Heather R. Adams

Neuropsychological Outcomes From a Randomized Trial of Triple Intrathecal Chemotherapy Compared With 18 Gy Cranial Radiation As CNS Treatment in Acute Lymphoblastic Leukemia: Findings From Dana-Farber Cancer Institute ALL Consortium Protocol 95-01

PURPOSE We evaluated late neuropsychological toxicity in children treated for standard-risk acute lymphoblastic leukemia (ALL) who were randomly assigned to receive either cranial radiation therapy (CRT) with double intrathecal (IT) chemotherapy or intensive triple IT chemotherapy (no CRT) as CNS-directed therapy. PATIENTS AND METHODS Between 1996 and 2000, 164 children with standard-risk ALL treated on Dana-Farber Cancer Institute Consortium Protocol 95-01 were randomly assigned to receive either 18 Gy CRT delivered in twice daily fractions (0.9 [DOSAGE ERROR CORRECTED] Gy) with double IT therapy (methotrexate and cytarabine) or intensive triple IT drug (methotrexate, cytarabine and hydrocortisone) without CRT. Neuropsychological testing was completed at a median 6 years postdiagnosis for 79 children (CRT, n = 39; triple IT, n = 40), all of whom were in continuous complete remission. RESULTS Cognitive function for both groups was solidly in the average range, with no consistent group differences in basic cognitive skills. Children treated on the CRT plus double IT arm did, however, exhibit less fluent output and were less effective at modulating their behavior by parent report. CONCLUSION This randomized trial revealed only subtle differences 6 years after diagnosis between children who received CNS therapy as CRT plus double IT drug or as intensive triple IT drug. In most situations where comparable therapeutic efficacy can be achieved without CRT, it is preferable to do so. Where therapeutically necessary, however, CRT at lower doses may not add risk for significant neurotoxicity.

Parental Assessments of Internalizing and Externalizing Behavior and Executive Function in Children with Primary Hypertension

OBJECTIVE To determine the relations between hypertension and parental ratings of behavior and executive functions in children with primary hypertension and to examine the potential moderating influence of obesity. STUDY DESIGN Hypertensive and normotensive control groups were matched for age, sex, race, intelligence quotient, maternal education, household income, and obesity. Parents completed the Child Behavior Checklist to assess Internalizing and Externalizing problems and the Behavior Rating Inventory of Executive Function to assess behavioral correlates of executive function. RESULTS Thirty-two hypertensive subjects and 32 normotensive control subjects (aged 10 to 18 years) were enrolled. On the Child Behavior Checklist, hypertensives had higher Internalizing T-scores (53 vs 44.5, P = .02) with 37% falling within the clinically significant range vs 6% of control subjects (P = .005). Internalizing score increased with increasing body mass index percentile in hypertensive but not normotensive subjects. Hypertensives had worse Behavior Rating Inventory of Executive Function Global Executive Composite T-scores compared with control subjects (50 vs 43, P = .009). CONCLUSIONS Children with both hypertension and obesity demonstrate higher rates of clinically significant internalizing problems, and hypertensives (irrespective of obesity) demonstrate lower parental ratings of executive function compared with normotensive control subjects.

Learning and attention problems among children with pediatric primary hypertension.

OBJECTIVE: The objective was to determine whether children with sustained primary hypertension are at increased risk for learning disabilities (LDs), as a school-related manifestation of neurocognitive problems. METHODS: A total of 201 children 10 to 18 years of age who were referred because of elevated blood pressure (BP) were included. Patients were categorized as having or not having hypertension, on the basis of BP evaluation at the initial hypertension clinic visit and subsequent confirmation of sustained elevated BP outside the clinic setting. Parents reported whether their child had a provider-confirmed LD or attention-deficit/hyperactivity disorder (ADHD). RESULTS: A total of 101 children without hypertension and 100 children with hypertension were evaluated; 18% of the children (n = 37) had LDs. In comparison with children without hypertension, children with hypertension were significantly more likely to have LDs (18% vs 9%; P < .001), irrespective of comorbid ADHD. With adjustment for demographic variables and obesity, the odds of having LDs were elevated for subjects with hypertension, in comparison with subjects without hypertension (odds ratio: 4.1 [95% confidence interval: 1.8–9.4]). CONCLUSIONS: The rate of LDs, with or without ADHD treatment, was significantly higher for children with sustained primary hypertension, compared with children without hypertension. These findings add to the growing evidence for an association between primary hypertension and cognitive function and may inform treatment and monitoring decisions for these children who may be at risk for learning problems.

A clinical rating scale for Batten disease Reliable and relevant for clinical trials

Background: Batten disease (juvenile neuronal ceroid lipofuscinosis [JNCL]) is an autosomal recessive neurodegenerative disorder characterized by blindness, seizures, and relentless decline in cognitive, motor, and behavioral function. Onset is in the early school years, with progression to death typically by late adolescence. Development of a clinical instrument to quantify severity of illness is a prerequisite to eventual assessment of experimental therapeutic interventions Objective: To develop a clinical rating instrument to assess motor, behavioral, and functional capability in JNCL. Methods: A clinical rating instrument, the Unified Batten Disease Rating Scale (UBDRS), was developed by the authors to assess motor, behavioral, and functional capability in JNCL. Children with verified JNCL were evaluated independently by three neurologists. Intraclass correlation coefficients (ICCs) were used to estimate the interrater reliability for total scores in each domain. Interrater reliability for scale items was assessed with weighted κ statistics Results: Thirty-one children with confirmed JNCL (10 boys, 21 girls) were evaluated. The mean age at symptom onset was 6.1 ± 1.6 years, and the mean duration of illness was 9.0 ± 4.4 years. The ICCs for the domains were as follows: motor = 0.83, behavioral = 0.68, and functional capability = 0.85. Conclusions: The Unified Batten Disease Rating Scale (UBDRS) is a reliable instrument that effectively tests for neurologic function in blind and demented patients. In its current form, the UBDRS is useful for monitoring the diverse clinical findings seen in Batten disease.

Classification and Natural History of the Neuronal Ceroid Lipofuscinoses

The neuronal ceroid lipofuscinoses represent a group of disorders characterized by neurodegeneration and intracellular accumulation of an auto-fluorescent lipopigment (ceroid lipofuscin). Together, they represent the most prevalent class of childhood neurodegenerative disease. The neuronal ceroid lipofuscinoses encompass several distinct biological entities that vary in age of onset, specific neurologic phenotype, and rate of progression. In this review, we describe 9 major forms and present a classification scheme. Understanding the age of onset, clinical features, and natural history can inform rational diagnostics. Better knowledge of the natural histories of these disorders is necessary to shed light on the underlying pathobiology and to develop new therapeutics.

Outcomes of a Randomized Trial of Hyperfractionated Cranial Radiation Therapy for Treatment of High-Risk Acute Lymphoblastic Leukemia: Therapeutic Efficacy and Neurotoxicity

PURPOSE We evaluated 8-year survival and late neuropsychologic toxicity in children with acute lymphoblastic leukemia treated in a randomized clinical trial to test whether hyperfractionated (twice daily) cranial radiation therapy (CRT) can reduce incidence and severity of late toxicities associated with 18 Gy of CRT. PATIENTS AND METHODS Between 1987 and 1995, 369 children treated on two consecutive Dana-Farber Cancer Institute Consortium protocols for high-risk acute lymphoblastic leukemia were randomly assigned to conventionally fractionated CRT (CFX) or hyperfractionated CRT (HFX) to a total dose of 18 Gy. Neuropsychologic testing was completed for 125 of 287 children in continuous complete remission. Event-free and overall survival, as well as neuropsychologic function, were compared for the two arms of the protocol. RESULTS Eight-year event-free survival (+/- SE) was 80% +/- 3% for children randomly assigned to CFX and 72% +/- 3% for HFX (P =.06). Overall survival was 85% +/- 3% for CFX and 78% +/- 3% for HFX (P =.06). CNS relapses occurred in 2.8% of patients receiving CFX and 2.7% receiving HFX (P =.99). Cognitive function for both groups was solidly in the average range, with no group differences in intelligence, academic achievement, visuospatial reasoning, or verbal learning. Children on the HFX arm exhibited a modest advantage for visual memory (P <.05). CONCLUSION HFX provides no benefit in terms of cognitive late effects and may compromise antileukemic efficacy. HFX should not be substituted for conventionally dosed CRT in children who require radiation therapy for treatment of acute lymphoblastic leukemia.

Clinical trials in rare disease: challenges and opportunities.

The neuronal ceroid lipofuscinoses constitute one of many groups of rare childhood diseases for which disease-modifying treatments are nonexistent. Disease-specific barriers to therapeutic success include incomplete understanding of disease pathophysiology and limitations of treatments that cannot adequately cross the blood-brain barrier to access the central nervous system. Therapeutic development in the neuronal ceroid lipofuscinoses shares many challenges with other rare diseases, such as incomplete understanding of natural history to inform trial design, need for alternatives to the randomized controlled clinical trial, requirement for more sensitive outcome measures to quantify disease, limited access to resources required to mount a clinical trial (including funding), and difficulties of recruiting a small sample to participation. Solutions to these barriers will require multicenter collaboration, partnership with patient organizations, training a new generation of researchers interested in rare diseases, and leveraging existing resources.

Parental assessment of executive function and internalizing and externalizing behavior in primary hypertension after anti-hypertensive therapy.

OBJECTIVE To determine the change in parental ratings of executive function and behavior in children with primary hypertension after anti-hypertensive therapy. STUDY DESIGN Parents of subjects with untreated hypertension and control subjects completed the Behavior Rating Inventory of Executive Function (BRIEF) to assess behavioral correlates of executive function and the Child Behavior Checklist (CBCL) to assess internalizing and externalizing behaviors. Subjects with hypertension subsequently received anti-hypertensive therapy to achieve casual blood pressure (BP)<95th percentile. After 12 months, all parents again completed the BRIEF and CBCL. RESULTS Twenty-two subjects with hypertension and 25 normotensive control subjects underwent both baseline and 12-month assessments. The BP of subjects with hypertension improved (24-hour systolic BP [SBP] load: mean baseline versus 12-months, 60% versus 25%, P<.001). Parent ratings of executive function improved from baseline to 12 months in the subjects with hypertension (BRIEF Global Executive Composite T-score, Delta=-5.9, P=0.001), but not in the normotensive control subjects (Delta=-0.36, P=.83). In contrast, T-scores on the CBCL Internalizing and Externalizing summary scales did not change significantly from baseline to 12 months in either subjects with hypertension or control subjects. CONCLUSIONS Children with hypertension demonstrated improvement in parental ratings of executive function after 12 months of anti-hypertensive therapy.

Neurocognitive Alterations in Hypertensive Children and Adolescents

J Clin Hypertens (Greenwich). 2012; 14:353–359. ©2012 Wiley Periodicals, Inc.

Oral Ketamine for Children with Chronic Pain: A Pilot Phase 1 Study

OBJECTIVE To assess whether oral ketamine is safe at higher dosages for sedating children and whether it may be an option for the control of chronic pain in children. STUDY DESIGN A prospective study was performed on 12 children with chronic pain to identify the maximum tolerated dosage of oral ketamine. Participants were given 14 days of oral ketamine, 3 times daily, at dosages ranging from 0.25-1.5 mg/kg/dose. Participants were assessed for toxicity and for pain severity at baseline and on day 14 of treatment. RESULTS Two participants, both treated at 1.5 mg/kg/dose, experienced dose-limiting toxicities (sedation and anorexia). One participant, treated at 1 mg/kg/dose, opted to stop ketamine treatment due to new pain on treatment. Nine participants completed their course of ketamine treatment. Of these 12 children, 5 experienced improvement in their pain scores, 2 with complete resolution of pain, lasting >4 weeks off ketamine treatment. CONCLUSION Oral ketamine at dosages of 0.25-1 mg/kg/dose appears to be safe when given for 14 days to children with chronic pain.