Elizabeth M. Wells

The cerebellar mutism syndrome and its relation to cerebellar cognitive function and the cerebellar cognitive affective disorder.

The postoperative cerebellar mutism syndrome (CMS), consisting of diminished speech output, hypotonia, ataxia, and emotional lability, occurs after surgery in up to 25% of patients with medulloblastoma and occasionally after removal of other posterior fossa tumors. Although the mutism is transient, speech rarely normalizes and the syndrome is associated with long-term adverse neurological, cognitive, and psychological sequelae. The clinical, neuroradiographic, and neuropsychological findings associated with CMS as well as possible mechanisms of injury are reviewed. Theories about the pathophysiology of CMS have evolved along with our understanding of the cerebellum as an important structure in the distributive neurocircuitry underlying complex speech, cognition, and behavior. CMS shares many similarities with the cerebellar cognitive affective syndrome, more commonly described in adults and consisting of disturbances of executive function, visuospatial skills, nonmotor language, and affect regulation. Future directions include more thorough neuropsychological characterization, functional and diffusion tensor imaging studies, and investigations into the underlying differences that may make some patients more vulnerable to CMS.

Patterns and severity of vincristine‐induced peripheral neuropathy in children with acute lymphoblastic leukemia

Vincristine, a critical component of combination chemotherapy treatment for pediatric acute lymphoblastic leukemia (ALL), can lead to vincristine‐induced peripheral neuropathy (VIPN). Longitudinal VIPN assessments were obtained over 12 months from newly diagnosed children with ALL (N = 128) aged 1–18 years who received vincristine at one of four academic childrens hospitals. VIPN assessments were obtained using the Total Neuropathy Score‐Pediatric Vincristine (TNS©‐PV), National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE©), Balis© grading scale, and Pediatric Neuropathic Pain Scale©–Five (PNPS©‐5). Of children who provided a full TNS©‐PV score, 85/109 (78%) developed VIPN (TNS©‐PV ≥4). Mean TNS©‐PV, grading scale, and pain scores were low. CTCAE©‐derived grades 3 and 4 sensory and motor VIPN occurred in 1.6%/0%, and 1.9%/0% of subjects, respectively. VIPN did not resolve in months 8–12 despite decreasing dose density. VIPN was worse in older children. Partition cluster analysis revealed 2–3 patient clusters; one cluster (n = 14) experienced severe VIPN. In this population, VIPN occurs more commonly than previous research suggests, persists throughout the first year of treatment, and can be severe.

Measuring vincristine-induced peripheral neuropathy in children with acute lymphoblastic leukemia

Background: Vincristine-induced peripheral neuropathy (VIPN) is difficult to quantify in children. Objective: The study objective was to examine the reliability, validity, and clinical feasibility of several VIPN measures for use in children with acute lymphoblastic leukemia. Interventions/Methods: Children (n = 65) aged 1 to 18 years receiving vincristine at 4 academic centers participated in the study. Baseline and pre–vincristine administration VIPN assessments were obtained using the Total Neuropathy Score–Pediatric Vincristine (TNS©-PV), the National Cancer Institute Common Terminology Criteria for Adverse Events, the Balis grading scale, and the FACES Pain Scale. The TNS-PV scores (n = 806) were obtained over 15 weeks. Blood was obtained at several time points to quantify pharmacokinetic parameters. Results: Cronbach’s &agr; for a reduced TNS-PV scale was .84. The TNS-PV scores correlated with cumulative vincristine dosage (r = 0.53, P = 0.01), pharmacokinetic parameters (r = 0.41, P = 0.05), and grading scale scores (r range = 0.46–0.52, P = .01). FACES scores correlated with the TNS-PV neuropathic pain item (r = 0.48; P = .01) and were attainable in all ages. A 2-item V-Rex score (vibration and reflex items) was the most responsive to change (effect size = 0.65, P < 0.001). The TNS-PV scores were attainable in 95% of children 6 years or older. Conclusions: The TNS-PV is reliable and valid for measuring VIPN. It is sensitive to change over time (15 weeks) and feasible for use in children 6 years or older. Implications for Practice: The TNS-PV may be a useful tool for assessing vincristine toxicity in children with acute lymphoblastic leukemia.

Clinical, Pathological, and Molecular Characterization of Infant Medulloblastomas Treated with Sequential High‐Dose Chemotherapy

High‐dose chemotherapy (HDC) strategies were developed to avoid unacceptable neurotoxicity associated with craniospinal irradiation in infants with embryonal brain tumors. However, the impact of molecular and pathological characterizations in such approaches and long‐term outcome have not been widely described in young children.

Treatment developments and the unfolding of the quality of life discussion in childhood medulloblastoma: a review

PurposeTo describe how the quality of life (QOL) discussion in childhood medulloblastoma (MB) relates to treatment developments, survival and sequelae from 1920 to 2014.MethodsArticles containing “childhood medulloblastoma” and “quality of life” were identified in PubMed. Those containing phrases pertaining to psychological, emotional, behavioral or social adjustment in the title, abstract or keywords were selected. Inclusion of relevant older publications was assured by cross-checking references.Results1920–1930s: suction, electro-surgery, kilovolt (KV) irradiation. Survival = months. Focus on operative mortality, symptoms and survival. 1940s: radiotherapy improved. 1950s: chemotherapy and intubation. Survival = years. Opinions oscillated between optimism/awareness of physical sequelae of radiotherapy. 1960s: magnified vision, ventriculo-peritoneal (VP) shunts, megavolt (MV) irradiation. Long-term survival shifted the attention towards neurological problems, disability and carcinogenesis of radiotherapy. 1970s: CT, microscope, bipolar coagulation, shunt filters, neuroanesthesia, chemotherapy trials and staging studies. Operative mortality decreased and many patients (re)entered school; emphasis on neuropsychological sequelae, IQ and academic performance. 1980s: magnetic resonance imaging (MRI), Cavitron ultrasonic aspiration (CUSA), laser surgery, hyper-fractionated radiotherapy (HFRT). Cerebellar mutism, psychological and social issues. 1990s: pediatric neurosurgery, proton beams, stem cell rescue. Reflections on QOL as such. 21st century: molecular genetics. Premature aging, patterns of decline, risk- and resilience factors.DiscussionQOL is a critical outcome measure. Focus depends on survival and sequelae, determined after years of follow-up. Detailed measurements are limited by time, money and human resources, and self-reporting questionnaires represent a crude measure limited by subjectivity. Therapeutic improvements raise the question of QOL versus cure. QOL is a potential primary research endpoint; multicenter international studies are needed, as are web-based tools that work across cultures.

Consensus paper on post-operative pediatric cerebellar mutism syndrome: the Iceland Delphi results

IntroductionConfusion has surrounded the description of post-operative mutism and associated morbidity in pediatric patients with cerebellar tumors for years. The heterogeneity of definitions and diagnostic features has hampered research progress within the field, and to date, no international guidelines exist on diagnosis, prevention, treatment, or follow-up of this debilitating condition. An international group of clinicians and researchers from multiple relevant disciplines recently formed a cohesive panel to formulate a new working definition and agree upon standardized methods for diagnosis and follow-up.MethodsConsensus was obtained using the modified nominal group technique, involving four rounds of online Delphi questionnaires interspersed with a structured consensus conference with lectures, group work, and open discussion sessions.ResultsA new, proposed definition of “post-operative pediatric CMS” was formed, preliminary recommendations for diagnostic and follow-up procedures were created, two working groups on a new scoring scale and risk prediction and prevention were established, and areas were identified where further information is needed.DiscussionThe consensus process was motivated by desire to further research and improve quality of life for pediatric brain tumor patients. The Delphi rounds identified relevant topics and established basic agreement, while face-to-face engagement helped resolve matters of conflict and refine terminology. The new definition is intended to provide a more solid foundation for future clinical and research work. It is thought as a consensus for moving forward and hopefully paves the way to developing a standard approach to this challenging problem with the advent of better scoring methods and ultimate goal of reducing the risk of CMS.

Pediatric Brain Tumors and Epilepsy

Seizures are a common complication of pediatric brain tumors and their treatment. This article reviews the epidemiology, evaluation, and treatment of seizures in children with brain tumors. Seizures in known brain tumor patients may signify tumor progression or recurrence, or treatment-related brain damage, as well as other causes, including low drug levels and metabolic disturbances. Careful selection of antiepileptic medications is needed in this population. There are advantages to nonenzyme-inducing antiepileptic drugs including valproic acid, which has potential antitumoral properties as a histone deacetylase inhibitor. Tumor surgery cures many cases of pediatric tumor-associated seizures, and some children are controlled with anti-epileptic medication, however additional epilepsy surgery may be needed for refractory cases.

Biologically targeted therapeutics in pediatric brain tumors.

Pediatric brain tumors are often difficult to cure and involve significant morbidity when treated with traditional treatment modalities, including neurosurgery, conventional chemotherapy, and radiotherapy. During the past two decades, a clearer understanding of tumorigenesis, molecular growth pathways, and immune mechanisms in the pathogenesis of cancer has opened up promising avenues for therapy. Pediatric clinical trials with novel biologic agents are underway to treat various pediatric brain tumors, including high and low grade gliomas and embryonal tumors. As the therapeutic potential of these agents undergoes evaluation, their toxicity profiles are also becoming better understood. These agents have potentially better central nervous system penetration and lower toxicity profiles compared with conventional chemotherapy. In infants and younger children, biologic agents may prove to be of equal or greater efficacy compared with traditional chemotherapy and radiation therapy, and may reduce the deleterious side effects of traditional therapeutics on the developing brain. Molecular pathways implicated in pediatric brain tumors, agents that target these pathways, and current clinical trials are reviewed. Associated neurologic toxicities will be discussed subsequently. Considerable work is needed to establish the efficacy of these agents alone and in combination, but pediatric neurologists should be aware of these agents and their rationale.

Paraneoplastic Neurologic Disorders in Children

Paraneoplastic neurologic syndromes are rare disorders that have potentially devastating effects on the developing brain. Recently, there has been increased interest in possible immunotherapy for these disorders. Recognition of paraneoplastic syndromes in children may lead to early detection and treatment of the pediatric cancer and may diminish the neurologic damage that is the major source of morbidity in children with successfully treated tumors. This article reviews the presenting symptoms, immunology, long-term sequelae, and management options for paraneoplastic neurologic syndromes, focusing on those most commonly reported in children: opsoclonus-myoclonus ataxia, limbic encephalitis, and anti-NMDAR encephalitis. The child neurologist plays an important role in recognizing these disorders, initiating a tumor search, and directing ongoing treatment and management of neurologic symptoms after oncologic treatment is complete. Given the rarity of these conditions, multisite collaborative efforts are needed to develop standardized approaches to characterization and treatment.

Long-term neurologic health and psychosocial function of adult survivors of childhood medulloblastoma/PNET: a report from the Childhood Cancer Survivor Study.

Background Medulloblastoma is the most common malignant childhood brain tumor, although long-term risks for chronic neurologic health and psychosocial functioning in aging adult survivors are incompletely characterized. Methods The Childhood Cancer Survivor Study (CCSS) includes 380 five-year survivors of medulloblastoma/primitive neuroectodermal tumor (PNET; median age at follow-up: 30 y, interquartile range 24-36) and sibling comparison (n = 4031). Cumulative incidence of neurologic health conditions was reported. Cox regression models provided hazard ratios (HRs) and 95% CIs. Cross-sectional outcomes were assessed using generalized linear models. Results Compared with siblings, survivors were at increased risk of late-onset hearing loss (HR: 36.0, 95% CI: 23.6-54.9), stroke (HR: 33.9, 95% CI: 17.8-64.7), seizure (HR: 12.8, 95% CI: 9.0-18.1), poor balance (HR: 10.4, 95% CI: 6.7-15.9), tinnitus (HR: 4.8, 95% CI: 3.5-6.8), and cataracts (HR: 31.8, 95% CI: 16.7-60.5). Temporal/frontal lobe radiotherapy of 50 Gy or more increased risk for hearing loss (HR: 1.9, 95% CI: 1.1-1.3), seizure (HR: 2.1, 95% CI: 1.1-3.9), stroke (HR: 3.5, 95% CI: 1.3-9.1), and tinnitus (HR: 2.0, 95% CI: 1.0-3.9). Survivors were less likely than siblings to earn a college degree (relative risk [RR]: 0.49, 95% CI: 0.39-0.60), marry (RR: 0.35, 95% CI: 0.29-0.42), and live independently (RR: 0.58, 95% CI: 0.52-0.66). Conclusions Adult survivors of childhood medulloblastoma/PNET demonstrate pronounced risk for hearing impairment, stroke, lower educational attainment, and social independence. Interventions to support survivors should be a high priority.