Children's Memorial Hospital Research Articles

Pediatric State of the Art Symposium: Infantile Spasms: Emerging Therapies and Novel Mechanisms 7:00 p.m.‐9:00 p.m.

Carl E. Stafstrom*, Douglas Nordli†, Andrew Lux‡ and Lionel Carmant§ *Neurology, University of Wisconsin, Madison, WI; †Neurology, Children's Memorial Hospital, Chicago, IL; ‡Pediatric Neurology, British Royal Hospital for Children, Bristol, United Kingdom and §Pediatric Neurology, Ste‐Justine Hospital, Montreal, QC, Canada Summary: Infantile spasms is a catastrophic epilepsy of childhood that poses unique challenges for the clinician. An optimal therapy is lacking, and to date there has been no animal model that sufficiently replicates clinical features, so our understanding of mechanism is incomplete. Existing therapies are limited by effectiveness, availability or both. Yet, each of these challenges offers a unique opportunity to advance clinical and basic knowledge of this developmental epilepsy. This symposium will discuss recent advances about the clinical profile, therapeutic modalities, outcome, and mechanisms of infantile spasms. Dr. Nordli will review infantile spasms presentations and clinial features, especially variants. Dr. Lux will discuss current and future treatments. Dr. Carmant will discuss outcomes of infantile spasms. Finally, Dr. Stafstrom will consider emerging animal models that might shed light on infantile spasms mechanisms.

A New Computer Enhanced Visual Learning Method to Train Urology Residents in Pediatric Orchiopexy: A Prototype for Accreditation Council for Graduate Medical Education Documentation

Residency programs must continue to restructure teaching and assessment of surgical skills to improve the documentation of Accreditation Council for Graduate Medical Education competencies. To improve teaching and documenting resident performance we developed a computer enhanced visual learning method that includes a curriculum and administrative reports. The curriculum consists of 1) study of a step-by-step surgical tutorial of computer enhanced visuals that show specific surgical skills, 2) a checklist tool to objectively assess resident performance and 3) a log of postoperative feedback that is used to structure deliberate practice. All elements of the method are repeated with each case performed. We used the Accreditation Council for Graduate Medical Education index case of orchiopexy to pilot this project. All urology residents who trained at our institution from January 2006 to October 2007 performed orchiopexy using the computer enhanced visual learning method. The computer enhanced visual learning tutorial for orchiopexy consisted of customized computer visuals that demonstrate 11 steps or skills involved in routine inguinal orchiopexy, eg ligate hernia. The attending urologist rated resident competence with each skill using a 5-point Likert scale and provided specific feedback to the resident suggesting ways to improve performance. These ratings were weighted by case difficulty. The computer enhanced visual learning weighted score at entry into the clinical rotation was compared to the best performance during the rotation in each resident. Seven attending surgeons and 24 urology residents (resident training postgraduate years 1 to 8) performed a total of 166 orchiopexies. Overall the residents at each postgraduate year performed an average of 7 cases each with complexity ratings that were not significantly different among postgraduate year groups (average 2.4, 1-way ANOVA p not significant). The 7 attending surgeons did not differ significantly in assessment of skill performance or case difficulty (1-way ANOVA p not significant). Of the 24 residents 23 (96%) showed improvement in computer enhanced visual learning score/skill performance. In the entire group the average computer enhanced visual learning weighted score increased more than 50% from entry to best performance (137 to 234 orchiopexy units, paired t test p <0.0001). Computer enhanced visual learning is a novel method that enhances resident learning by breaking a core procedure into discrete steps and providing a platform for constructive feedback. Computer enhanced visual learning, which is a checklist tool, complies with Accreditation Council for Graduate Medical Education documentation requirements. Computer enhanced visual learning has wide applicability among surgical specialties.

Massage therapy in outpatient pediatric chronic pain patients: do they facilitate significant reductions in levels of distress, pain, tension, discomfort, and mood alterations?

This study was designed to look at the efficacy of adjuvant massage therapy in children and adolescents who presented to a chronic pediatric pain clinic for management. After Institutional Review Board approval and informed consent and assent was obtained, all pediatric patients who presented to the outpatient chronic pain clinic at Children's Memorial Hospital from July 2006 to May 2007 were invited to participate in a study that offered massage therapy as an adjunct to conventional pain treatment. Patients (n = 80 sessions, 57 patients) were asked to rate their levels of distress, pain, tension, discomfort, and degree of upset mood on a scale of 1-5 (e.g. for distress 1 = very calm; 5 = very distressed) before and after massage therapy. Paired t-tests were used to compare pre- and postmassage ratings and probability values were corrected for multiple comparisons using the Bonferroni procedure. After massage therapy, patients reported highly significant improvement in their levels of distress, pain, tension, discomfort, and mood compared with their premassage ratings (all t-values >6.1, ****P < 1 x 10(-8). To control for the possible effects of patients reporting improvements simply as a result of rating their symptoms, we collected control ratings before and after a comparable 'no intervention' time period in a subset of 25 patients. The 'no intervention' time period typically took place in the treatment room with the therapist present. Approximately 60% of the control ratings were obtained before the intervention and 40% were obtained after the massage therapy. None of the differences between the pre- and postratings associated with the 'no intervention' control time period were significant. In these same patients, the difference between the pre- and postmassage ratings were significant, all t-values >3.8, **P < 0.001.

Invited Commentary

Invited Commentary

Clinical Features of Prolonged Febrile Seizures

The results of a prospective, multicenter study of 119 children (age 1 month through 5 years) with prolonged febrile seizures (30 min or longer) are reported from Montefiore Medical Center, and Columbia University, New York; Children's Memorial Hospital, Chicago; and other members of the FEBSTAT study group.

Editorial Comment

No AccessJournal of UrologyPediatric Urology1 Jul 2008Editorial Comment William E. Kaplan William E. KaplanWilliam E. Kaplan More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2008.03.220AboutFull TextPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail "Editorial Comment." The Journal of Urology, 180(1), p. 316 References 1 : Nomograms of total renal volume, urinary bladder volume and bladder wall thickness index in 3,376 children with a normal urinary tract. Pediatr Radiol2007; 37: 181. Google Scholar 2 : Standardized ultrasound method for assessing detrusor muscle thickness in children. J Urol2000; 164: 134. Link, Google Scholar 3 : Age related bladder capacity and bladder capacity growth in children with myelomeningocele. J Urol1997; 158: 1261. Link, Google Scholar Division of Urology, Children's Memorial Hospital, Chicago, Illinois© 2008 by American Urological AssociationFiguresReferencesRelatedDetails Volume 180Issue 1July 2008Page: 316 Advertisement Copyright & Permissions© 2008 by American Urological AssociationMetricsAuthor Information William E. Kaplan More articles by this author Expand All Advertisement PDF DownloadLoading ...

An Integrated Approach to the Care of Adult Patients with Prior Atriopulmonary Fontan Surgery

Because of improved survival among children born with heart disease, more adults than children are now living with congenital heart defects, providing a new challenge for ongoing evaluation and care. At Children's Memorial Hospital in Chicago, we have gained extensive expertise in the long-term outcome of patients with repaired single ventricle anatomy, particularly with regard to arrhythmias and impaired hemodynamics, and have developed an integrated approach to their care. This article will summarize (a) single ventricle physiology, (b) evolution of the Fontan operation and the long-term multi-system sequelae, (c) treatment options for patients with prior Fontan surgery, focusing on Fontan conversion with arrhythmia surgery, and (d) unique management of adult patients with prior Fontan surgery. For the foreseeable future, pediatric nurse practitioners will have an important role, including coordination of care and providing continuity in the care of adults with prior Fontan surgery.

Improving Surgical Services Performance Through Changing Work Culture

Children's memorial hospital administrators knew that they needed to improve their surgical services infrastructure to accommodate growing patient volume, implement new technology, and address a major shift from inpatient to outpatient surgery. The hospital partnered with an outside consultant to better understand the impact of the work environment and culture on performance and to identify opportunities for improvement. During a seven-month period, new work processes, tools, and staff training helped significantly boost surgical services volume and revenue. Today, the hospital continues to sustain the performance gains achieved through the surgical care coordination initiative.

Neuroimaging findings in children with rare or novel de novo chromosomal anomalies

De novo constitutional chromosomal anomalies provide important insights into the genetic loci responsible for congenital neurological disorders. However, most phenotypic descriptions of patients with rare chromosomal abnormalities are published as individual case reports or small group studies, making genotype-phenotype correlations unclear. Moreover, many clinical genetic reports do not include neuroimaging. We conducted a retrospective case series study of all children who had genetic testing done at Children's Memorial Hospital in Chicago, Illinois between 1985 and 2006. The case series was selected from a database containing all chromosomal testing results, clinical data, and neuroimaging. Clinical examination results were assigned by board certified geneticists and/or neurologists and neuroimages were reviewed by both a neurologist or neuroradiologist and a blinded neurologist. Of the 28,108 children in the series, we identified 34 children with novel or apparently novel de novo chromosomal abnormalities. Several of the cases represent potentially new genetic loci for neurological malformations and novel syndromic conditions. This study demonstrates the utility of large clinical databases in assessing genotype-phenotype correlations and mapping loci for congenital neurological disorders. We describe a case-series strategy to analyze existing databases to reveal new genotype-phenotype correlations.

201: Extracorporeal Photopheresis (ECP) is an Effective Therapy for the Treatment of Children with Steroid Refractory (SR) Chronic Graft vs Host Disease (cGVHD)

ECP is an immune modulatory therapy that works by causing donor lymphocyte apoptosis and tolerance. We hypothesize that ECP is an effective therapy in treating SR cGVHD and allows for reduction in corticosteroids. We performed a retrospective study at Children's Memorial Hospital to evaluate the effectiveness of ECP in SR cGVHD in children.

291: Comparison of Outcomes in Children Undergoing a Single Allogeneic Transplant using Bone Marrow (BM) or Umbilical Cord Blood (UCB) as Stem Cell Source. The Children's Memorial Hospital Experience

291: Comparison of Outcomes in Children Undergoing a Single Allogeneic Transplant using Bone Marrow (BM) or Umbilical Cord Blood (UCB) as Stem Cell Source. The Children's Memorial Hospital Experience

Maze Procedure in Single Ventricle Patients

As of September 2007, 120 patients have undergone a Fontan conversion procedure at Children's Memorial Hospital (Chicago, IL). One of the primary indications for surgery in these patients has been arrhythmias, either atrial reentry tachycardia or atrial fibrillation. The surgical treatment of those two lesions has been with the modified right atrial maze and the Cox-maze III. The purpose of this review is to describe our strategy for performing the maze procedure in these single-ventricle patients. The primary tool for performing the maze in this series has been with the cryocatheter with cryoablation at -160 degrees C for 1 minute. These cryoablation lesions have been combined with standard surgical incisions in the right and left atria. The early mortality in this series is 1%, late mortality is 5%. Freedom from atrial reentry tachycardia recurrence at 5 years is 86%. Freedom from atrial fibrillation recurrence is 98% at 5 years.

When do seizures usually improve with the ketogenic diet?

Parents often expect immediate seizure improvement after starting the ketogenic diet (KD) for their children. The purpose of this study was to determine the typical time to seizure reduction as well as the time after which it was unlikely to be helpful in those children started on the KD. Records of all children started on the KD at Johns Hopkins Hospital, Baltimore (n = 83) and Children's Memorial Hospital, Chicago (n = 35) from November 2003 to December 2006 were examined to determine the first day in which seizures were reportedly improved. Of the 118 children started on the KD, 99 (84%) had documented seizure reduction. The overall median time to first improvement was 5 days (range: 1-65 days). Seventy-five percent of children improved within 14 days. In those children who were fasted at KD onset, the time to improvement was quicker (median 5 vs. 14 days, p < 0.01) with a higher percentage improving within 5 days (60% vs. 31%, p = 0.01). No difference was identified between fasting and nonfasting in regards to long-term outcomes, however. The KD works quickly when effective, typically within the first 1-2 weeks. Starting the KD after a fasting period may lead to a more rapid, but equivalent long-term seizure reduction, confirming prior reports. If the KD has not led to seizure reduction after 2 months, it can probably be discontinued.

Cost of Influenza Hospitalization at a Tertiary Care Children's Hospital and Its Impact on the Cost-Benefit Analysis of the Recommendation for Universal Influenza Immunization in Children Age 6 to 23 Months

Hall JL, Katz BZ. J Pediatr. 2005;147:807–811 PURPOSE OF THE STUDY. To calculate the costs of influenza hospitalization at a tertiary care children's hospital as the basis of a cost/benefit analysis of the new influenza vaccine recommendation for children 6 to 23 months old. STUDY DESIGN. The investigators reviewed the medical charts of all patients diagnosed with influenza and admitted to Children's Memorial Hospital in Chicago, Illinois, in 2002. Total hospital costs were obtained from the business development office. RESULTS. Thirty-five charts were analyzed. Both of the 2 patients who required mechanical ventilation and 4 of the 6 patients admitted to the ICU had high-risk underlying medical conditions. Nine children were 6 to 23 months old; 4 of these 9 had no preexisting medical conditions. Had all 18 high-risk children over 6 months old been protected from influenza, approximately $350 000 in hospital charges could have been saved. CONCLUSIONS. Preventing the additional 4 hospitalizations in the otherwise low-risk children 6 to 23 months old for whom vaccine was currently recommended would have cost approximately $281 000 ($46 per child) more than the hospital charges saved. When all children 6 to 23 months old were considered, influenza vaccination would have been less costly than other prophylactic measures. Addition of indirect costs, deaths, outpatient costs, and the cost of secondary cases would favor the cost/benefit ratio for influenza vaccination of all children 6 to 23 months old. REVIEWER COMMENTS. A few years ago when recommendations were made to immunize all children 6 to 23 months of age with the influenza vaccine, they were not initially accepted with open arms because of an already-busy infant-immunization schedule. This article provided interesting data regarding actual charges of hospitalization for care of children with influenza. Analyzing the ages and underlying medical conditions of these children, as well as using conservative estimates of vaccine efficacy and only direct costs of hospitalization, the investigators predicted substantial cost savings from vaccinating children with underlying medical conditions and modest spending ($46 per child) when vaccinating healthy children 6 through 23 months of age. Recognized limitations of the investigation included extrapolation of findings from a tertiary care center and underrepresentation of children without underlying conditions. Hopefully, in the future, we will have more data such as these that will be useful in assessing the cost/benefit ratio of influenza vaccination recommendations in pediatric patients.

Prominent vascular endothelial proliferation in clinically aggressive neuroblastoma

10611 Background: Tumor blood vessels are disorganized and vascular endothelial cell proliferation (VEP) has been identified as a poor prognosticator in many adult cancers. To determine the clinical significance of VEP in neuroblastoma (NB), we evaluated blood vessel architecture in tumor sections from 51 children diagnosed at Children's Memorial Hospital, Chicago (CMH) and in 154 NB tumors on a Tissue Microarray (TMA) constructed at Children's Hospital of Philadelphia (CHOP). Methods: H&amp;E-stained tumor sections were examined for the presence of structurally abnormal vessels and further characterized by immunostaining with anti-CD31 and von Willebrand factor (vWF) antibody to highlight endothelial cells. Tumors that contained vessels with disorganized walls and more than one endothelial cell layer were classified as VEP positive. Tumor sections that contained only thin walled vessels with no more than one layer of endothelial cells were classified as VEP negative. Associations between VEP and established clinico-pathologic features and outcome were assessed. Results: In the CHOP series, VEP was associated with high-risk group classification and MYCN amplification (p&lt;0.001 and p=0.006). In the CMH series only 5 of the 10 children with MYCN amplification had VEP but 4 of these 5 patients have died, while there were no deaths in the subset of patients with MYCN amplified tumors that lacked VEP (n=5). In both study groups, VEP was significantly associated with Schwannian stroma-poor histology (CMH series: p=0.008; CHOP series: p&lt;0.001) and decreased survival probability (CMH series: p=0.017; CHOP series: p= 0.014). Conclusions: The association between structurally abnormal vessels and poor outcome provides further support for the concept that angiogenesis plays an important role in determining the biologic behavior of NB tumors. Our results also indicate that angiogenesis is regulated differently in Schwannian stroma-rich versus stroma-poor NB tumors. Further studies investigating the activity of angiogenic inhibitors in children with clinically aggressive stroma-poor NB are warranted. No significant financial relationships to disclose.

Prominent Microvascular Proliferation in Clinically Aggressive Neuroblastoma

Tumor vasculature is disorganized and glomeruloid microvascular proliferation (MVP) has been identified as a poor prognosticator in some adult cancers. To determine the clinical significance of MVP, including glomeruloid MVP in neuroblastoma, we initially examined vessel architecture in tumor sections from 51 children diagnosed at Children's Memorial Hospital (CMH) and subsequently evaluated 154 neuroblastoma tumors on a tissue microarray constructed at Children's Hospital of Philadelphia (CHOP). H&E sections were examined for the presence of structurally abnormal vessels and further characterized by immunostaining for CD31 and von Willebrand factor to highlight endothelial cells and alpha-smooth muscle actin for pericytes. Tumors with thickened walls containing a complete layer of hypertrophic endothelial cells plus additional layers of vascular mural cells were classified as MVP positive. Associations between MVP and established clinicopathologic features and outcome were assessed. In both series, MVP was significantly associated with Schwannian stroma-poor histology (CMH, P = 0.008; CHOP, P < 0.001) and decreased survival probability (CMH, P = 0.017; CHOP, P = 0.014). In the CHOP series, MVP was associated with high-risk group classification (P < 0.001), although this association was not seen in the smaller CMH cohort. The association between MVP and poor outcome provides further support for the concept that angiogenesis plays an important role in determining the biological behavior of neuroblastoma tumors. Our results also indicate that angiogenesis is regulated differently in Schwannian stroma-rich versus stroma-poor neuroblastoma tumors. Further studies investigating the activity of angiogenic inhibitors in children with clinically aggressive stroma-poor neuroblastoma are warranted.

Maimon M. Cohen, PhD

Maimon M. Cohen, PhD

Optic Pathway Gliomas in Neurofibromatosis 1 (NF-1)

Advances in the pathophysiology and clinical behavior of NF-1 associated optic pathway gliomas (OPG) made over the past 10 years are examined, and evidence-based recommendations for diagnosis and management are proposed by researchers from Children's Memorial Hospital, Chicago; St Thomas's Hospital, London; Children's Hospital of Philadelphia; University of Pennsylvania School of Medicine, Philadelphia; and Washington University School of Medicine, St Louis, MO, The initial diagnostic and management guidelines proposed by a task force in 1997 are extended, and unanswered questions are addressed.

Growth Considerations of the Immature Spine

Corresponding author: John Sarwark, MD , Division of Orthopaedic Surgery, Children's Memorial Hospital, 2300 Children's Plaza, Chicago, IL 60614. , E-mail address: [email protected]

Epilepsy syndromes undetermined whether focal or generalized in infants

Purpose To describe the seizures in infants with epilepsy syndromes undetermined whether focal or generalized. Methods This was a retrospective video-EEG study of seizures recorded at Children's Memorial Hospital (CMH), Chicago, IL, in infants diagnosed with epilepsy syndromes undetermined whether focal or generalized. Results Of 69 infants with seizures recorded, 23 (33%) had epilepsies undetermined whether focal or generalized with both generalized and focal seizures, 17 of which (25% of the total) had epilepsies with both focal and generalized seizures not further specified. The predominant seizure type was spasms with focal seizures. Conclusions We propose several small modifications to the existing 1989 ILAE epilepsy syndrome classification: epilepsies with both focal and generalized seizures could be re-labeled “pleomorphic epilepsies” for simplicity and should include idiopathic and symptomatic subgroups. We believe these epilepsies are not uncommon in the group of infants with intractable seizures and may have yet to be discovered metabolic and genetic determinants.