Cutaneous toxicities of mitogen-activated protein kinase inhibitors in children and young adults with neurofibromatosis-1.

PURPOSE: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder which commonly causes neoplasms leading to disfigurement or dysfunction. Mitogen-activated protein kinase inhibitors (MEKi) are generally well-tolerated treatments which target neural tumor progression in patients with NF1. However, cutaneous adverse events (CAEs) are common and may hinder patients' abilities to remain on treatment, particularly in children. We aim to characterize CAEs secondary to MEKi treatment in pediatric and young adult patients with NF1. METHODS: We reviewed institutional medical records of patients under 30 years with a diagnosis of "NF1," "NF2," or "other neurofibromatoses" on MEKi therapy between January 1, 2019 and June 1, 2022. We recorded the time-to-onset, type, and distribution of CAEs, non-cutaneous adverse events (AEs), AE management, and tumor response. RESULTS: Our cohort consisted of 40 patients with NF1 (median age, 14 years). Tumor types included low-grade gliomas (51%) and plexiform neurofibromas (38%). MEKi used included selumetinib (69%), trametinib (25%), and mirdametinib (6%). A total of 74 CAEs occurred, with 28 cases of acneiform rash (38%). Other common CAEs were paronychia, seborrheic dermatitis, eczema, xerosis, and oral mucositis. The most common treatments included oral antibiotics and topical corticosteroids. Most patients had clinical (stable or improved) tumor response (71%) while 29% had tumor progression while on a MEKi. There was no significant association between CAE presence and tumor response (p = 0.39). CONCLUSIONS: Improvement in characterization of MEKi toxicities and their management is important to develop treatment guidelines for pediatric and young adult patients with NF1 on MEKi therapy.

Contrast Enhancement Patterns in Pediatric Glioblastomas.

BACKGROUND AND PURPOSE: Brain tumors are the most common cause of cancer-related deaths among the pediatric population. Among these, pediatric glioblastomas (GBMs) comprise 2.9% of all central nervous system tumors and have a poor prognosis. The purpose of this study is to determine whether the imaging findings can be a prognostic factor for survival in children with GBMs. MATERIALS AND METHODS: The imaging studies and clinical data from 64 pediatric patients with pathology-proven GBMs were evaluated. Contrast enhancement patterns were classified into focal, ring-like, and diffuse, based on preoperative postcontrast T1-weighted magnetic resonance images. We used the Kaplan-Meier method and Cox proportional hazard regression to evaluate the prognostic value of imaging findings. RESULTS: Patients with ring-enhanced GBMs who underwent gross total resection or subtotal resection were found to have a significantly shorter progression-free survival ( P = 0.03) comparing with other enhancing and nonenhancing glioblastomas. CONCLUSIONS: In this study, we analyzed survival factors in children with pediatric glioblastomas. In the group of patients who underwent gross total resection or subtotal resection, those patients with focal-enhanced GBMs had significantly longer progression-free survival ( P = 0.03) than did those with other types of enhancing GBMs (diffuse and ring-like).

Seizures' impact on cognition and quality of life in childhood cancer survivors.

BACKGROUND: The objective of this study was to determine the impact of seizure-related factors on neurocognitive, health-related quality of life (HRQOL), and social outcomes in survivors of childhood cancer. METHODS: Survivors of childhood cancer treated at St. Jude Children's Hospital (n = 2022; 48.3% female; median age, 31.5 years; median time since diagnosis, 23.6 years) completed neurocognitive testing and questionnaires. The presence, severity, resolution, and treatment history of seizures were abstracted from medical records. Adjusting for the age at diagnosis, sex, and prior cancer therapy, multivariable models examined the impact of seizures on neurocognitive and HRQOL outcomes. Mediation analyses were conducted for social outcomes. RESULTS: Seizures were identified in 232 survivors (11.5%; 29.9% of survivors with central nervous system [CNS] tumors and 9.0% of those without CNS tumors). In CNS tumor survivors, seizures were associated with poorer executive function and processing speed (P < .02); in non-CNS tumor survivors, seizures were associated with worse function in every domain (P < .05). Among non-CNS survivors, seizure severity was associated with worse processing speed (P = .023), and resolution was associated with better executive function (P = .028) and attention (P = .044). In CNS survivors, seizure resolution was associated with improved attention (P = .047) and memory (P < .02). Mediation analysis revealed that the impact of seizures on social outcomes was mediated by neurocognitive function. CONCLUSIONS: Seizures in cancer survivors adversely affect long-term functional and psychosocial outcomes independently of cancer therapy. The resolution of seizure occurrence is associated with better outcomes. Seizure severity is associated with poorer outcomes and should be a focus of clinical management and patient education.

Surveillance for subsequent neoplasms of the CNS for childhood, adolescent, and young adult cancer survivors: a systematic review and recommendations from the International Late Effects of Childhood Cancer Guideline Harmonization Group.

Exposure to cranial radiotherapy is associated with an increased risk of subsequent CNS neoplasms among childhood, adolescent, and young adult (CAYA) cancer survivors. Surveillance for subsequent neoplasms can translate into early diagnoses and interventions that could improve cancer survivors' health and quality of life. The practice guideline presented here by the International Late Effects of Childhood Cancer Guideline Harmonization Group was developed with an evidence-based method that entailed the gathering and appraisal of published evidence associated with subsequent CNS neoplasms among CAYA cancer survivors. The preparation of these guidelines showed a paucity of high-quality evidence and highlighted the need for additional research to inform survivorship care. The recommendations are based on careful consideration of the evidence supporting the benefits, risks, and harms of the surveillance interventions, clinical judgment regarding individual patient circumstances, and the need to maintain flexibility of application across different health-care systems. Currently, there is insufficient evidence to establish whether early detection of subsequent CNS neoplasms reduces morbidity and mortality, and therefore no recommendation can be formulated for or against routine MRI surveillance. The decision to start surveillance should be made by the CAYA cancer survivor and health-care provider after careful consideration of the potential harms and benefits of surveillance for CNS neoplasms, including meningioma.

Height, weight, and cardiovascular effects of stimulants on children with brain tumors.

INTRODUCTION: Children with brain tumors may develop inattention, slow processing, and hypersomnia. Stimulant medications improve these problems, but their effect on growth, heart rate, and blood pressure (BP) are inadequately explored. PROCEDURE: We retrospectively studied children with brain tumors treated at our institution that had data available for 1 year pre and 2 years on stimulant treatment. Tumor location, gender, radiation treatment (RT), age at RT, drug type, and hormone therapy were variables of interest. RESULTS: We identified 65 children (35 males) that fulfilled eligibility criteria. Focal RT was utilized in 58; 11 additionally had whole brain RT; and seven received no RT. Thirty were treated for hypersomnia and inattention, eight for hypersomnia alone, and rest for inattention. Modafinil was the first drug in 18 (27.7%), and methylphenidate in the others. Forty-seven (72.3%), 45 (69.2%), and 49 (75.4%) were on thyroxine, cortisone, and growth hormones, respectively. There was no difference in pre- and post-stimulant body mass index (BMI), heart rate, and BP. There was also no difference between modafinil and methylphenidate groups. Rate of height acquisition slowed on stimulants (P = .0096). Thyroxine treatment correlated with increase in BMI after stimulants (P = .04). Younger age (P = .0003) and higher prestimulant BMI (P = .0063) correlated with increased heart rate on stimulants, while higher age at RT (P =.016) correlated with elevated systolic BP on stimulants. No associations were found with height acquisition and diastolic BP. CONCLUSION: Stimulants are well tolerated by children with brain tumors that are appropriately managed for endocrine deficiencies, but may reduce the trajectory of height attainment.

Pediatric high-grade glioma: aberrant epigenetics and kinase signaling define emerging therapeutic opportunities.

INTRODUCTION: Supratentorial pediatric high-grade gliomas (pHGGs) are aggressive malignancies that lack effective treatment options. Deep genomic sequencing by multiple groups has revealed that the primary alterations unique to pHGGs occur in epigenetic and kinase genes. These mutations, fusions, and deletions present a therapeutic opportunity by use of small molecules targeting epigenetic modifiers and kinases that contribute to pHGG growth. METHODS: Using a targeted search of the pre-clinical literature and clinicaltrials.gov for kinase and epigenetic pathways in pHGG, we collectively describe how these mechanisms are being targeted in pre-clinical animal models and in current clinical trials, as well as propose unexplored therapeutic possibilities for future investigations. RESULTS: Relevant pHGG kinases are targetable by several FDA-approved or clinical-stage kinase inhibitors, including altered BRAF/MET/NTRK/ALK and wild-type PI3K/EGFR/PDGFR/VEGF/AXL. Epigenetic proteins implicated in pHGG are also clinically targetable and include histone erasers, writers and readers such as HDACs, demethylases LSD1/JMJD3, methyltransferase EZH2, chromatin reader bromodomains, and chromatin remodeler subunit BMI-1. Crosstalk between these pathways can occur involving kinases such as EGFR and AMPK interacting with epigenetic modifiers such as HDACs or EZH2. Single agent trial results of kinase inhibitors or epigenetic targets alone are underwhelming and hampered by poor pharmacokinetics, adaptive resistance, and broad inclusion criteria. CONCLUSIONS: The genetic and phenotypic diversity of pHGGs is now well characterized after large-scale sequencing studies on patient tissue. However, clinical treatment paradigms have not yet shifted in response to this information. Combination therapies targeting multiple kinases or epigenetic targets may hold more promise, especially if attempted in selected patient populations with hemispheric pHGG tumors and relevant targeted therapeutic biomarkers.

Evaluating pediatric spinal low-grade gliomas: a 30-year retrospective analysis.

PURPOSE: Most pediatric spinal tumors are low-grade gliomas (LGGs). Characterization of these tumors has been difficult given their heterogeneity and rare incidence. The objective was to characterize such tumors diagnosed at our institution. METHODS: Spinal tumors diagnosed in our pediatric patients between 1984 and 2014 were reviewed retrospectively. Demographics, presentation, pathology, imaging, management, and sequelae were examined. RESULTS: Forty patients had spinal LGG tumors, 24 (62%) of which were pilocytic astrocytomas. The most common initial presentations were pain (n = 15), partial extremity paralysis (n = 13), and ataxia (n = 11), with the diagnosis frequently delayed by months (median = 5.9 months, range 4 days-6.2 years). Twenty-nine patients had some tumor resection, and 8 required adjuvant therapy with chemotherapy (n = 4) or radiation (n = 4) post-resection. Ten other patients received only biopsy for histologic diagnosis, who were treated with chemotherapy (n = 4) or radiation (n = 5) post biopsy. Tumor progression was noted in 16 patients (2 after gross-total resection; 10, partial resection; and 4, biopsy). During the evaluation period, 3 patients died secondary to tumor progression. BRAF status could have shortened progression-free survival: patients with BRAFV600E mutations (n = 3) all experienced progression within 10 months. Long-term sequelae of the disease/treatment were mostly residual neurologic deficits (paresthesia, paralysis), chemotherapy-induced hearing loss, and scoliosis. CONCLUSIONS: Spinal LGG is a rare entity with significant long-term effects. Although surgery is the most common initial treatment option, more in-depth analysis of molecular biomarkers may improve stratification and prognostication.

Prevalence, risk factors, and response to treatment for hypersomnia of central origin in survivors of childhood brain tumors.

Daytime sleepiness is recognized in childhood brain tumor survivors. Our objective was to determine prevalence, risk factors for PSG/MLST proven hypersomnia/narcolepsy, and response to stimulants in childhood brain tumor survivors. Standard PSG/MSLT criteria were used to diagnose hypersomnia/narcolepsy. Medical records of brain tumor survivors having undergone a PSG/MSLT were reviewed for the diagnostic code of hypersomnia/narcolepsy. Survivors with hypersomnia/narcolepsy were matched with 2-3 survivors without reported hypersomnia/narcolepsy by age at tumor diagnosis, gender, and time from tumor diagnosis. Between January 2000 to April 2015, 39 of the 2336 brain tumor patients treated at our institution were diagnosed with hypersomnia/narcolepsy for a prevalence rate of 1670/100,000. Hypersomnia/narcolepsy was diagnosed at a median of 6.1 years (range 0.4-13.2) from tumor diagnosis and 4.7 years (range - 1.5 to 10.4) from cranial radiation. Midline tumor location (OR 4.6, CI 1.7-12.2, p = 0.002) and anti-epilepsy drug (AED) use (OR 11, CI 2.4-54) correlated with hypersomnia/narcolepsy while radiation dose > 30 Gray trended towards significance (OR 1.8, CI 0.9-3.6); posterior fossa tumor location reduced the risk (OR 0.1, CI 0.04-0.5, p = 0.002). AED use also correlated with midline tumor location. Thirty-seven survivors were treated with stimulants and reported improved wakefulness and school performance [response rate CI 0.97 (0.86-0.99) and 0.83 (0.65-0.94)]. Prevalence of hypersomnia/narcolepsy among childhood brain tumor survivors was higher than the general population. Tumor location and radiation dose were possible risk factors, and stimulants were reported to be beneficial.

Neurologic impairments from pediatric low-grade glioma by tumor location and timing of diagnosis.

BACKGROUND: The neurologic outcomes of low-grade gliomas (LGGs) according to tumor location and duration of presenting symptoms remain poorly characterized in children. PROCEDURE: We retrospectively reviewed neurologic impairments in 246 pediatric patients with LGGs (88 with optic pathway and midline tumors, 56 with posterior fossa tumors, 52 with cerebral hemisphere tumors, 35 with brainstem tumors, and 15 with spinal cord tumors) who were treated at St. Jude Children's Research Hospital between 1995 and 2005. We compared neurologic impairments (defined by Common Terminology Criteria for Adverse Events, version 4.03) by tumor location and prediagnosis symptom interval (PSI) (≥ 3 months or < 3 months) at first and last patient visits. RESULTS: The median age of diagnosis was 7.1 years; median PSI was 2.1 months; and median time to last follow-up was 11.6 years. LGGs in the cerebral hemispheres resulted in significantly fewer neurologic impairments, compared with that of other locations at baseline (P < 0.001) and at last follow-up (P < 0.001). In all patients, PSIs greater than 3 months resulted in a significantly higher incidence of ataxia and dysmetria at last follow-up (42%, P = 0.003). Greater PSI was also significantly associated with worsening lower extremity motor weakness from cerebral hemisphere tumors; dysmetria from optic pathway and midline tumors; eye and visual dysfunction from posterior fossa tumors; and ear and vestibular disturbances from brainstem tumors (P ≤ 0.05). CONCLUSION: Neurologic impairment in pediatric LGGs varies by tumor location, and PSIs greater than 3 months affect some functionally important neurologic outcomes.

Imaging Patterns and Outcome of Posterior Reversible Encephalopathy Syndrome During Childhood Cancer Treatment.

BACKGROUND: Diagnosis of posterior reversible encephalopathy syndrome (PRES) requires presence of headache, seizures, impaired vision, or altered mentation accompanied by specific imaging findings. We aimed to study long-term clinical and radiologic outcome of PRES in children with cancer to augment limited available data. PROCEDURE: Retrospective review of children with cancer who were diagnosed with PRES. RESULTS: We identified PRES in 21 males and 16 females among 5,217 children treated during the study period. Median time from cancer diagnosis to PRES was 6.6 months in 25 leukemia (1.6%), five brain tumor (0.3%), and seven other solid tumor (0.4%) patients; P = <0.0001 for leukemia versus all other tumors. Symptoms included seizures (97%), headaches (40%), altered mentation (68%), and vision impairment (27%). Hypertension was seen in 97%, and steroids use was seen in 78%. Headaches, visual disturbance, and mental status resolved within a median of <3 days, whereas epilepsy developed in 19%. T2 hyperintense signal was present in 100% of occipital, 47% of temporal, 75% of parietal, and 55% of frontal lobes, as well as 22% of cerebellum and 5% of basal ganglia. Follow-up magnetic resonance imaging (MRI) in 34 patients showed partial or complete T2 resolution in 79%, development of laminar necrosis in five, microhemorrhages in six, and focal atrophy in three. CONCLUSION: PRES in children is more common in hematological malignancy compared with other tumors and is associated with hypertension and steroid use. Seizure is the most common acute manifestation. Most MRI changes resolve, but persistent imaging abnormality and epilepsy may develop in a significant minority.

Incidence of Ophthalmological Complications in NF-1 Patients Treated with MEK Inhibitors.

MEK inhibitors (MEKi) represent innovative and promising treatments for managing manifestations of neurofibromatosis type 1 (NF1). To mitigate potential ophthalmic side effects, such as MEKi-associated retinopathy (MEKAR), patients undergoing MEKi therapy routinely receive ophthalmology evaluations. Our study aims to assess the necessity of this regular screening within a predominantly pediatric NF1 population by examining the occurrence of ocular adverse events (OAE). A retrospective study evaluated 45 NF1 patients receiving MEKi. Inclusion criteria included baseline and follow-up examinations following the initiation of MEKi therapy. At each assessment, a comprehensive eye evaluation was performed, comprising a dilated fundus examination, ocular coherence tomography of the macula and nerve fiber layer, and Humphrey visual field testing. Twenty-six patients, with an average age of 13 years (range 2-23 years) and an average follow-up duration of 413 days were included in the analysis. Three different MEKi were used: selumetinib (77%), trametinib (23%), and mirdametinib (4%). None of the patients experienced retinopathy at any point during the study. Some patients had pre-existing optic neuropathies (27%), but no instances of nerve changes occurred after commencing MEKi therapy. Four patients (15%) exhibited symptoms of dry eye, all of which were effectively managed with topical lubrication.

Renal Cell Carcinoma Unclassified with Medullary Phenotype in a Patient with Neurofibromatosis Type 2.

We present, to our knowledge, the first reported case of germline neurofibromatosis Type 2 (NF2) associated with renal cell carcinoma unclassified with medullary phenotype (RCCU-MP) with somatic loss by immunohistochemistry of the SMARCB1 tumor suppressor gene located centromeric to NF2 on chromosome 22q. Our patient is a 15-year-old with germline neurofibromatosis Type 2 (NF2) confirmed by pathogenic mutation of c.-854-??46+??deletion. Her NF2 history is positive for a right optic nerve sheath meningioma, CNIII schwannoma requiring radiation therapy and post gross total resection of right frontotemporal anaplastic meningioma followed by radiation. At age 15 she developed new onset weight loss and abdominal pain due to RCCU-MP. Hemoglobin electrophoresis was negative for sickle hemoglobinopathy. Chemotherapy (cisplatin, gemcitabine and paclitaxel) was initiated followed by radical resection. Given the unique renal pathology of a high grade malignancy with loss of SMARCB1 expression via immunohistochemistry, and history of meningioma with MLH1 loss of expression and retained expression of PMS2, MSH2 and MSH6, further germline genetic testing was sent for SMARCB1 and mismatch repair syndromes. Germline testing was negative for mutation in SMARCB1. Therefore, this is the first reported case of RCCU-MP associated with germline NF2 mutation. This suggests the importance of closer surveillance in the adolescent and young adult population with NF2 with any suspicious findings of malignancy outside of the usual scope of practice with NF2.

Handedness switching as a presenting sign for pediatric low-grade gliomas: An insight into brain plasticity from a short case series.

PURPOSE: To describe clinical data, rehabilitation services, and outcomes of children with handedness switching as their presenting symptom before low-grade glioma (LGG) diagnosis. METHODS: A retrospective chart review was performed for five patients (four female and four white) with LGG and confirmed handedness switching before LGG diagnosis. RESULTS: All children were less than 8 years at diagnosis, and two patients were less than 3 years. All children were initially right-handed and experienced loss of motor function, ranging from weakness to paresis, in their dominant hand. The median time from switching handedness to diagnosis was 1 month (range: 0.75-60 months). Rehabilitation was offered for three patients, and motor function deficits in the initial dominant hand were resolved in two of the total cohort. At long-term follow-up, hand dominance returned to the initial hand in three patients. CONCLUSIONS: Handedness switching should be acknowledged as a potential sign of LGG in children, and early long-term rehabilitation services should be offered for these children.

Clinical features, neurologic recovery, and risk factors of postoperative posterior fossa syndrome and delayed recovery: a prospective study.

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.

Immune Effector Cell Associated Neurotoxicity (ICANS) in Pediatric and Young Adult Patients Following Chimeric Antigen Receptor (CAR) T-Cell Therapy: Can We Optimize Early Diagnosis?

The Cornell Assessment for Pediatric Delirium (CAPD) was first proposed by the Pediatric Acute Lung Injury and Sepsis Investigators Network-Stem Cell Transplantation and Cancer Immunotherapy Subgroup and MD Anderson CARTOX joint working committees, for detection of immune effector cell associated neurotoxicity (ICANS) in pediatric patients receiving chimeric antigen receptor (CAR) T-cell therapy. It was subsequently adopted by the American Society for Transplantation and Cellular Therapy. The utility of CAPD as a screening tool for early diagnosis of ICANS has not been fully characterized. We conducted a retrospective study of pediatric and young adult patients (n=15) receiving standard-of-care CAR T-cell products. Cytokine release syndrome (CRS) and ICANS occurred in 87% and 40% of patients, respectively. ICANS was associated with significantly higher peaks of serum ferritin. A change in CAPD from a prior baseline was noted in 60% of patients with ICANS, 24-72 h prior to diagnosis of ICANS. The median change from baseline to maximum CAPD score of patients who developed ICANS versus those who did not was 13 versus 3, respectively (p=0.0004). Changes in CAPD score from baseline may be the earliest indicator of ICANS among pediatric and young adult patients which may warrant closer monitoring, with more frequent CAPD assessments.

Profound hearing loss following surgery in pediatric patients with posterior fossa low-grade glioma.

BACKGROUND: Hearing loss may occur in patients with posterior fossa low-grade glioma who undergo surgery. METHODS: We retrospectively reviewed 217 patients with posterior fossa low-grade glioma, including 115 for whom results of hearing tests performed after surgery and before chemotherapy or radiation therapy were available. We explored the association of UHL with age at diagnosis, sex, race, tumor location, extent of resection, posterior fossa syndrome, ventriculoperitoneal shunt placement, and histology. RESULTS: Of the 115 patients, 15 (13.0%: 11 male, 6 black, 8 white, 1 multiracial; median age 7 years [range, 1.3-17.2 years]) had profound UHL after surgery alone or before receiving ototoxic therapy. Median age at tumor diagnosis was 6.8 years (range, 0.7-14.1 years), and median age at surgery was 6.8 years (range, 0.7-14.1 years). Patients with UHL had pathology characteristic of pilocytic astrocytoma (n = 10), ganglioglioma (n = 4), or low-grade astrocytoma (n = 1). Of these 15 patients, 4 underwent biopsy, 1 underwent gross total resection, 1 underwent near-total resection, and 9 underwent subtotal resection. UHL was more frequent in black patients than in white patients (OR 7.3, P = .007) and less frequent in patients who underwent gross total resection or near-total resection than in those who underwent subtotal resection (OR 0.11, P = .02). CONCLUSIONS: Children undergoing surgery for posterior fossa low-grade glioma are at risk for UHL, which may be related to race or extent of resection. These patients should receive postoperative audiologic testing, as earlier intervention may improve outcomes.

The Complex Diagnostic Challenge in Children With Non-Central Nervous System Cancer and Cerebellar Mutism.

Multiple etiologies should be considered in the differential diagnosis of immunocompromised patients with non-central nervous system cancer and viral infections who develop mutism. Acute cerebellitis, caused by infections or by neurotoxicity resulting from chemotherapy; paraneoplastic cerebellar degeneration; atypical posterior reversible encephalopathy syndrome; and acute disseminated encephalomyelitis may all cause mutism in such patients. This condition warrants prompt recognition and may require treatment with immunotherapy, as it may be an immune-mediated process. We present 2 patients with leukemia and viral illness who developed cerebellar mutism in the setting of acute cerebellitis and responded to immunotherapy, suggesting that the condition involved a parainfectious immune-mediated response.

Clinical Characteristics and Long-Term Outcomes of Movement Disorders in Childhood Thalamic Tumors.

BACKGROUND: We studied the outcomes of movement disorders that were associated with childhood thalamic tumors. METHODS: We retrospectively reviewed 83 children with thalamic tumors treated at our institution from 1996 to 2013 to document the incidence and outcome of movement disorders. Magnetic resonance imaging was used to analyze the involvement of thalamic nuclei, and three instruments were used to rate the severity of the disorders. RESULTS: Nine (11%) patients had one or more of the following movement disorders: postural tremor, resting tremor, ballism, dystonia, myoclonus, and athetosis. Median age at tumor diagnosis was seven years (range, 0.25 to 11 years), and the average age at movement disorder onset was eight years (range, 1.5 to 11 years). Movement disorders developed at a median of 1.5 months (range, 0 to 4 months) after surgical resection. The severity of the disorders was either unchanged or slightly improved during follow-up. The red nuclei were the only thalamic structures that showed tumor involvement in all nine patients. CONCLUSIONS: No specific injury of the thalamic nuclei was associated with movement disorders in children with thalamic tumors, and the severity of these disorders did not change over time.

Long-Term Neurocognitive Functioning and Social Attainment in Adult Survivors of Pediatric CNS Tumors: Results From the St Jude Lifetime Cohort Study.

PURPOSE: To assess the prevalence and severity of neurocognitive impairment in adult survivors of pediatric CNS tumors and to examine associated treatment exposures. PATIENTS AND METHODS: Participants included 224 survivors of CNS tumors who were treated at St Jude Children's Research Hospital (current median age [range], 26 years [19 to 53 years]; time from diagnosis, 18 years [11 to 42 years]) and completed neurocognitive testing. Information on cranial radiation therapy (CRT) doses and parameters of delivery were abstracted from medical records. The prevalence of severe impairment (ie, at least two standard deviations below normative mean) was compared across radiation treatment groups (no CRT, focal irradiation, craniospinal irradiation) using the χ(2) test. Log-binomial models were used to estimate risk ratios (RRs) and corresponding 95% CIs for severe impairment. RESULTS: In multivariable models, craniospinal irradiation was associated with a 1.5- to threefold increased risk of severe impairment compared with no CRT (eg, intelligence: RR = 2.70; 95% CI, 1.37 to 5.34; memory: RR = 2.93; 95% CI, 1.69 to 5.08; executive function: RR = 1.74; 95% CI, 1.24 to 2.45). Seizures were associated with impaired academic performance (RR = 1.48; 95% CI, 1.02 to 2.14), attention (RR = 1.54; 95% CI, 1.12 to 2.13), and memory (RR = 1.44; 95% CI, 1.04 to 1.99). Hydrocephalus with shunt placement was associated with impaired intelligence (RR = 1.78; 95% CI, 1.12 to 2.82) and memory (RR = 1.42; 95% CI, 1.03 to 1.95). Differential follow-up time contributed to variability in prevalence estimates between survivors treated with older nonconformal and those treated with more contemporary conformal radiation therapy methods. Neurocognitive impairment was significantly associated with lower educational attainment, unemployment, and nonindependent living. CONCLUSION: Survivors of pediatric CNS tumors are at risk of severe neurocognitive impairment in adulthood. The prevalence of severe impairment is greater than expected in the general population, even in the absence of CRT, and is associated with disrupted attainment of adult social milestones.

Diagnostic Clues to Human Herpesvirus 6 Encephalitis and Wernicke Encephalopathy After Pediatric Hematopoietic Cell Transplantation.

Human herpesvirus 6 (HHV6) encephalitis and Wernicke encephalopathy are treatable yet frequently undiagnosed causes of encephalopathy in pediatric recipients of allogeneic and autologous hematopoietic cell transplantation. Here we review representative cases of both conditions to highlight specific and relevant neurologic features that prompted effective diagnosis and treatment. Two patients with confusion accompanied by seizures, memory changes, or specific visual hallucinations and HHV6 detectable by polymerase chain reaction (PCR) in cerebrospinal fluid had improvement in viral load with ganciclovir or foscarnet treatment. Two patients had confusion, ataxia, or ocular changes and low serum thiamine levels, which resolved with parenteral thiamine. In all cases, definitive diagnosis and treatment were facilitated by a high index of suspicion and search for specific pathognomonic neurologic deficits accompanying the confusional state. It is critical to clinically differentiate these 2 conditions from other common neurologic syndromes occurring after transplant, allowing potentially improved patient outcomes by prompt diagnosis and effective treatment.