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Cerebellar mutism syndrome is a disorder of speech, movement and affect that can occur after tumour removal from the posterior fossa. Projections from the fastigial nuclei to the periaqueductal grey area were recently implicated in its pathogenesis, but the functional consequences of damaging these projections remain poorly understood. Here, we examine functional MRI data from patients treated for medulloblastoma to identify functional changes in key brain areas that comprise the motor system for speech, which occur along the timeline of acute speech impairment in cerebellar mutism syndrome. One hundred and twenty-four participants, all with medulloblastoma, contributed to the study: 45 with cerebellar mutism syndrome, 11 patients with severe postoperative deficits other than mutism, and 68 without either (asymptomatic). We first performed a data-driven parcellation to spatially define functional nodes relevant to the cohort that align with brain regions critical for the motor control of speech. We then estimated functional connectivity between these nodes during the initial postoperative imaging sessions to identify functional deficits associated with the acute phase of the disorder. We further analysed how functional connectivity changed over time within a subset of participants that had suitable imaging acquired over the course of recovery. Signal dispersion was also measured in the periaqueductal grey area and red nuclei to estimate activity in midbrain regions considered key targets of the cerebellum with suspected involvement in cerebellar mutism pathogenesis. We found evidence of periaqueductal grey dysfunction in the acute phase of the disorder, with abnormal volatility and desynchronization with neocortical language nodes. Functional connectivity with periaqueductal grey was restored in imaging sessions that occurred after speech recovery and was further shown to be increased with left dorsolateral prefrontal cortex. The amygdalae were also broadly hyperconnected with neocortical nodes in the acute phase. Stable connectivity differences between groups were broadly present throughout the cerebrum, and one of the most substantial differences-between Broca's area and the supplementary motor area-was found to be inversely related to cerebellar outflow pathway damage in the mutism group. These results reveal systemic changes in the speech motor system of patients with mutism, centred on limbic areas tasked with the control of phonation. These findings provide further support for the hypothesis that periaqueductal grey dysfunction (following cerebellar surgical injury) contributes to the transient postoperative non-verbal episode commonly observed in cerebellar mutism syndrome but highlights a potential role of intact cerebellocortical projections in chronic features of the disorder.
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Enfermedades Cerebelosas , Neoplasias Cerebelosas , Meduloblastoma , Mutismo , Humanos , Meduloblastoma/cirugía , Meduloblastoma/patología , Habla , Mutismo/etiología , Mutismo/patología , Neoplasias Cerebelosas/patología , Cerebelo/patología , Enfermedades Cerebelosas/complicaciones , Mesencéfalo , Complicaciones PosoperatoriasRESUMEN
OBJECTIVE: Sickle cell disease (SCD) is an inherited blood disorder associated with neurocognitive deficits. In contrast to variable-centered approaches, no known research has utilized person-centered strategies to identify multidimensional patterns of neurocognitive functioning of an individual with SCD. The purpose of the present study was to create empirically derived profiles and identify predictors of neurocognitive functioning subgroups among youth and young adults with SCD. METHODS: Individuals with SCD (N = 393, mean age 14.05 years, age range 8-24, 50.4% female/49.6% male) completed neurocognitive assessments. Latent profile analysis derived subgroups/classes of neurocognitive functioning and determined relations with demographic and medical variables. RESULTS: Three latent classes emerged: average functioning (n = 102, 27%), low average functioning (n = 225, 60%), and exceptionally low functioning (n = 46, 12%). Older age was associated with membership in the low average and exceptionally low functioning groups (relative to the average group). Being prescribed hydroxyurea was associated with membership in the average functioning group (relative to the low average group) and absence of hydroxyurea use was associated with membership in the exceptionally low group (relative to the low average group). Lower social vulnerability was associated with membership in the average functioning group compared to the low average and exceptionally low groups. CONCLUSIONS: Clinicians can help reduce disparities in cognitive development for individuals with SCD by promoting early treatment with hydroxyurea and implementing methods to reduce social vulnerabilities that can interfere with access to evidence-based care.
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Background: Telehealth is an emerging method which may overcome barriers to rehabilitation access for pediatric cancer survivors (aged ≤19 years). This systematic review aimed to examine telehealth-based rehabilitation interventions aimed at preventing, maintaining, or improving disability in pediatric cancer survivors. Methods: We performed systematic searches in Ovid MEDLINE, Ovid EMBASE, Cochrane Library, SCOPUS, Web of Science, and CINAHL Plus between 1994 and 2022. Eligible studies included telehealth-based interventions assessing disability outcomes in pediatric cancers. Results: Database searches identified 4,040 records. Nine unique interventions met the eligibility criteria. Telehealth delivery methods included telephone (n = 6), email (n = 3), mobile health applications (n = 3), social media (n = 3), videoconferencing (n = 2), text messaging (n = 2), active video gaming (n = 2), and websites (n = 2). Interventions focused on physical activity (n = 8) or self-management (n = 1). Outcomes assessing disability varied (n = 6). Three studies reported statistically and clinically significant results. Narrative synthesis of findings was constructed based on the Picker's principles for patient-centered care: (1) values, preferences, and needs; (2) involve family and friends; (3) coordination of care; (4) provide social support; (5) holistic well-being; and (6) information and communication. Conclusions: Telehealth-based rehabilitation interventions for pediatric cancer survivors is an emerging research area with potential to improve disability outcomes. Adequately powered trials with consistency in disability outcome measures are warranted. Additional research is needed to determine the effectiveness and best practices for telehealth-based pediatric cancer rehabilitation.
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Personas con Discapacidad , Aplicaciones Móviles , Neoplasias , Automanejo , Telemedicina , Niño , Humanos , Telemedicina/métodos , Evaluación de Resultado en la Atención de SaludRESUMEN
IMPORTANCE: Individuals with sickle cell disease (SCD) are at heightened risk of poor neurocognitive and academic outcomes. The relationship between fine motor skills and academic outcomes is not well understood. OBJECTIVE: To compare the fine motor skills of individuals with SCD with normative expectations, test whether demographic and medical factors are associated with fine motor performance, and determine the impact of fine motor performance on academic performance. DESIGN: Cross-sectional. SETTING: St. Jude Children's Research Hospital. PARTICIPANTS: Individuals with SCD (N = 376; ages 8-24 yr). OUTCOMES AND MEASURES: Fine motor outcomes included visual-motor integration, manual dexterity, and graphomotor speed. Academic outcomes included math fluency and word reading. Demographic and medical variables were obtained via medical records and interviews. RESULTS: Compared with normative expectations, the performance of individuals with SCD on all fine motor measures was lower than expected. Male sex, lower socioeconomic status, and lower oxygen saturation was associated with slower graphomotor speed. Lower socioeconomic status and older age were associated with lower visual-motor integration scores. Performance on all fine motor measures was positively associated with math fluency and word reading. CONCLUSIONS AND RELEVANCE: Individuals with SCD exhibited poorer than expected fine motor skills across multiple motor domains, and these deficits were associated with poorer academic outcomes. Early referral to intervention services for fine motor skills may facilitate improved academic outcomes for individuals with SCD. Plain-Language Summary: This study had three objectives: (1) Compare the fine motor skills of people with sickle cell disease (SCD) with normative expectations, (2) test whether demographic and medical factors are associated with fine motor performance, and (3) determine the impact of fine motor performance on academic performance. We found that SCD is a risk factor for lower than expected fine motor performance across multiple fine motor domains and that these deficits also affect functional academic skills.
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Anemia de Células Falciformes , Destreza Motora , Humanos , Anemia de Células Falciformes/fisiopatología , Masculino , Femenino , Adolescente , Estudios Transversales , Niño , Adulto Joven , Rendimiento Académico , Factores de Edad , Factores SexualesRESUMEN
BACKGROUND: Sickle cell disease (SCD) is associated with poor neurocognitive outcomes due to biomedical and psychosocial factors. The aims of this study were to investigate associations between household and neighborhood socioeconomic status (SES) with cognitive and academic outcomes in SCD and to determine if these relationships were modified by sickle genotype, fetal hemoglobin, or age. PROCEDURE: We prospectively recruited patients to complete a battery of neurocognitive and academic measures. Household SES was measured using the Barratt Simplified Measure of Social Status, a composite index of parent education and occupation. The Social Vulnerability Index was used to classify individuals based on social vulnerabilities at the neighborhood level. RESULTS: Overall, 299 patients between the ages of 4 and 18 (mean = 11.4, standard deviation = 4.3) years diagnosed with SCD (57% SS/SB0 -thalassemia) completed testing. Stepwise multivariate models demonstrated that patients with low social vulnerability (i.e., high SES) at the neighborhood level displayed intelligence and math scores that were 4.70 and 7.64 points higher than those living in areas with moderate social vulnerability, respectively (p < .05). Reading performance did not differ based on neighborhood SES; however, the effect of neighborhood SES was dependent on age, such that older participants living in neighborhoods with moderate or high levels of social vulnerability displayed poorer reading scores than those with low social vulnerability (p < .05). CONCLUSIONS: This study identified patients with SCD at higher risk of poor academic performance based on SES. Interventions addressing academic difficulties should be offered to all children with SCD, but should be emergently offered to this subpopulation.
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Rendimiento Académico , Anemia de Células Falciformes , Niño , Humanos , Preescolar , Adolescente , Determinantes Sociales de la Salud , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/psicología , Clase SocialRESUMEN
INTRODUCTION: Up to 34% of patients with medulloblastoma develop posterior fossa syndrome (PFS) following brain tumor resection and have increased risk of long-term neurocognitive impairments. Lack of agreement in conceptualization and diagnosis of PFS calls for improvements in diagnostic methods. The current study aimed to describe psychometric properties of a new posterior fossa syndrome questionnaire (PFSQ). METHODS: The PFSQ was informed by prior research and developed by a multidisciplinary team with subject matter expertise. Participants (N = 164; 63.4% Male; 78.7% White; Mage at diagnosis = 10.38 years, SD = 5.09, range 3-31 years) included patients with newly diagnosed medulloblastoma enrolled in the SJMB12 clinical trial. Forty-four patients (26.8%) were classified as having PFS based on attending physician's post-surgical yes/no report. A PFSQ was completed by a neurologist within 2 weeks of coming to St. Jude Children's Research Hospital for adjuvant treatment, irrespective of suspicion for PFS. RESULTS: PFSQ items ataxia (100.00%), dysmetria (95.45%), and speech/language changes (79.55%) were most sensitive. However, ataxia (26.50%) and dysmetria (46.61%) demonstrated low specificity. Speech/language changes (81.36%), mutism (95.76%), orofacial apraxia (98.29%) and irritability (96.61%) had high specificity. A principal component analysis found four components: (1) speech/language changes, (2) apraxias (including mutism), (3) motor/oromotor, and (4) emotional lability. CONCLUSIONS: The PFSQ is a dimensional diagnostic approach that can be used to improve diagnostic consistency across clinical and research groups to help accelerate understanding of PFS etiology, identify surgical correlates of risk, predict long-term impairments, and develop targeted interventions. Additional measure validation, including correlation with symptom resolution, is required.
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Ataxia Cerebelosa , Neoplasias Cerebelosas , Meduloblastoma , Mutismo , Adolescente , Adulto , Ataxia , Ataxia Cerebelosa/complicaciones , Neoplasias Cerebelosas/cirugía , Niño , Preescolar , Femenino , Humanos , Masculino , Meduloblastoma/cirugía , Mutismo/etiología , Complicaciones Posoperatorias/etiología , Encuestas y Cuestionarios , Adulto JovenRESUMEN
BACKGROUND: Transcranial doppler (TCD) ultrasonography can be used to identify stroke risk in children with sickle cell anemia. Previous studies have reported mixed findings on neurocognitive outcomes in children with elevated TCD. This study examined associations between TCD velocity and neurocognitive outcomes in children and adolescents without prior history of stroke. PROCEDURE: Participants were selected from the Sickle Cell Clinical Research Intervention Program cohort. The highest recorded mean maximum TCD velocity was selected for analysis, along with participant's most recent data from serial neurocognitive surveillance. RESULTS: A total of 200 children with sickle cell anemia completed neurocognitive testing (109 males, 91 females; mean age 12.7 years [SD = 3.56]). Most participants were prescribed hydroxyurea (72%) at the time of neurocognitive testing and nearly 16% had a history of chronic transfusions prior to neurocognitive evaluation. Mean age at time of highest TCD value was 6.6 years (SD = 2.5) and 13.5% of screenings were abnormal (≥200 cm/s). Mean interval between TCD and most recent neurocognitive evaluation was 6.1 years (±3.5). There were no significant differences in the interval between TCD and neurocognitive testing across normal, conditional, and abnormal groups. Maximum TCD velocity was not significantly associated with neurocognitive outcomes in multivariate models. CONCLUSIONS: History of elevated TCD in the absence of overt stroke should not be considered a risk factor for poor neurocognitive outcomes in children and adolescents with sickle cell anemia on modern disease-modifying therapy.
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Anemia de Células Falciformes , Accidente Cerebrovascular , Adolescente , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/diagnóstico por imagen , Anemia de Células Falciformes/tratamiento farmacológico , Velocidad del Flujo Sanguíneo , Transfusión Sanguínea , Niño , Femenino , Humanos , Hidroxiurea/uso terapéutico , Masculino , Accidente Cerebrovascular/complicaciones , Accidente Cerebrovascular/etiología , Ultrasonografía Doppler TranscranealRESUMEN
OBJECTIVE: Risk for neurocognitive deficits in sickle cell disease (SCD) is well established, yet minimal research has evaluated the risk for deficits in adaptive functioning. We assessed adaptive functioning in pediatric patients with SCD to test the hypothesis that disease, treatment, and demographic factors were associated with adaptive outcomes. METHODS: Two hundred fifty-six patients (57% HbSS/HbSß0-thalassemia and 43% HbSC/HbSß+-thalassemia), ages 8-18, received routine neuropsychological assessments as part of a larger prospective lifetime cohort study. Adaptive functioning was measured using the Behavior Assessment System for Children, Second or Third Edition. Adaptive scores were compared with normative values using t-test or Wilcoxon signed rank test and linear regression models were used to measure associations between adaptive functioning and age, hydroxyurea (HU) use, sickle genotype, and socioeconomic status. Furthermore, we examined the influence of intellectual and executive functioning on adaptive behavior using hierarchical linear regression analyses. RESULTS: Parent ratings of adaptive functioning skills did not differ from normative expectations (all false discovery rate [FDR] adjusted p-value [pFDR] > 0.05). Social vulnerability was negatively associated with adaptive scores on most adaptive scales in both genotypes (pFDR < 0.05). HU treatment was not significantly associated with any adaptive scale. Overall IQ was positively associated with Functional Communication and Leadership only for those with HbSS/HbSß0-thalassemia. Higher parent ratings of executive difficulties were correlated with lower adaptive scores (estimate = -0.64, standard error = 0.051, p < .001). CONCLUSIONS: Poorer parent-rated adaptive skills were associated with increased social vulnerability, lower Full-Scale IQ, and parent-rated executive difficulties. Most adaptive scores were in the normal range; however, parent ratings may not fully capture the impact of disease complications and neurocognitive deficits on daily functioning.
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Anemia de Células Falciformes , Función Ejecutiva , Adolescente , Anemia de Células Falciformes/psicología , Niño , Estudios de Cohortes , Función Ejecutiva/fisiología , Hemoglobina Falciforme , Humanos , Estudios ProspectivosRESUMEN
Neurocognitive impairment is common in sickle cell disease (SCD) and is associated with significant functional limitations. In a cross-sectional analysis, we examined the association between hydroxyurea (HU) treatment and neurocognitive functioning from school-age to young adulthood in individuals with SCD. A total of 215 patients with HbSS/HbSß0 -thalassaemia (71% HU treated) and 149 patients with HbSC/HbSß+ -thalassaemia (20% HU treated) completed neurocognitive measures at one of four developmental stages: school-age (age 8-9 years), early adolescence (age 12-13 years), late adolescence (age 16-17 years) and young adulthood (ages 19-24 years). For participants with multiple assessments, only the most recent evaluation was included. In multivariable analysis adjusted for social vulnerability, HU treatment and sex, older age was associated with a reduction in overall intelligence quotient (IQ) of 0·55 points per year of life [standard error (SE) = 0·18, false discovery rate adjusted P value (PFDR) = 0.01] for patients with HbSS/HbSß0 -thalassaemia. Earlier initiation of HU (n = 152) in HbSS/HbSß0 -thalassaemia was associated with higher scores on neurocognitive measures across most domains, including IQ [estimate (SE) 0·77 (0·25)/year, PFDR = 0·01], after adjusting for social vulnerability, sex and treatment duration. These results support the early use of HU to limit the detrimental neurocognitive effects of SCD, while highlighting the need for additional measures to further mitigate neurocognitive deterioration.
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Anemia de Células Falciformes/tratamiento farmacológico , Antidrepanocíticos/efectos adversos , Hidroxiurea/efectos adversos , Trastornos Neurocognitivos/prevención & control , Adolescente , Factores de Edad , Anemia de Células Falciformes/complicaciones , Antidrepanocíticos/administración & dosificación , Antidrepanocíticos/uso terapéutico , Estudios de Casos y Controles , Niño , Estudios Transversales , Femenino , Hemoglobina Fetal/análisis , Hemoglobina Falciforme , Humanos , Hidroxiurea/administración & dosificación , Hidroxiurea/uso terapéutico , Masculino , Trastornos Neurocognitivos/diagnóstico , Trastornos Neurocognitivos/etiología , Vulnerabilidad Social , Talasemia/complicaciones , Adulto JovenRESUMEN
Objective: Sickle cell disease (SCD) is an inherited hematologic disorder that impacts approximately 100,000 Americans. This disease is associated with progressive organ damage, cerebral vascular accident, and neurocognitive deficits. Recent guidelines from the American Society of Hematology (ASH) recommend cognitive screening with a psychologist to help manage cerebrovascular risk and cognitive impairment in this population. SCD patients benefit from neuropsychology services and several institutions already have programs in place to monitor cognitive risk. Program Description: We describe a longitudinal neurocognitive evaluation program at our institution that serves all patients with SCD, regardless of disease severity or referral question. The Sickle Cell Assessment of Neurocognitive Skills (SCANS) program was established in 2012. We outline the program's theoretical framework, timepoints for evaluation, test battery, logistics, patient demographics, integration with research programming, and multidisciplinary collaboration to support optimal outcomes. Program Outcomes: Our program has provided 716 targeted neuropsychological evaluations for patients over the last decade. Nearly 26% of patients in the program have been followed longitudinally. The most common diagnoses generated across cross-sectional and longitudinal evaluations include cognitive disorder (n = 191), attention-deficit/hyperactivity disorder (n = 75), and specific learning disorder (n = 75). Approximately 87% of patients who participated in SCANS during late adolescence successfully transitioned from pediatric to adult care. Conclusion: We discuss considerations for developing programming to meet the needs of this population, including tiered assessment models, timing of evaluations, scope, and reimbursement. Program models that utilize prevention-based tiered models or targeted evaluations can assist with serving large volumes of patients.
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PURPOSE: Neurocognitive impairment is a common and debilitating complication of sickle cell disease (SCD) resulting from a combination of biological and environmental factors. The catechol-O-methyltransferase (COMT) gene modulates levels of dopamine availability in the prefrontal cortex. COMT has repeatedly been implicated in the perception of pain stimuli and frequency of pain crises in patients with SCD and is known to be associated with neurocognitive functioning in the general population. The current study aimed to examine the associations of genetic variants in COMT and neurocognitive functioning in patients with SCD. PATIENTS AND METHODS: The Sickle Cell Clinical Research and Intervention Program (SCCRIP) longitudinal cohort was used as a discovery cohort (n = 166). The genotypes for 5 SNPs (rs6269, rs4633, rs4818, rs4680, and rs165599) in COMT were extracted from whole genome sequencing data and analyzed using a dominant model. A polygenic score for COMT (PGSCOMT) integrating these 5 SNPs was analyzed as a continuous variable. The Cooperative Study of Sickle Cell Disease (CSSCD, n = 156) and the Silent Cerebral Infarction Transfusion (SIT, n = 114) Trial were used as 2 independent replication cohorts. Due to previously reported sex differences, all analyses were conducted separately in males and females. The Benjamini and Hochberg approach was used to calculate false discovery rate adjusted p-value (q-value). RESULTS: In SCCRIP, 1 out of 5 SNPs (rs165599) was associated with IQ at q<0.05 in males but not females, and 2 other SNPs (rs4633 and rs4680) were marginally associated with sustained attention at p<0.05 in males only but did not maintain at q<0.05. PGSCOMT was negatively associated with IQ and sustained attention at p<0.05 in males only. Using 3 cohorts' data, 4 out of 5 SNPs (rs6269, rs4633, rs4680, rs165599) were associated with IQ (minimum q-value = 0.0036) at q<0.05 among male participants but not female participants. The PGSCOMT was negatively associated with IQ performance among males but not females across all cohorts. CONCLUSION: Select COMT SNPs are associated with neurocognitive abilities in males with SCD. By identifying genetic predictors of neurocognitive performance in SCD, it may be possible to risk-stratify patients from a young age to guide implementation of early interventions.
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Anemia de Células Falciformes , Catecol O-Metiltransferasa , Polimorfismo de Nucleótido Simple , Humanos , Catecol O-Metiltransferasa/genética , Anemia de Células Falciformes/genética , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/psicología , Masculino , Femenino , Adulto , Adulto Joven , Estudios Longitudinales , Adolescente , Genotipo , Cognición/fisiología , Persona de Mediana EdadRESUMEN
BACKGROUND: Cerebellar mutism syndrome (CMS) is characterized by deficits of speech, movement, and affect that can occur following tumor removal from the posterior fossa. The role of cerebro-cerebellar tract injuries in the etiology of CMS remains unclear, with recent studies suggesting that cerebro-cerebellar dysfunction may be related to chronic, rather than transient, symptomatology. METHODS: We measured functional connectivity between the cerebellar cortex and functional nodes throughout the brain using fMRI acquired after tumor removal but prior to adjuvant therapy in a cohort of 70 patients diagnosed with medulloblastoma. Surgical lesions were mapped to the infratentorial anatomy, and connectivity with cerebral cortex was tested for statistical dependence on extent of cerebellar outflow pathway injury. RESULTS: CMS diagnosis was associated with an increase in connectivity between the right cerebellar and left cerebral hemisphere, maximally between cerebellum and ventromedial prefrontal cortex (VM-PFC). Connectivity dependence on cerebellar outflow was significant for some speech nodes but not for VM-PFC, suggesting altered input to the cerebellum. Connectivity between posterior regions of cerebellar cortex and ipsilateral dentate nuclei was abnormal in CMS participants, maximally within the right cerebellar hemisphere. CONCLUSIONS: The functional abnormalities we identified are notably upstream of where causal surgical injury is thought to occur, indicating a secondary phenomenon. The VM-PFC is involved in several functions that may be relevant to the symptomatology of CMS, including emotional control and motor learning. We hypothesize that these abnormalities may reflect maladaptive learning within the cerebellum consequent to disordered motor and limbic function by the periaqueductal gray and other critical midbrain targets.
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Neoplasias Cerebelosas , Cerebelo , Imagen por Resonancia Magnética , Mutismo , Humanos , Masculino , Mutismo/etiología , Mutismo/fisiopatología , Femenino , Niño , Adolescente , Neoplasias Cerebelosas/patología , Cerebelo/patología , Cerebelo/fisiopatología , Cerebelo/diagnóstico por imagen , Adulto , Adulto Joven , Meduloblastoma/patología , Preescolar , Corteza Cerebral/patología , Corteza Cerebral/diagnóstico por imagen , Corteza Cerebral/fisiopatología , Vías Nerviosas/fisiopatología , Estudios de SeguimientoRESUMEN
BACKGROUND: Pediatric postoperative cerebellar mutism syndrome (CMS) is a rare but well-known complication of medulloblastoma (Mb) resection with devastating effects on expressive language, mobility, cognition, and emotional regulation that diminishes quality of life for many Mb survivors. The specific anatomical and neuronal basis of CMS remains obscure. We address this issue by identifying patterns of surgical damage and secondary axonal degeneration in Mb survivors with CMS. METHODS: Children with Mb deemed high risk for CMS based on intraventricular location of the tumor had T1 images analyzed for location(s) of surgical damage using a specially developed algorithm. We used three complementary methods of spatial analysis to identify surgical damage linked to CMS diagnosis. Magnetization transfer ratio (MTR) images were analyzed for evidence of demyelination in anatomic regions downstream of the cerebellum, indicating neuronal dysfunction. RESULTS: Spatial analyses highlighted damage to the fastigial nuclei and their associated cerebellar cortices as the strongest predictors of CMS. CMS-related MTR decrease was greatest in the ventral periaqueductal gray (PAG) area and highly consistent in the left red nucleus. CONCLUSION: Our evidence points to disruption of output from the fastigial nuclei as a likely causal trigger for CMS. We propose that core CMS symptoms result from a disruption in the triggering of survival behaviors regulated by the PAG, including the gating of vocalization and volitional movement. The fastigial nuclei provide the densest output to the PAG from the cerebellum, thus sparing these structures may provide a greater likelihood of CMS prevention.
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Enfermedades Cerebelosas , Neoplasias Cerebelosas , Meduloblastoma , Mutismo , Niño , Humanos , Sustancia Gris Periacueductal/patología , Mutismo/etiología , Calidad de Vida , Complicaciones Posoperatorias , Enfermedades Cerebelosas/complicaciones , Enfermedades Cerebelosas/diagnóstico , Meduloblastoma/patología , Neoplasias Cerebelosas/cirugía , Neoplasias Cerebelosas/complicacionesRESUMEN
Although Sturge-Weber (SWS) syndrome is associated with behavioral and academic problems in childhood, it is unknown whether those problems are concomitants of the disorder itself or of the seizure disorder that is common in SWS. We compared two groups of children with SWS-- one with seizures (n=20) and one without seizures (n=14)--on parent-report and teacher-report measures of behavioral and academic functioning. The two subgroups were compared with each other as well as with children with epilepsy alone (n=29) and a group of healthy controls (n=21). The SWS group with seizures was more impaired than the seizure-free group on 9 of 15 measures and the children with seizures were 10 times as likely to have received special education services. Overall, children with SWS and seizures were similar to the epilepsy group, whereas children with SWS and no seizures were similar to the controls.
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Trastornos de la Conducta Infantil/etiología , Trastornos del Conocimiento/etiología , Convulsiones/complicaciones , Síndrome de Sturge-Weber/complicaciones , Adolescente , Análisis de Varianza , Niño , Escolaridad , Femenino , Humanos , Masculino , Pruebas Neuropsicológicas , Padres/psicología , Inventario de Personalidad , Escalas de Valoración Psiquiátrica , Convulsiones/psicología , Conducta Social , Estadísticas no Paramétricas , Síndrome de Sturge-Weber/psicologíaRESUMEN
PURPOSE OF THE STUDY: Fetal hemoglobin (HbF) is a modifier of the clinical and hematologic phenotype of sickle cell anemia (SCA). Three quantitative trait loci (QTL) modulate HbF expression. The neurocognitive effects of variants in these QTL have yet to be explored. We evaluated the relation between 11 SNPs in the three HbF QTL: BCL11A, MYB, the HBB gene cluster, and full-scale intelligence (IQ) in SCA. PATIENTS AND METHODS: The prospective longitudinal cohort study, Sickle Cell Clinical Research and Intervention Program, was used as a discovery cohort (n = 166). The genotypes for 11 SNPs were extracted through whole genome sequencing and were analyzed using an additive model. A polygenic score for HbF (PGSHbF) integrating the numbers of low HbF alleles from 11 SNPs was analyzed as a continuous variable. The Cooperative Study of Sickle Cell Disease (n = 156) and the Silent Cerebral Infarction Transfusion (n = 114) Trial were used as two independent replication cohorts. Benjamini and Hochberg approach was used to calculate false discovery rate adjusted p-value (pFDR). RESULTS: HbF was positively associated with IQ (minimum raw p = 0·0018) at pFDR<0·05. HbF mediated the relationship between two BCL11A SNPs, rs1427407 and rs7606173, HBS1L-MYB: rs9494142, and PGSHbF with IQ (minimum raw p = 0·0035) at pFDR<0·05. CONCLUSION: As the major modulator of the severity of SCA, HbF also influences neurocognition, which is done through mediation of its QTL. These findings have implications for early identification of neurocognitive risk and targeted intervention.
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Anemia de Células Falciformes , Hemoglobina Fetal , Anemia de Células Falciformes/complicaciones , Anemia de Células Falciformes/genética , Hemoglobina Fetal/análisis , Hemoglobina Fetal/genética , Hemoglobina Fetal/metabolismo , Humanos , Estudios Longitudinales , Estudios Prospectivos , Proteínas Represoras/genéticaRESUMEN
BACKGROUND: Posterior fossa syndrome (PFS) is a known consequence of medulloblastoma resection. Our aim was to clinically define PFS, its evolution over time, and ascertain risk factors for its development and poor recovery. METHODS: Children with medulloblastoma treated at St Jude Children's Research Hospital from 6/2013 to 7/2019 received standardized neurological examinations, before and periodically after radiation therapy. Most (98.3%) were enrolled on the ongoing multi-institutional protocol (SJMB12; NCT01878617). RESULTS: Sixty (34%) of 178 evaluated children had PFS. Forty (23%) had complete mutism (PFS1) and 20 (11%) had diminished speech (PFS2). All children with PFS had severe ataxia and 42.5% of PFS1 had movement disorders. By multivariable analysis, younger age (P = .0005) and surgery in a low-volume surgery center (P = .0146) increased PFS risk, while Sonic Hedgehog tumors had reduced risk (P = .0025). Speech and gait returned in PFS1/PFS2 children at a median of 2.3/0.7 and 2.1/1.5 months, respectively, however, 12 (44.4%) of 27 PFS1 children with 12 months of follow-up were nonambulatory at 1 year. Movement disorder (P = .037) and high ataxia score (P < .0001) were associated with delayed speech recovery. Older age (P = .0147) and high ataxia score (P < .0001) were associated with delayed gait return. Symptoms improved in all children but no child with PFS had normal neurologic examination at a median of 23 months after surgery. CONCLUSIONS: Categorizing PFS into types 1 and 2 has prognostic relevance. Almost half of the children with PFS1 with 12-month follow-up were nonambulatory. Surgical experience was a major modifiable contributor to the development of PFS.
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Neoplasias Cerebelosas , Meduloblastoma , Mutismo , Anciano , Neoplasias Cerebelosas/cirugía , Niño , Proteínas Hedgehog , Humanos , Meduloblastoma/cirugía , Complicaciones Posoperatorias/epidemiología , Complicaciones Posoperatorias/etiología , Periodo Posoperatorio , Estudios Prospectivos , Factores de RiesgoRESUMEN
BACKGROUND: Despite recent efforts, disagreement remains among frontline clinicians regarding the operational definition of a syndrome commonly referred to as posterior fossa syndrome or cerebellar mutism syndrome. METHODS: We surveyed experts in the clinical care of children with posterior fossa tumors to identify trends and discrepancies in diagnosing posterior fossa syndrome. RESULTS: All surveyed professionals conceptualized posterior fossa syndrome as a spectrum diagnosis. The majority agreed that mutism is the most important symptom for diagnosis. However, results highlighted ongoing discrepancies related to important features of posterior fossa syndrome. CONCLUSIONS: Greater posterior fossa syndrome conceptual alignment among providers is needed to formulate specific diagnostic criteria that would further research and clinical care. The authors propose preliminary diagnostic criteria for posterior fossa syndrome that require refinement through careful clinical characterization and targeted empirical investigation.
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Enfermedades Cerebelosas/diagnóstico , Neoplasias Infratentoriales/diagnóstico , Mutismo/diagnóstico , Adulto , Enfermedades Cerebelosas/complicaciones , Consenso , Encuestas de Atención de la Salud , Personal de Salud , Humanos , Neoplasias Infratentoriales/complicaciones , Mutismo/etiología , Guías de Práctica Clínica como AsuntoRESUMEN
Mirtazapine is indicated for major depression and used for anxiety in adults; however, little is known about its application in pediatric populations. This is an 8-week open-label pilot study of mirtazapine in children with social phobia age 8-17 years. Primary outcomes were symptom improvement based on clinician rating and self-report, as well as tolerability based on rates of discontinuation due to adverse effects. Fifty-six percent (10/18) responded to treatment, 17% (3/18) achieved full remission. Social phobia symptoms improved significantly during the first 2 weeks of treatment, as did comorbid symptoms of depression and anxiety. Eleven patients (61%) did not complete all 8 weeks of treatment; four patients (22%) discontinued due to adverse effects including fatigue and irritability. The others discontinued due to study burden (28%), insufficient response (6%), or to pursue herbal treatment (6%). Significant weight gain was observed. Larger controlled trials are needed to further evaluate efficacy and safety.
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Antidepresivos Tricíclicos/uso terapéutico , Mianserina/análogos & derivados , Trastornos Fóbicos/tratamiento farmacológico , Adolescente , Factores de Edad , Antidepresivos Tricíclicos/efectos adversos , Niño , Relación Dosis-Respuesta a Droga , Humanos , Mianserina/efectos adversos , Mianserina/farmacología , Mianserina/uso terapéutico , Mirtazapina , Proyectos PilotoRESUMEN
OBJECTIVE: To characterize the adverse effects of treatment with selective serotonin reuptake inhibitors (SSRIs) started in children under age 7 yr. METHODS: We conducted a retrospective review of medical records for all children who had begun treatment with an SSRI under age 7 at an academic psychiatry department in Boston. RESULTS: Thirty-nine children (26 males, 13 females) met the inclusion criteria. Mean age at start of treatment was 5.9 +/- 0.8 yr, and median treatment duration was 5.0 months. The target diagnoses for SSRI treatment were anxiety disorders in 54%, depressive disorders in 23%, and both anxiety and depressive disorders in 20% of patients. There were no reports of suicidal ideation or attempt. No children were medically or psychiatrically hospitalized for adverse effects (AEs). Eleven patients (28%) reported an AE of at least moderate severity; 7 (18%) discontinued the SSRI due to the AE. Six patients discontinued due to behavioral activation and 1 due to gastrointestinal upset. The median time to onset of an AE was 23 days, and median resolution was 19 days from onset. CONCLUSIONS: The high rate of adverse effects, especially activation, in this sample argues for continued caution in using SSRIs in young children. Controlled trials are warranted.
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Trastornos Mentales/tratamiento farmacológico , Inhibidores Selectivos de la Recaptación de Serotonina/efectos adversos , Síntomas Afectivos/inducido químicamente , Factores de Edad , Agresión/efectos de los fármacos , Niño , Preescolar , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Predisposición Genética a la Enfermedad , Humanos , Hipercinesia/inducido químicamente , Masculino , Trastornos Mentales/genética , Estudios RetrospectivosRESUMEN
OBJECTIVE: To evaluate hepatic enzyme elevations during treatment with olanzapine, divalproex, and their combination. METHOD: Fifty-two children, aged 4 to 18 years, with hepatic enzyme levels measured during treatment with olanzapine (n = 17), divalproex (n = 23), or their combination (n = 12), were identified in the computerized records at a pediatric medical center. Clinical characteristics as well as serial alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase levels were collected. RESULTS: Mean and peak hepatic enzyme levels were significantly higher for the combined treatment group compared to the olanzapine or divalproex groups. All 12 patients who received combined treatment had at least one peak enzyme elevation during the treatment. For 42% of these patients, at least one enzyme level remained elevated during the time for which values were available (mean 8 +/- 6 months). For those treated with divalproex either alone or in combination, the findings were not explained by variations in divalproex plasma levels. Two patients receiving combined treatment had the combination treatment discontinued because of medical complications (pancreatitis in one and steatohepatitis in the other). CONCLUSIONS: Combined treatment with olanzapine and divalproex was associated with more elevations of hepatic enzymes than treatment with either agent alone. The long-term significance of this is unknown but warrants study.