Brenda J. Spiegler

Change in neurocognitive functioning after treatment with cranial radiation in childhood.

PURPOSE To evaluate the pattern of stability and change over time across multiple domains of neurocognitive function in radiated survivors of posterior fossa (PF) tumors. PATIENTS AND METHODS Thirty-four children (25 males) treated for malignant PF tumors were observed with serial clinical neuropsychologic assessments. Thirty patients were treated for medulloblastoma and four patients were treated for ependymoma. Twelve patients were treated with reduced-dose and 21 patients were treated with standard-dose cranial radiation. All patients received an additional boost to the PF. One patient was treated with PF radiation only. Standardized neuropsychologic tests were administered at different times after diagnosis for each child. The rate of change in scores was determined using a mixed model regression. RESULTS Results showed a 2- to 4-point decline per year in intelligence scores. For our relatively young sample, intellectual function declined quickly in the first few years after treatment, and then more gradually. Significant declines in visual-motor integration, visual memory, verbal fluency, and executive functioning were also documented. No decline was evident for verbal memory and receptive vocabulary. CONCLUSION Cranial radiation is associated with a decline in multiple neurocognitive domains, with a few notable exceptions. Our results must be interpreted in the context of common limitations of clinical research, including patient variability, changes in test versions, small sample size, and clinical referral bias.

Serial Evaluation of Academic and Behavioral Outcome After Treatment With Cranial Radiation in Childhood

PURPOSE To evaluate academic and behavioral outcome in radiated survivors of posterior fossa (PF) tumors. PATIENTS AND METHODS Fifty-three patients (36 males) treated for malignant PF tumors were seen for evaluation of academics and/or behavioral functioning. Forty-six patients were treated for medulloblastoma, and seven patients were treated for ependymoma. Fourteen patients were treated with reduced-dose cranial radiation, and 34 patients were treated with standard-dose cranial radiation (dose was not available for four patients). All patients received an additional boost to the PF. One patient was treated with PF radiation only. Standardized achievement tests and behavioral questionnaires were administered at different times after diagnosis for each child. First, the influence of demographic and medical variables on outcome was examined. Second, the rate of change in scores was determined using mixed model regression for patients seen for serial assessment. RESULTS The presence of hydrocephalus was related to poorer academics, but outcome was not related to radiation dose, extent of surgery, or treatment with chemotherapy. Younger age predicted poor reading ability and lower parent rating of academic achievement. Childrens performance declined for spelling, mathematics, and reading. Significant declines were also evident in parent and teachers ratings of academic ability. Behavioral functioning was generally not related to medical and demographic variables, and few clinically significant problems in externalizing behavior were evident. Increases in social and attention problems emerged over time. CONCLUSION Cranial radiation is associated with declines in academic ability, social skills, and attention. However, neither psychological distress nor behavior problems were a significant concern for this sample.

Neuropsychological sequelae of the treatment of children with medulloblastoma

SummaryWhen a malignant tumor invades the childs cerebellum, the cost of successful treatment is often significant cognitive morbidity. A review of neuropsychological outcome revealed that survivors of childhood medulloblastoma (MB) have long-term deficits in intelligence, memory, language, attention, academic skills, psychosocial function, and a compromised quality of life. These deficits varied with chronological age at tumor diagnosis and/or adjuvant treatment, type and duration of presenting symptoms, tumor extension beyond the cerebellum, a history of adjuvant radiation treatment, and time since treatment. The effects on neuropsychological outcome of other factors, such as post-surgical hydrocephalus, were less clear. To understand the interaction between two factors predictive of outcome, age at diagnosis and time since treatment, we analyzed IQ results for a new sample of 25 surgically-treated and radiated MB survivors, and found that age at diagnosis and time since treatment made separable contributions to intellectual morbidity. PIQ appeared to measure some general effects of diffuse cerebral insult because it varied with chronological age of the child at tumor diagnosis but was relatively constant in magnitude, once established. VIQ, in contrast, was somewhat less sensitive to age at diagnosis in treated MB survivors, but declined with time since treatment. These results are important for understanding the academic attainments and continuing rehabilitation needs of childhood MB survivors, because they suggest that these children progressively fail to assimilate new verbally-based knowledge at a developmentally-appropriate rate.

Comparison of Long-Term Neurocognitive Outcomes in Young Children With Acute Lymphoblastic Leukemia Treated With Cranial Radiation or High-Dose or Very High-Dose Intravenous Methotrexate

PURPOSE Cranial radiation therapy (CRT) is associated with neurocognitive morbidity in survivors of childhood acute lymphoblastic leukemia (ALL). For most patients, CRT has been replaced with intensified systemic and intrathecal chemotherapy, often including methotrexate (MTX). The impact of chemotherapy-only protocols on neurocognitive outcomes is unclear, and the importance of systemic MTX dose has not been established. PATIENTS AND METHODS Seventy nine of 120 eligible children diagnosed with high-risk ALL between the ages of 1.0 and 4.9 years participated in this retrospective cohort study. All patients were treated on a uniform chemotherapy protocol with one of three modalities of CNS prophylaxis, depending on their treatment era. In addition to intrathecal therapy, CNS-directed therapy consisted of CRT (18 Gy in 10 fractions) in 25 patients, high-dose intravenous (IV) MTX (8 g/m2 x 3 doses) in 32 patients and very high-dose IV MTX (33.6 g/m2 x 3 doses) in 22 patients. Participants completed tests of intelligence, academic achievement, attention, and memory. RESULTS Neurocognitive assessment was conducted at least 5 years after diagnosis (mean, 10.5 years, standard deviation, 2.7 years). No difference was detected on any neurocognitive measure between children treated with high-dose or very high-dose IV MTX. The combined MTX groups scored near the population mean on 17/18 measures. Children treated with CRT performed more poorly than the MTX group on most measures. CONCLUSION Treatment strategies for young children with ALL that avoid CRT are associated with good long-term neurocognitive outcomes. In this cohort, the dose of IV MTX did not influence these outcomes.

Impact of Craniospinal Dose, Boost Volume, and Neurologic Complications on Intellectual Outcome in Patients With Medulloblastoma

PURPOSE To examine the impact of radiation (ie, craniospinal irradiation [CSR] dose and boost volume) and complications (ie, hydrocephalus and other neurologic complications, including mutism) on patterns of change in intellectual functioning in medulloblastoma survivors. PATIENTS AND METHODS We conducted a retrospective review of 113 patients treated for medulloblastoma between 1983 and 2011 who were seen for neuropsychological assessment, including longitudinal follow-up of intellectual function. Patients were treated with either standard-dose CSR with a posterior fossa (PF) boost (n=51), standard-dose CSR plus tumor bed (TB) boost (n=9), reduced-dose CSR plus PF boost (n=28), or reduced-dose CSR plus TB boost (n=23), with or without chemotherapy. A subset of patients developed hydrocephalus that required cerebrospinal fluid (CSF) diversion (n=54) and/or other neurologic complications (n=40), more than half of which were postoperative mutism (n=25). Growth curve analysis was used to determine stability or change in intelligence scores over time. RESULTS Patients treated with reduced-dose CSR plus TB boost showed stable intellectual trajectories, whereas patients treated with higher doses and larger boost volumes experienced intellectual declines. Presence of complications was associated with worse intellectual outcome; however, hydrocephalus requiring CSF diversion and mutism differed in their pattern of decline. CONCLUSION These results improve our understanding of factors that impair intellectual outcome in patients treated for medulloblastoma. Lower doses of CSR and smaller boost volumes seem to mitigate intellectual decline. Our findings validate the use of TB boost and suggest PF boost should be reconsidered.

Early aging in adult survivors of childhood medulloblastoma: long-term neurocognitive, functional, and physical outcomes.

Treatment for medulloblastoma during childhood impairs neurocognitive function in survivors. While those diagnosed at younger ages are most vulnerable, little is known about the long-term neurocognitive, functional, and physical outcomes in survivors as they approach middle age. In this retrospective cohort study, we assessed 20 adults who were treated with surgery and radiotherapy for medulloblastoma during childhood (median age at assessment, 21.9 years [range, 18-47 years]; median time since diagnosis, 15.5 years [range, 6.5-42.2 years]). Nine patients also underwent chemotherapy. Cross-sectional analyses of current neurocognitive, functional, and physical status were conducted. Data from prior neuropsychological assessments were available for 18 subjects; longitudinal analyses were used to model individual change over time for those subjects. The group was well below average across multiple neurocognitive domains, and 90% had required accommodations at school for learning disorders. Longer time since diagnosis, but not age at diagnosis, was associated with continued decline in working memory, a common sign of aging. Younger age at diagnosis was associated with lower intelligence quotient and academic achievement scores, even many years after treatment had been completed. The most common health complications in survivors were hearing impairment, second cancers, diabetes, hypertension, and endocrine deficiencies. Adult survivors of childhood medulloblastoma exhibit signs of early aging regardless of how young they were at diagnosis. As survival rates for brain tumors continue to improve, these neurocognitive and physical sequelae may become evident in survivors diagnosed at different ages across the lifespan. It will become increasingly important to identify factors that contribute to risk and resilience in this growing population.

Long-term effects of transient cerebellar mutism after cerebellar astrocytoma or medulloblastoma tumor resection in childhood

BackgroundFollowing cerebellar tumor resection, some patients develop transient cerebellar mutism (TCM). Although the mutism resolves, it is not known whether there are long-term motor speech deficits in patients with TCM that are in excess of those in individuals with cerebellar tumors who had not developed postoperative TCM.MethodsLong-term survivors of cerebellar tumors resected in childhood who developed TCM were matched to survivors without TCM and to controls. Speech samples were formally analyzed by two speech pathologists.ResultsTumor survivors who had TCM had significantly more ataxic dysarthric speech and slower speech than either those without TCM or controls and were more dysfluent than controls. Tumor survivors without TCM did not differ from controls on ataxic dysarthria or speech rate.ConclusionsSurvivors who had TCM showed more speech deficits than controls or survivors without TCM. The data suggest that speech deficits are chronic if not permanent sequelae of TCM.

Longitudinal evaluation of neurocognitive function after treatment for central nervous system germ cell tumors in childhood.

Central nervous system germ cell tumors (CNS GCT) are typically localized to midline structures of the brain, including the pineal and suprasellar/pituitary regions. Management of these tumors depends on underlying histology (germinoma or nongerminomatous germ cell tumor). Knowledge about neurocognitive outcome in these patients is limited. Longitudinal neurocognitive outcome in CNS GCT patients seen for neuropsychological evaluation at a single institution was explored.

Neuromotor Speech Deficits in Children and Adults with Spina Bifida and Hydrocephalus

Acquired cerebellar lesions are associated with motor speech deficits. Spina bifida with hydrocephalus (SBH) is a neurodevelopmental disorder that involves significant dysmorphology of the cerebellum. Videotaped narratives produced by 40 children and adults with SBH and their 40 age-matched controls were coded for three motor speech deficits: dysfluency, ataxic dysarthria (articulatory inaccuracy, prosodic excess, and phonatory-prosodic insufficiency) (Brown, Darley, & Aronson, 1970; Darley, Aronson, & Brown, 1969a), and speech rate. Individuals with SBH had more motor speech deficits than controls. Dysfluency was related to an interaction between chronological age and SBH. Speech rate was related independently to chronological age and SBH. Ataxic dysarthria was related to the biology of SBH, and was associated with both physical phenotype (level of spinal cord lesion) and medical history (number of shunt revisions). The data show that developmental as well as acquired lesions of the cerebellum disrupt motor speech, and add to the developmental role of the cerebellum in the automatization of motor skills, including speech.

Long-term neurocognitive outcomes in young adult survivors of childhood acute lymphoblastic leukemia.

Five-year survival rates of childhood acute lymphoblastic leukemia (ALL) exceed 80% due to central nervous system-directed treatment including cranial radiation (CRT) and chemotherapy. However, these treatments are associated with neurocognitive compromise, the extent of which is correlated with higher dose and younger age at treatment. The aims of this study were to explore long-term neurocognitive outcomes in adult survivors of childhood ALL, and to identify measures sensitive to neurotoxicity in long-term survivors. We examined 24 adults who received 18 Gy CRT and chemotherapy for treatment of ALL between ages 2 and 15 years (median, 5.5). Time since diagnosis ranged from 6 to 26 years (median, 16.6). Younger age at diagnosis and longer time since diagnosis were associated with lower scores on a computerized battery that requires speed and accuracy across a number of domains (MicroCog), and other standardized neurocognitive tests. When compared with population norms, MicroCog indices were below average in survivors diagnosed with ALL before age 5, but only the reasoning/calculation index was below average in survivors diagnosed with ALL after age 5. In contrast, intelligence quotient (IQ) scores were average. In addition to confirming earlier studies showing that younger children are more vulnerable to treatment-related neurotoxicity, here we show that deficits exist many years post treatment even with a relatively lower dose of CRT, and that these deficits are especially evident on tasks involving rapid processing of information.