Mental Health of School-Aged Children Treated with Propranolol or Atenolol for Infantile Hemangioma and Their Parents.

BACKGROUND: Infants with infantile hemangioma (IH) have been effectively treated with propranolol or atenolol. Concerns were raised about the mental health of these children at school age, due to central nervous system effects of propranolol and visible nature of IH. OBJECTIVE: This study aimed to compare the mental health at school age of children treated with propranolol to children treated with atenolol for IHs and their parents. METHODS: This two-centered cross-sectional study included children aged ≥6 years and treated with either propranolol or atenolol for IH during infancy. Children's outcomes were performance-based affect recognition (Dutch version of the Developmental Neuropsychological Assessment-II [NEPSY-II-NL]), parent-reported emotional and behavioral functioning (Child Behavioral Checklist [CBCL]), and health-related quality of life (KIDSCREEN-27). Parents' outcome was parenting stress (Parenting Stress Questionnaire [OBVL]). RESULTS: Data of 105 children (36 propranolol, 69 atenolol; 6.0-11.8 years) were analyzed. Mental health outcomes did not differ between both ß-blocker groups. Although overall functioning was in line with norms, children presented specific problems concerning affect recognition, parent-reported attention, and social quality of life. Parents showed increased physical symptoms, depressive symptoms, and parent-child relationship problems. CONCLUSION: No difference in mental health at school age was found between children treated with propranolol or atenolol for IH. Although few overall mental health problems were found, specific problems require follow-up. Follow-up of children should be directed toward affect recognition, attention, and social functioning in daily life. Problems reported by parents could be ameliorated by mental health support during and after their infant's ß-blocker treatment.

Prognostic Factors for Long-term Aesthetic Outcome of Infantile Haemangioma Treated with Beta-blockers.

Parents of infants treated with beta-blockers for infantile haemangioma are often concerned about the long-term aesthetic outcome. This cross-sectional study assessed the influence on the long-term aesthetic outcome of characteristics of the infantile haemangioma, the beta-blocker treatment, and the infant. The study included 103 children aged 6-12 years, treated with beta-blockers (propranolol or atenolol) for infantile haemangioma during infancy (age at treatment initiation ≤1 year) for ≥6 months. Dermatologists and parents scored the Patient Observer Scar Assessment Scale, and the child scored a visual analogue scale. Dermatologists identified whether telangiectasia, fibrofatty tissue, and atrophic scar tissue were present. The long-term aesthetic outcome of infantile haemangioma was judged more negatively by dermatologists and parents in case of a superficial component, ulceration, older age at treatment initiation, higher cumulative dose, and/or shorter follow-up time. According to children, infantile haemangioma located on the head had better aesthetic outcome than infantile haemangioma located elsewhere. Close monitoring, particularly of infantile haemangioma with a superficial component, is essential for early initiation of treatment, and to prevent or treat ulceration. These outcome data can support parental counselling and guide treatment strategy.

Long-term neurocognitive functioning of children treated with propranolol or atenolol for infantile hemangioma.

The purpose of this study was to compare long-term neurocognitive functioning (working memory, processing speed, and attention) between children who had been treated with either propranolol or atenolol for infantile hemangioma during infancy. All eligible children (n = 158) aged 6 years or older and treated with propranolol or atenolol as infants were invited to participate in this two-center cross-sectional study. The primary outcome was the Wechsler Intelligence Scale for Children-V Cognitive Proficiency Index (CPI), a measure of working memory, processing speed, and attention. Secondary outcomes were general intelligence, auditory, visuospatial, and narrative memory, as well as executive functioning and sleep. A total of 105 children, of whom 36 had been treated with propranolol (age 6.0-11.8 years, follow-up time 1.6-9.7 years, 19% male) and 69 had been treated with atenolol (age 6.9-9.7 years, follow-up time 4.5-8.4 years, 19% male), were analyzed. The CPI and other neurocognitive outcomes did not differ between the propranolol and atenolol groups and were in line with general population test norms. Post hoc analyses revealed lower CPI scores for males, both compared to participating females (10.3 IQ points, medium effect size) and compared to matched test norms (12.4 IQ points, medium effect size). CONCLUSIONS:  Long-term neurocognitive functioning did not differ between children treated with propranolol and those treated with atenolol for IH. Overall, propranolol and atenolol appear to be safe treatments for IH regarding long-term neurocognitive functioning. The substantially lower CPI scores in males warrant further investigation. TRIAL REGISTRATION:  Netherlands Trial Register, NL7703 https://www.trialregister.nl/trial/7703 What is Known: • Infants with infantile hemangioma are effectively treated with propranolol or atenolol. • Parents and professionals are concerned about long-term neurocognitive effects. WHAT IS NEW: • No long-term (≥ 6 years) differences in neurocognitive functioning were found between children treated with propranolol or atenolol. • Males treated with beta-blockers had substantially lower IQ scores than treated females and males from the general population, which is a matter of concern and should be considered when evaluating the risk/benefit ratio in less severe forms of infantile hemangioma.

Aesthetic Outcome of Propranolol vs Atenolol Treatment of Children with Infantile Haemangioma.

Infantile haemangiomas are common benign tumours of infancy, which can be treated effectively with beta-blockers such as propranolol and atenolol. Different types of beta-blockers may result in different long-term aesthetic outcomes. This study evaluated the difference in long-term aesthetic outcomes between infantile haemangiomas treated with either propranolol or atenolol, including the perspective of physicians, parents, and children. Children, aged ≥6 years, treated with propranolol or atenolol for infantile haemangioma during infancy, participated in this 2-centre cross-sectional study. The primary endpoint was change in appearance of the infantile haemangioma from pre-treatment to follow-up, using a physician-rated visual analogue scale (VAS). Secondary outcomes were the Patient Observer Scar Assessment Scale (physician- and parent-rated) and a VAS (child-rated), assessing the residual lesion. In total, 103 children (35 treated with propranolol, 68 with atenolol) were analysed. No differences were found between children treated with propranolol and children treated with atenolol on physician-rated VAS (p = 0.10) or any secondary outcomes. Physicians indicated a large aesthetic improve-ment from pre- treatment to follow-up. Physicians, parents and children were positive about the current state of the residual lesion. Minor sequelae were common (86%). These results, in combination with the favourable safety profile of atenolol, should be considered when choosing beta-blocker treatment for infantile haemangioma.

Emotional and Behavioral Problems in Children With a Cleft Lip With or Without Palate or an Infantile Hemangioma.

OBJECTIVE: Life can be challenging for children with a visible difference due to a medical condition, and they might be at risk for emotional and behavioral problems. This study examines emotional and behavioral problems in children with a cleft lip with or without palate (CL ± P) or an infantile hemangioma (IH) in relation to the visibility of the condition, the presence of additional condition-related problems, and parental affect. SETTING: This cross-sectional study took place in an academic medical hospital in the Erasmus MC Sophia Children's Hospital, the Netherlands. PARTICIPANTS: A total of 309 parents (mean age = 40.34, 44.00% male) of 182 children with CL ± P and 48 parents (mean age = 39.21, 37.50% male) of 33 children with an IH completed questionnaires. Children were 1.5 to 12 years old. RESULTS: Parents reported fewer child emotional and behavioral problems compared to normative data. Problems reported were mainly related to learning difficulties and parent gender, while visibility of the condition had no significant influence. Parental negative affect was related to child internalizing problems. Parental positive affect was not related to any of the outcome measures. CONCLUSIONS: Parents reported fewer problems for their children compared to normative data. This is inconsistent with previous research, showing similar or worse scores for these children compared to peers. Our findings may be explained by a protective parenting style, a response shift in parents, or problems developing at a later point in life.

Contemporary management and outcome of myelomeningocele: the Rotterdam experience.

OBJECTIVE: Myelomeningocele (MMC) is the most common form of spina bifida, with a lifelong impact on the quality of life for infants born with this condition. In recent decades, fetal surgery has evolved from an experimental therapy to standard of care for many centers in the world. In this study, the authors aimed to provide an overview of the current management and outcomes for infants with MMC managed at their institution. This then provides a center-specific historical cohort for comparison with future antenatal-treated MMC cases. METHODS: This is a retrospective, single-institution cohort study including all consecutive MMC cases between January 1, 2000, and June 1, 2018, at Erasmus MC. Outcome data included closure of the defect (location, timing, and surgical parameters), hydrocephalus management, Chiari malformation type II (CMTII) management, incidence of spinal cord tethering and outcome, motor outcomes, and continence. RESULTS: A total of 93 patients were included with predominantly lumbosacral lesions. Two patients died during follow-up. Hydrocephalus was present in 84%, with a 71% ventriculoperitoneal shunt reoperation rate. Surgery was performed in 12% for a tethered spinal cord at a mean age of 8 years. Decompression surgery was performed in 3 patients for CMTII. Special education in 63% was significantly associated with hydrocephalus (p < 0.015). Nineteen percent of patients were able to walk independently, and 47% were nonambulators. Social continence for urine was obtained in 75% of patients, 4% had fecal incontinence. CONCLUSIONS: This study provides an overview of current MMC outcomes at the authors' center and will serve as a historical cohort for comparison with future fetal surgery cases operated on at the center in the coming years. Apart from a relatively low surgical untethering rate, the authors' outcome data are comparable to those in the literature. Hydrocephalus is highly prevalent in postnatally treated MMC patients; in this study as in much of the literature, hydrocephalus is correlated with a low cognitive function. Fetal surgery for MMC halves the need for shunt treatment in a select group of MMC pregnancies, constituting a major indication for us to undergo the transition to a fetal surgery center. The fetal benefits of open antenatal surgery for MMC are well established, yet long-term data on especially tethered spinal cord are eagerly awaited.

Scoring the therapeutic effects of oral propranolol for infantile hemangioma: A prospective study comparing the Hemangioma Activity Score (HAS) with the Hemangioma Severity Scale (HSS).

BACKGROUND: Validated and reliable instruments to measure disease severity are needed to substantiate the benefit of therapies for infantile hemangioma. Two purpose-made systems have been described: the Hemangioma Activity Score (HAS) and the Hemangioma Severity Scale (HSS). OBJECTIVE: We sought to compare the HAS with the HSS in terms of ease of use, accuracy, and outcome in infants treated with oral propranolol. METHODS: A prospective study of 54 infants with infantile hemangioma was conducted from October 2009 to December 2012. Propranolol was initiated at 0.5 mg/kg/d and increased to 2 mg/kg/d on day 3. The HAS and the HSS were applied independently by 2 observers. RESULTS: Intraclass correlation coefficients of the HAS and HSS between the observers was comparable but HSS scores often remained the same upon improvement of the infantile hemangioma and therefore did not reflect disease severity. HAS decreased over time, with a dramatic drop in the first week reflecting an immediate therapeutic response. LIMITATIONS: This is a single-institution study and there may have been some selection bias in the patients who were referred for treatment. CONCLUSIONS: This study suggests that the HAS is preferable to the HSS in evaluating infantile hemangioma response to treatment.

Educational paper: Pathogenesis of infantile haemangioma, an update 2014 (part I).

UNLABELLED: Infantile haemangioma (IH) is the most frequent childhood tumour. Although it is benign and self-limiting, severe complications can arise due to localisation and fast tumour growth. Management and therapy of IH has changed greatly after 2008 with propranolol. However, the pathogenesis remains elusive. This update provides an overview of all possible mechanisms currently considered. We discuss the possibility that several mechanisms act together, although local hypoxia seems to be important. Clinically, in about half of the cases, an IH is preceded by an anaemic macula (local ischaemia) or a so-called precursor lesion. Laboratory findings indicate stabilisation and an increased transcription activity of hypoxia-inducible factor 1 alpha (HIF1α), leading to up-regulation of its downstream target genes (such as vascular endothelial growth factor (VEGF)), which normally occurs in cases of hypoxia. CONCLUSION: Three main hypotheses have been proposed, namely (1) the theory of tissue hypoxia, (2) the theory of embolization of placental endothelial cells and (3) the theory of increased angiogenic and vasculogenic activity.

Educational paper: therapy of infantile haemangioma--history and current state (part II).

UNLABELLED: Infantile haemangioma (IH) is the most frequent tumour of infancy. Although it is benign and self-limiting, severe complications can arise due to localisation and fast tumour growth. Also, IHs leave scars after regression in more than half of the cases. Management and therapy of IH have changed greatly after 2008. This update provides an overview of the older therapy options before 2008, which mainly consisted of the administration of corticosteroids, and discusses the modern management with new therapy options such as ß-blockers (both systemically and topically). CONCLUSION: ß-blockers are promising and are currently preferred above corticosteroids, but ß-blockers still do not give a definitive treatment.

Educational paper: parenting a child with a disfiguring condition-how (well) do parents adapt?

UNLABELLED: Studies indicate serious levels of stress among parents of children with a medical condition. Moreover, adaptation seems to be a specific challenge for parents of children with a disfiguring condition because of the visible nature of the condition. In the present overview, we performed a literature search in PubMed, Embase, and PsycINFO to identify both qualitative and quantitative studies concerning psychological distress among parents of children with a disfiguring condition. Two of the authors critically appraised the retrieved citations. A total of 1,459 publications were identified, of which 21 qualitative and 22 quantitative studies met our inclusion criteria. Most qualitative studies infer that the birth of a child with a disfiguring condition starts an adaptation process in which parents experience a range of negative emotions and have concerns related to the visible nature of the condition. The results of quantitative studies are mixed and contradictory, and together suggest that some, but not all parents of a child with a disfiguring condition experience stress. Methodological limitations of the quantitative studies and potential stressors are discussed, and recommendations for future research are made. CONCLUSION: The present overview neither shows that the existing literature is conclusive about the perceived strain among the parents of children with a disfiguring condition nor does it provide evidence for a relationship between visibility and parental strain.

Infantile hemangioma: treatment with short course systemic corticosteroid therapy as an alternative for propranolol.

Infantile hemangiomas (IHs) are increasingly being treated with propranolol or other beta-blockers, but before this therapeutic option was available, oral glucocorticosteroids (GCSs) were the criterion standard treatment and are still the alternative modality in problematic cases. Nevertheless, there is no standard treatment protocol for the dose and duration of GCSs. Long-term treatment with GCSs is associated with unwanted side effects such as growth suppression, behavioral changes, and reflux. Twenty-one children with troublesome IHs were treated according to an algorithm with 3 mg/kg/day of oral prednisolone divided three times per day with varying duration and number of GCS courses. Two blinded investigators independently interpreted therapy results using the Hemangioma Activity Score (HAS). Side effects were determined according to reports in patient charts and parental questionnaires. The median duration of a short course of GCSs was 2 weeks (range 1-6 weeks). The number of courses was 2 (range 1-5). The median cumulative dose was 91 mg/kg. Growth stabilized in all patients, with a good response (>50% reduction in HAS) in 62% and a favorable response (30-50% reduction is HAS) in 23%. Twelve of the 21 children (57%) had minor side effects. Persistent side effects did not occur. Intermittent short course, systemic, high-dose GCS therapy is an effective and safe treatment modality for IH, with a substantially lower cumulative dose of GCSs compared to prolonged therapy and no major side effects. This treatment is an alternative in cases in which propranolol fails or is contraindicated.

Magnitude and relevance of change in health-related quality of life in patients with vascular malformations treated with sirolimus.

Introduction: Vascular malformations are rare congenital anomalies of the vascular system, which can involve the capillaries, veins, arteries, lymphatics, or a combination of vessel types. Patients with vascular malformations experience an impaired health-related quality of life (HRQoL) because of their symptoms (e.g., pain, swelling, and bleeding) and psychosocial distress. Sirolimus is an effective drug used in the medical treatment of these patients; however, relatively little is known about the effect of sirolimus on specific changes in the HRQoL domains and its magnitude. Methods: The magnitude of change (effect size) following intervention is more informative to clinical practitioners than statistically significant but clinically unimportant changes; therefore, this study aimed to examine the magnitude and meaningfulness of change in the HRQoL of children and adults with vascular malformations following sirolimus treatment using low target levels. Results: In total, 50 patients with vascular malformations (19 children, 31 adults) were included in this study. These patients experienced a lower HRQoL than the general population, with the adults reporting a significantly lower score in almost all domains. A 6-month sirolimus treatment improved the HRQoL in 29 patients, including 77.8% of the children (Pediatric Quality of Life Inventory score [PedsQL]) and 57.7% of the adults (Short Form 36 [SF-36]). The effect sizes of sirolimus for each SF-36/PedsQL domain ranged from 0.19 to 1.02. The clinically relevant moderate magnitude of changes was seen in the domains of the children's reports: "Physical functioning" and "Social functioning" and in the domains of the parent reports: "Social functioning," "School functioning," and "Psychosocial." A high-magnitude change was seen in the domains "Emotional functioning" and "Psychosocial" in the children's reports and "Physical functioning" in the parent reports. In addition, the moderate magnitude of changes was also seen in the adults SF-36: in all domains except for "Role limitations-physical problems," "Role limitations-emotional problems," and "General health perception." Conclusion: We believe this is the first study showing the magnitude of change in HRQoL after sirolimus treatment in patients with vascular malformations. Before treatment, these patients experienced an impaired HRQoL compared with the general Dutch population. A 6-month sirolimus treatment with low target levels led to moderate-to-high clinically relevant changes in multiple domains, which significantly improved the HRQoL. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT03987152?cond=Vascular+Malformations&cntry=NL&city=Nijmegen&draw=2&rank=1, identifier: NCT03987152.

Clinical differences in sirolimus treatment with low target levels between children and adults with vascular malformations - A nationwide trial.

The clinical presentation of patients with slow-flow vascular malformations is very heterogeneous. High clinical burden and subsequent reduced health-related quality of life is something they have in common. There is an unmet medical need for these patients for whom regular treatments like surgery and embolization are either insufficient or technically impossible. Sirolimus has been reported to be effective and overall well-tolerated in most patients. However, the main limitation of sirolimus is the reported high toxicity, especially when target levels of 10-15 ng/mL are being used. We report the results of a phase IIB single-arm open-label clinical trial consisting of 68 (67 in the challenge phase and 68 in the rechallenge phase) evaluable patients (children n = 33 and adults n = 35) demonstrating that treatment with low sirolimus target levels (4-10 ng/mL) is effective in 79.1% of the patients. When sirolimus treatment was stopped, the majority of patients experienced a recurrence of symptoms, supporting prolonged or even lifelong treatment requirement. Adults experienced a higher baseline pain score compared with children, having an estimated marginal mean of 6.2 versus 4.1, p < 0.05; however, they showed a similar decrease to children. Furthermore, the pediatric population experienced less often a sirolimus-related grade I-IV adverse event (35.9% vs. 64.1%, p > 0.05) compared with adults. Additionally, response rates were higher in children compared with adults (93.8% vs. 65.7%, p < 0.05), and children responded faster (28 vs. 91 days, p < 0.05). These results suggest benefits of sirolimus in patients with slow-flow vascular malformations and support its initiation as young as possible.

Evaluation of intra-lesional corticosteroids in the treatment of peri-ocular haemangioma of infancy: still an alternative besides propranolol.

PURPOSE: Haemangioma of infancy (HOI) is the most frequently occurring benign tumour of infancy. Alarming HOI require treatment. Current therapy is empirically based; corticosteroids are often administered but in recent publications propranolol was reported to be more effective. Peri-ocular HOI are highly sensitive to corticosteroids. Our goal was to evaluate the effectiveness of intra-lesional corticosteroids in the treatment of peri-ocular HOI. METHODS: We selected all patients with peri-ocular HOI who had only been treated with intra-lesional corticosteroids at our hospital from 1993 until 2009. Treatment was standardized according to a prospective protocol. RESULTS: A total of n = 34 patients were included. There were no complications at all after therapy. A second intra-lesional injection was necessary in five patients. At follow-up after 6 and 12 months after injection, 94 and 91% of the patients, respectively, had regression of the HOI. Astigmatism, Haemangioma Activity Score and global assessments all had improved after therapy. CONCLUSIONS: This study shows that intra-lesional therapy with corticosteroids is very safe in the treatment of peri-ocular HOI. It remains a good and safe alternative besides propranolol or when propranolol therapy is not possible (e.g. asthma, PHACE syndrome, and certain cardiac diseases).

Early MRI diagnosis of Sturge Weber Syndrome type 1 in infants.

BACKGROUND: Patients with Sturge-Weber syndrome type 1 (SWS1) have a port-wine birthmark (PWB) as cutaneous hallmark. Up to 35% of neonates with a high risk PWB develop SWS1. Clinical manifestations are severe and often progressive. Especially early onset seizures are associated with worse neurocognitive outcome. Identification of pre-symptomatic SWS1 patients is hampered because brain MRI in the first months of life does not always show the for SWS1 characteristic leptomeningeal capillary malformation (LMC). OBJECTIVES: Identification of sensitive and specific MRI predictors for early SWS1 diagnosis. METHODS: In this retrospective single centre study, we included 24 SWS1 patients and 20 controls. We studied specificity and sensitivity for SWS1 diagnosis of LMC and indirect MRI signs such as choroid plexus (CP) size and thickness, abnormal white matter signal, lobar cerebral atrophy, ischemia and cortical calcifications. RESULTS: In SWS1 patients CP thickness and CP thickness ratio on non-contrast brain MRI was significantly increased. The optimal cut-off value of 5.6 mm on the affected side corresponded with a sensitivity of 91.7% and a specificity of 100% for confirmation of SWS1 diagnosis. In 21% of children aged ≤3 months with a later confirmed SWS1 diagnosis, LMC on initial MRI could not be discerned but CP thickness ≥5.6 mm on the affected side confirmed SWS1 diagnosis. CONCLUSIONS: In this study, CP size ratio and thickness were found to be sensitive and specific signs additional to earlier described criteria to support SWS1 diagnosis in neonates and infants which need to be confirmed in other series.

Rhabdoid tumor mimicking hemangioma.

We report a young boy with a malignant tumor, which remained unrecognized for 8 months because it was assumed to be a hemangioma. The presentation of a rhabdoid tumor mimicking hemangioma is very rare. It was reported only on two earlier occasions. Rhabdoid tumors are one of the most aggressive types of malignancies encountered in pediatric oncology. It is important to recognize that a fast growing vascular lesion in a child will often be a hemangioma, but could also be an aggressive tumor.

Patients with Congenital Low-Flow Vascular Malformation Treated with Low Dose Sirolimus.

INTRODUCTION: Patients with congenital vascular malformations often suffer from an impaired quality of life (QoL) because of pain and functional disabilities. Previous studies have shown that the mTOR inhibitor sirolimus can reduce complaints and improve QoL in some patients. High target levels of sirolimus of 10-15 ng/ml were well tolerated; however, in a relative high percentage of patients sirolimus caused serious adverse events (AEs). METHODS: A case series of 12 patients with therapy-resistant low-flow vascular malformations was treated with sirolimus, using low target levels of 4-10 ng/ml. Efficacy of sirolimus was evaluated in regard to pain symptoms using the visual analogue scale/numeric rating scale and patients reported QoL. To rule out a placebo effect of sirolimus, sirolimus was stopped after a certain time point and reintroduced as soon as complaints returned. Adverse events were closely monitored and graded using the Common Terminology Criteria for Adverse Events (CTCAE) grading. RESULTS: An improvement in symptoms was seen in 92% (n = 11/12) of patients. In nine patients pain complaints returned. Seven out of nine of them (78%) again experienced a reduction of symptoms after restarting sirolimus treatment. Despite low target levels, these response rates are comparable to those found in the literature using higher target levels of sirolimus. However, significantly less serious AEs were observed with low dose sirolimus, suggesting low dose sirolimus might be safer. Unfortunately, young adolescent female patients developed serious menstrual disturbances during treatment with low dose sirolimus. We describe this adverse event for the first time in patients with congenital vascular malformations and this might be specifically related to low dose sirolimus. CONCLUSIONS: Low dose sirolimus showed a high efficacy in patients with therapy-resistant and low-flow malformation, with a lower incidence of serious adverse events. At the same time a new adverse event, namely menstrual cycle disturbance, was observed in young adolescents, indicating the need for caution when sirolimus is given. This is extremely relevant to patients with low-flow vascular malformation, who are likely to require lifelong treatment for their condition.