contraception and topiramate 200 to 800 mg/day. To ensure adequate contraception the investigators recommended that the daily dosage of ethinylestradiol should be increased when this contraceptive combination is used in conjunction with topiramate. Administration of topiramate 200 mg/day for 6 days was associated with reduced digoxin Cmax and AUC values after a single oral dose of digoxin 0.6mg. Placebo-controlled studies of topiramate have been conducted in children with partial seizures and generalised tonic-clonic seizures [mixed adult/paediatric populations; also in Lennox-Gastaut syndrome (LGS)], and small pilot studies in children with West syndrome (infantile spasms) have also been completed. Partial Seizures A statistically significant reduction in seizure frequency was demonstrated in a placebo-controlled trial of adjunctive topiramate (mean final dosage 4.8 mg/kg/day) in 86 children with partial-onset epilepsy. After 16 weeks of double-blind treatment, topiramate caused a median 33.1% reduction in monthly seizure frequency compared with a reduction of 10.5% in those who received placebo. A subgroup of patients (20 in each group) who experienced secondarily generalised seizures also exhibited a marked reduction in seizure rate when receiving topiramate. During a nonblind extension, the mean topiramate dosage was titrated according to clinical response to a mean of 9 mg/kg/day. Further reductions in the frequency of seizures were observed (71% compared with prestudy levels). Generalised Tonic-Clonic Seizures Trials of adjunctive topiramate for the treatment of primary generalised tonic-clonic seizures have not been performed in an exclusively paediatric population; however, 2 well controlled trials in a mixed population have been completed. While the seizure rate decreased in topiramate-treated patients (target dosage 5.2 to 9.3 mg/kg/day) compared with placebo in both trials, this difference was significant in one trial (56.7 vs 9%), but not the other (57.1 vs 33.2%). A subanalysis of the paediatric patients found a favourable effect of topiramate on seizure rate that did not appear to be age-related. An unpublished post-hoc analysis of the pooled data from both trials added further support to the contention that topiramate is an effective adjunctive treatment of both adults and children with primary generalised tonic-clonic seizures. Topiramate was also found to be useful as adjunctive therapy in the management of LGS. In a well controlled double-blind 11-week trial of 98 adults and children with LGS, the addition of topiramate (median average dosage 5.1 mg/kg/day) to therapy significantly reduced the mean frequency of drop attacks by 14.8% compared with an increase of 5.1% in the placebo group. During a nonblind follow-up in which the topiramate dosage was titrated to a mean of 10 mg/kg/day, further gains in seizure control were made (the mean percentage reduction in drop attacks after ≥6 months of treatment was 56% and 15% of patients achieved complete control of seizures). Two small pilot studies in children with West syndrome, 1 with an 18-month extension, have been completed. Nine of 11 patients in one trial and 5 of 10 in the other achieved a ≥50% reduction in seizure rate with topiramate (target dosage up to 24 mg/kg/day). In the 18-month extension of 1 trial a ≥50% reduction in seizures was maintained in 7 of 11 children with a mean dosage of 29 mg/kg/day; however, this efficacy measure is not regarded as reliable in West syndrome and further trials are required. Topiramate has been compared with carbamazepine or valproic acid in a 119 children (aged 6 to 16 years) with newly diagnosed epilepsy of all types. After ≥6 months of therapy 63, 59, 39 and 53% of children treated with topiramate 100 or topiramate 200 mg/day, carbamazepine or valproic acid, respectively, were seizure free. The time to first seizure or drug-related withdrawal did not differ between treatments. Somnolence, anorexia, fatigue, nervousness, concentration/attention/memory difficulties, aggression and weight loss were the most frequently reported events (incidence at least 5% higher than that in placebo recipients) in a pooled analysis of placebo-controlled studies involving 199 children with partial or generalised seizures who received topiramate (mean dosage 6.2 mg/kg/day) for a mean 107 days. In a retrospective analysis of the factors associated with behavioural and cognitive abnormalities in children receiving topiramate, 11 of 75 (14.7%) children experienced behavioural or cognitive abnormalities 2 to 16 weeks after initiation of therapy. Nearly 50% of these 11 children had a previous history of these problems but 14% did not (p = 0.03). Concurrent use of lamotrigine was also associated with behavioural or cognitive abnormalities (p = 0.05). On occasion, behavioural problems can be severe and are likely to be a cause of withdrawal. Most adverse events occurring in topiramate-treated children taking part in double-blind trials were regarded as mild or moderate in severity and the withdrawal rate was low (4.8%). However, the withdrawal rate in some noncomparative studies has been much higher. In 2 retrospective studies of paediatric patients with intractable epilepsy 41.4 and 39% discontinued topiramate because of adverse events. Other noncomparative studies have reported withdrawal rates of 11, 7.2 and 4.5%. Dose-related weight loss is a common event in topiramate-treated individuals. In placebo-controlled, double-blind trials of children with epilepsy, weight loss in those treated with topiramate for 11 to 16 weeks (n = 98) was 0.4kg compared with a weight gain of 1.2kg in those receiving placebo (n = 101). A subanalysis of patients treated with topiramate for ≥2 years showed a slight decrease in body-weight during the first 6 months (0.3kg), but a gain of 3.2kg by 2 years. In a retrospective study, the height of topiramate-treated (n = 77) and non-topiramate-treated (n = 67) age- and seizure-matched patients was measured at initiation of treatment and after a mean of 21 months’ therapy. No statistical difference in the rate of linear growth was found. Topiramate is a weak carbonic anhydrase inhibitor with the potential to cause acidosis and the formation of renal calculi in adults. The incidence in children has not yet been established, but only 1 of 313 children taking part in clinical trials of topiramate developed a renal calculus. Oral topiramate is indicated for the adjunctive treatment of children (aged between 2 and 16 years) with partial onset seizures or primary generalised tonic-clonic seizures. The drug should be titrated to achieve an optimal clinical response (seizure control without intolerable adverse effects) using a ‘start low, go slow’ approach. The manufacturer recommends that titration begins at 25 mg/day (or less, based on a range of 0.5 to 3 mg/kg/day), given nightly for the first week. The dosage should then be increased at 1- or 2-week intervals by increments of 1 to 3 mg/kg/day (administered in divided doses). The recommended total daily maintenance dosage after titration is 5 to 9 mg/kg/day (as a divided dose). In clinical trials, the minimum effective dosage appeared to be 4 to 6 mg/kg/day. Although some patients respond to lower dosages, others may require in excess of 15 mg/kg/day, and higher dosages may be required when concomitant enzyme-inducing AEDs are used. Topiramate is available as 25, 50, 100 and 200mg tablets (availability may vary among countries) or as bioequivalent 15 and 25mg ‘sprinkle’ capsules. The latter can be opened and the contents sprinkled on a teaspoon of soft food (such as apple sauce) and swallowed without chewing, a method of administration which can be useful in children. Topiramate is cleared by the kidneys. Therefore, dosage should be adjusted in patients with renal impairment [creatinine clearance <4.2 L/h/1.73m2 (<70 ml/min/1.73m2)]. Studies of topiramate in children with renal impairment have not been conducted, but in adults with moderate renal failure 50% of the usual dosage is recommended. Topiramate is cleared by dialysis and supplementary doses of topiramate may be required in dialysed patients. In patients with significant hepatic impairment, plasma concentrations of topiramate may be increased.

In diabetes insipidus, the amount of water ingested and the quantity and concentration of urine produced needs to be carefully regulated if fluid volume and osmolality are to be maintained within the normal range. One of the principal mechanisms controlling urine output is vasopressin which is released from the posterior pituitary gland and enhances water reabsorption from the renal collecting duct. In diabetes insipidus, the excessive production of dilute urine, and the causes of this clinical picture can be divided into three main groups: the first is primary polydipsia where the amount of fluid ingested is inappropriately large; the second group is cranial diabetes insipidus where the production of vasopressin is abnormally low; and, the third group is nephrogenic diabetes insipidus where the kidney response to vasopressin is impaired. The history and examination may suggest an underlying explanation for diabetes insipidus but a range of baseline and more extensive investigations may be required before a diagnosis can be reached. These investigations are not without risk, and the results need to be interpreted carefully because children do not always segregate neatly into a particular diagnostic category on the basis of one test alone. Children with cranial diabetes insipidus typically respond to arginine vasopressin or its manufactured analogue, desmopressin, with an increase in urine osmolality and an associated reduction in urine output. Such children usually require neuroimaging to look for evidence of evolving CNS pathology, such as an intracranial tumour. Vasopressin ‘replacement’ with desmopressin is the treatment of choice in patients with cranial diabetes insipidus although extreme caution is required when treating babies or small children because of the danger of fluid overload. Abnormal production of other pituitary hormones in children with CNS disease can also influence fluid balance. Nephrogenic diabetes insipidus can be due to abnormal electrolyte concentrations, therefore these should be measured as part of the initial assessment. In a small number of children the defect is a primary abnormality of the vasopressin receptor or one of the water channel proteins (aquaporins) involved in water transport. The treatment of these patients is difficult and typically involves therapy with a diuretic such as chlorothiazide, as well as indomethacin. These agents enhance urine osmolality by their effect on circulating volume and renal solute and water handling. The fluid intake of most young children with primary polydipsia can be safely reduced to a more appropriate level.