Emergence of the natural history of Myhre syndrome: 47 patients evaluated in the Massachusetts General Hospital Myhre Syndrome Clinic (2016-2023).

Myhre syndrome is an increasingly diagnosed ultrarare condition caused by recurrent germline autosomal dominant de novo variants in SMAD4. Detailed multispecialty evaluations performed at the Massachusetts General Hospital (MGH) Myhre Syndrome Clinic (2016-2023) and by collaborating specialists have facilitated deep phenotyping, genotyping and natural history analysis. Of 47 patients (four previously reported), most (81%) patients returned to MGH at least once. For patients followed for at least 5 years, symptom progression was observed in all. 55% were female and 9% were older than 18 years at diagnosis. Pathogenic variants in SMAD4 involved protein residues p.Ile500Val (49%), p.Ile500Thr (11%), p.Ile500Leu (2%), and p.Arg496Cys (38%). Individuals with the SMAD4 variant p.Arg496Cys were less likely to have hearing loss, growth restriction, and aortic hypoplasia than the other variant groups. Those with the p.Ile500Thr variant had moderate/severe aortic hypoplasia in three patients (60%), however, the small number (n = 5) prevented statistical comparison with the other variants. Two deaths reported in this cohort involved complex cardiovascular disease and airway stenosis, respectively. We provide a foundation for ongoing natural history studies and emphasize the need for evidence-based guidelines in anticipation of disease-specific therapies.

Addenbrooke's Cognitive Examination-Third Edition Predicts Neuropsychological Test Performance.

OBJECTIVE: Effective screening tools can help providers with treatment decisions, including when to refer patients for neuropsychological evaluations, which are the gold standard for cognitive assessment of neurodegenerative disease. The authors examined whether performance on the Addenbrooke's Cognitive Examination-Third Edition (ACE-III), a readily available cognitive screening tool for older adults, predicted performance on subsequent neuropsychological evaluations. METHODS: In total, 217 patients referred for neurocognitive concerns completed a neuropsychological evaluation, including the ACE-III. Patients were diagnosed as having normal cognition (NC, N=67), mild neurocognitive disorder (mild NCD, N=105), or major NCD (N=45). Regression analyses were used to determine whether ACE-III subscale scores predicted performance on neuropsychological measures assessing similar constructs. Logistic regression was used to assess whether ACE-III total score and overall neuropsychological test performance predicted diagnosis. Separate analyses compared those with higher and lower educational attainments. ACE-III subscales and total scores were compared by diagnostic group. RESULTS: Across all groups, ACE-III subscale scores predicted within-construct neuropsychological performances with moderate to strong effects (p<0.001) but were less predictive for those with lower educational attainment. ACE-III total score was less sensitive than overall neuropsychological test performance in predicting neurocognitive disorders. ACE-III subscale and total scores distinguished diagnostic groups (NC>mild NCD>major NCD, p<0.001). CONCLUSIONS: ACE-III subscale scores predicted performance on neuropsychological measures assessing similar constructs. However, overall performance on neuropsychological testing was more sensitive than ACE-III total score in predicting neurocognitive disorder diagnosis. Total ACE-III score differed by level of cognitive impairment. Comprehensive neuropsychological testing is recommended for patients who have lower educational status or complex symptom presentations or are younger.

Cognitive, Graphomotor, and Psychosocial Challenges in Pediatric Autoimmune Neuropsychiatric Disorders Associated With Streptococcal Infections (PANDAS).

OBJECTIVES: Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infection (PANDAS) is characterized by the sudden onset of obsessive-compulsive disorder (OCD) and other neurobehavioral symptoms following group A streptococcal infection. The cardinal neuropsychiatric symptoms are believed to reflect an aberrant autoimmune or inflammatory response that may selectively disrupt basal ganglia function. The investigators examined whether neuropsychological skills associated with frontostriatal networks (executive functions and motor skills) are affected in patients with PANDAS following resolution of acute symptoms and the degree to which there are persistent social, emotional, and academic difficulties. METHODS: Twenty-seven patients ages 6-14 years (mean age=9.63 years [SD=1.78]; male, N=22) completed neuropsychological testing as part of routine clinical care. Performances on measures of intellectual ability, executive function, motor skills, and academic skills are reported, as well as parent-reported emotional, behavioral, and social skills. RESULTS: On neuropsychological measures, patients exhibited average intellectual functioning with relative and mild difficulties in skills supporting cognitive efficiency, including attentional regulation, inhibitory control, and processing speed. Dexterity was normal but graphomotor skills were reduced. Core reading, math, and writing skills were within expectations, but reading and math fluency were reduced, and the majority of patients received special education services or accommodations. Parents reported high levels of concern about anxiety, depression, inattention, hyperactivity, and social skills. CONCLUSIONS: These findings indicated relative difficulties with aspects of executive and motor functions. Although evaluations were performed following the resolution of acute symptoms, ongoing and significant academic difficulties and emotional, behavioral, and social concerns were targets for clinical intervention and support.

Cognitive Complaints in Motor Functional Neurological (Conversion) Disorders: A Focused Review and Clinical Perspective.

Functional neurological (conversion) disorder (FND) is a neuropsychiatric condition characterized by sensorimotor symptoms exhibiting features incompatible with other neurologic diseases. Individuals with motor FND (mFND) typically present with limb weakness, nonepileptic seizures, and/or abnormal movements. However, this population also frequently reports clouded thinking, inattention, and memory difficulties. Cognitive complaints in individuals with mFND are important to evaluate as they may negatively impact quality of life and impede treatment engagement. We provide a narrative review of the neuropsychological testing literature detailing neurocognitive profiles of individuals with mFND. We also present three illustrative clinical cases at the intersection of mFND and cognitive concerns. Several studies and our case examples highlight that generally normal cognitive performance can be observed concurrently with subjective cognitive complaints in some individuals with mFND; this mismatch may be a possible "rule-in" sign of functional cognitive symptoms. Other studies have reported impairments in attention, memory, language, visuospatial, and executive functioning in individuals with mFND. These impairments could be related to medical-psychiatric comorbidities, psychotropic medication side effects, and intrinsic disease mechanisms. When evaluating individuals with mFND and their cognitive complaints, clinicians can use performance validity test and psychopathology findings to help them interpret the neuropsychological test results. Perceptual mismatches between intact objective cognitive performance and subjective cognitive complaints may reflect a negative attentional bias for cognitive abilities that can be targeted with cognitive retraining and cognitive behavioral therapy. Neuropsychological evaluations may provide a useful adjunctive tool clinicians can use to help assess individuals with mFND and cognitive concerns.

Recognition and management of adults with Turner syndrome: From the transition of adolescence through the senior years.

Turner syndrome is recognized now as a syndrome familiar not only to pediatricians and pediatric specialists, medical geneticists, adult endocrinologists, and cardiologists, but also increasingly to primary care providers, internal medicine specialists, obstetricians, and reproductive medicine specialists. In addition, the care of women with Turner syndrome may involve social services, and various educational and neuropsychologic therapies. This article focuses on the recognition and management of Turner syndrome from adolescents in transition, through adulthood, and into another transition as older women. It can be viewed as an interpretation of recent international guidelines, complementary to those recommendations, and in some instances, an update. An attempt was made to provide an international perspective. Finally, the women and families who live with Turner syndrome and who inspired several sections, are themselves part of the broad readership that may benefit from this review.

Where Do You Think You Are? A Grounded Theory Study of the Critical Factors Triggering the Existence and Fueling the Persistence of Incivility in Nursing.

BACKGROUND: Incivility in health care settings was first identified in 1976. The Institute of Medicine has called for a safer health care environment, and the Joint Commission emphasizes that disruptive behavior compromises patient safety. Incivility in nursing is a topic of interest, yet it had not been explored as a social process. AIM: The purpose of this study was to acquire an understanding and develop a theory to address incivility in nursing. METHOD: Twenty-nine RNs were interviewed based on Charmaz's constructionist grounded theory. RESULTS: Four categories emerged (neglecting, alienating, relinquishing, and finding oneself) that developed into the theory of self-positioning. CONCLUSION: To understand incivility in nursing, one must, immersed within the institution, profession, and society, find and position the self. It is only then that we can address the health and well-being of RNs, provide quality care, and ensure patient safety.

Cross-Disorder Cognitive Impairments in Youth Referred for Neuropsychiatric Evaluation.

OBJECTIVES: Studies suggest that impairments in some of the same domains of cognition occur in different neuropsychiatric conditions, including those known to share genetic liability. Yet, direct, multi-disorder cognitive comparisons are limited, and it remains unclear whether overlapping deficits are due to comorbidity. We aimed to extend the literature by examining cognition across different neuropsychiatric conditions and addressing comorbidity. METHODS: Subjects were 486 youth consecutively referred for neuropsychiatric evaluation and enrolled in the Longitudinal Study of Genetic Influences on Cognition. First, we assessed general ability, reaction time variability (RTV), and aspects of executive functions (EFs) in youth with non-comorbid forms of attention-deficit/hyperactivity disorder (ADHD), mood disorders and autism spectrum disorder (ASD), as well as in youth with psychosis. Second, we determined the impact of comorbid ADHD on cognition in youth with ASD and mood disorders. RESULTS: For EFs (working memory, inhibition, and shifting/ flexibility), we observed weaknesses in all diagnostic groups when participants' own ability was the referent. Decrements were subtle in relation to published normative data. For RTV, weaknesses emerged in youth with ADHD and mood disorders, but trend-level results could not rule out decrements in other conditions. Comorbidity with ADHD did not impact the pattern of weaknesses for youth with ASD or mood disorders but increased the magnitude of the decrement in those with mood disorders. CONCLUSIONS: Youth with ADHD, mood disorders, ASD, and psychosis show EF weaknesses that are not due to comorbidity. Whether such cognitive difficulties reflect genetic liability shared among these conditions requires further study. (JINS, 2018, 24, 91-103).

Extending the 'cross-disorder' relevance of executive functions to dimensional neuropsychiatric traits in youth.

BACKGROUND: Evidence that different neuropsychiatric conditions share genetic liability has increased interest in phenotypes with 'cross-disorder' relevance, as they may contribute to revised models of psychopathology. Cognition is a promising construct for study; yet, evidence that the same cognitive functions are impaired across different forms of psychopathology comes primarily from separate studies of individual categorical diagnoses versus controls. Given growing support for dimensional models that cut across traditional diagnostic boundaries, we aimed to determine, within a single cohort, whether performance on measures of executive functions (EFs) predicted dimensions of different psychopathological conditions known to share genetic liability. METHODS: Data are from 393 participants, ages 8-17, consecutively enrolled in the Longitudinal Study of Genetic Influences on Cognition (LOGIC). This project is conducting deep phenotyping and genomic analyses in youth referred for neuropsychiatric evaluation. Using structural equation modeling, we examined whether EFs predicted variation in core dimensions of the autism spectrum disorder, bipolar illness, and schizophrenia (including social responsiveness, mania/emotion regulation, and positive symptoms of psychosis, respectively). RESULTS: We modeled three cognitive factors (working memory, shifting, and executive processing speed) that loaded on a second-order EF factor. The EF factor predicted variation in our three target traits, but not in a negative control (somatization). Moreover, this EF factor was primarily associated with the overlapping (rather than unique) variance across the three outcome measures, suggesting that it related to a general increase in psychopathology symptoms across those dimensions. CONCLUSIONS: Findings extend support for the relevance of cognition to neuropsychiatric conditions that share underlying genetic risk. They suggest that higher-order cognition, including EFs, relates to the dimensional spectrum of each of these disorders and not just the clinical diagnoses. Moreover, results have implications for bottom-up models linking genes, cognition, and a general psychopathology liability.

Neurocognitive effects of proton radiation therapy in adults with low-grade glioma.

To understand neurocognitive effects of proton radiation therapy (PRT) in patients with low-grade glioma, we evaluated 20 patients who received this therapy prospectively and over 5 years with a comprehensive neuropsychological battery. 20 patients were evaluated at baseline and at yearly intervals for up to 5 years with a battery of neuropsychological measures that assessed intellectual, attention, executive, visuospatial and memory functions as well as mood and functional status. We evaluated change in cognitive functioning over time. We analyzed the relationship between cognitive performance and tumor location and also examined whether patients' performance differed from that reported in a study of normative practice effects. Overall, patients exhibited stability in cognitive functioning. Tumor location played a role in performance; those with tumors in the left hemisphere versus in the right hemisphere were more impaired at baseline on verbal measures (p < .05). However, we found greater improvement in verbal memory over time in patients with left than with right hemisphere tumors (p < .05). Results of our study, the first to investigate, in depth, neurocognitive effects of PRT in adults with low-grade gliomas, are promising. We hypothesize that the conformal advantage of PRT may contribute to preservation of cognitive functioning, although larger sample sizes and a longer period of study are required. Our study also highlights the need to consider normative practice effects when studying neurocognitive functioning in response to treatment over time, and the need to utilize comprehensive neuropsychological batteries given our findings that differentiate patients with left and right hemisphere tumors.

Proton therapy for low-grade gliomas: Results from a prospective trial.

BACKGROUND: In this prospective study, the authors evaluated potential treatment toxicity and progression-free survival in patients with low-grade glioma who received treatment with proton radiation therapy. METHODS: Twenty patients with World Health Organization grade 2 glioma who were eligible for radiation therapy were enrolled in a prospective, single-arm trial of proton therapy. The patients received proton therapy at a dose of 54 Gy (relative biological effectiveness) in 30 fractions. Comprehensive baseline and regular post-treatment evaluations of neurocognitive function, neuroendocrine function, and quality of life (QOL) were performed. RESULTS: All 20 patients (median age, 37.5 years) tolerated treatment without difficulty. The median follow-up after proton therapy was 5.1 years. At baseline, intellectual functioning was within the normal range for the group and remained stable over time. Visuospatial ability, attention/working memory, and executive functioning also were within normal limits; however, baseline neurocognitive impairments were observed in language, memory, and processing speed in 8 patients. There was no overall decline in cognitive functioning over time. New endocrine dysfunction was detected in 6 patients, and all but 1 had received direct irradiation of the hypothalamic-pituitary axis. QOL assessment revealed no changes over time. The progression-free survival rate at 3 years was 85%, but it dropped to 40% at 5 years. CONCLUSIONS: Patients with low-grade glioma tolerate proton therapy well, and a subset develops neuroendocrine deficiencies. There is no evidence for overall decline in cognitive function or QOL.

Altered Trajectories: Considering the Long-Term Impact of Educational Disruption during the COVID-19 Pandemic on Neurodevelopment and a Call to Action for Neuropsychology.

OBJECTIVE: The COVID-19 pandemic resulted in educational disruption of historic breadth and duration. The impact of school closures and remote learning have been evaluated in recent studies and reflect critical data for neuropsychologists who routinely assess brain development as it relates to diagnosis, recommendations, and informing public policy. METHOD: Pre-pandemic and contemporaneous literature was summarized, including data on educational disruption and child and adolescent mental health challenges reported during the pandemic, and research on the impact of stress, social isolation, educational achievement, and other factors on brain development during critical developmental windows. RESULTS: Studies indicate that prolonged educational disruption has resulted in attenuated learning gains, most remarkably for those already at risk for educational disparities. Studies have shown increased mental health challenges for youth during the pandemic, with higher rates of mood and eating disorders, and suicidal ideation. Given that some skills develop optimally within specific time periods, pandemic-related disruption has likely contributed to altered developmental trajectories. CONCLUSION: Trajectory of neuropsychological development of children and adolescents, especially marginalized students, may be affected by effects on learning and mental health due to prolonged educational disruption and psychological stressors. Evaluation and treatment may be delayed due to backlog and increased demand. Clinical neuropsychological practice recommendations are presented with a call to action for the field in moving forward flexibly to increase access to evaluation services.

Tele-Neuropsychology: From Science to Policy to Practice.

OBJECTIVE: The primary aim of this paper is to accelerate the number of randomized experimental studies of the reliability and validity in-home tele-neuropsychological testing (tele-np-t). METHOD: We conducted a critical review of the tele-neuropsychology literature. We discuss this research in the context of the United States' public and private healthcare payer systems, including the Centers for Medicare & Medicaid Services (CMS) and Current Procedural Terminology (CPT) coding system's telehealth lists, and existing disparities in healthcare access. RESULTS: The number of tele-np publications has been stagnant since the onset of the COVID-19 pandemic. There are less published experimental studies of tele-neuropsychology (tele-np), and particularly in-home tele-np-t, than other tele-np publications. There is strong foundational evidence of the acceptability, feasibility, and reliability of tele-np-t, but relatively few studies of the reliability and validity of in-home tele-np-t using randomization methodology. CONCLUSIONS: More studies of the reliability and validity of in-home tele-np-t using randomization methodology are necessary to support inclusion of tele-np-t codes on the CMS and CPT telehealth lists, and subsequently, the integration and delivery of in-home tele-np-t services across providers and institutions. These actions are needed to maintain equitable reimbursement of in-home tele-np-t services and address the widespread disparities in healthcare access.

Integrating Lifestyle Factor Science into Neuropsychological Practice: A National Academy of Neuropsychology Education Paper.

OBJECTIVE: The primary aim of this paper is to review evidence and clinical implications related to lifestyle activities associated with promoting brain and cognitive health. Our review targets four key lifestyle factors: physical activity and exercise, social engagement, cognitively stimulating activity, and consuming Mediterranean-style diets. METHOD: We conducted a critical review of the lifestyle factor literature in the four domains listed earlier. We contextualize this literature review by translating findings, when possible, into evidence-based recommendations to consider when providing neuropsychological services. RESULTS: There is significant current evidence supporting the role of physical activity and exercise, social engagement, cognitively stimulating activity, and consuming Mediterranean-style diets on positive brain and cognitive health outcomes. While some null findings are present in all four areas reviewed, the weight of the evidence supports the notion that engaging in these activities may promote brain and cognitive functioning. CONCLUSIONS: Clinical neuropsychologists can have confidence in recommending engagement in physical activity, social activity, and cognitively stimulating activity, and adhering to a Mediterranean-style diet to promote brain and cognitive health. We discuss limitations in existing lifestyle factor research and future directions to enhance the existing evidence base, including additional research with historically underrepresented groups and individuals with neurological conditions.

Differences in cognitive and academic performance during the COVID-19 pandemic in child psychiatric outpatients.

This study examined the impact of the COVID-19 pandemic on cognitive and academic functioning in 574 youth presenting for outpatient clinical neuropsychiatric evaluations. We extended the prior literature by (a) determining the extent to which academic difficulties documented in population and community samples also occurred in child psychiatric outpatients; (b) evaluating the impact of the pandemic on neuropsychological functions relevant to academic performance (overall cognition, executive functions, and graphomotor skill); and (c) investigating the moderating impact of attention deficit hyperactivity disorder (ADHD) diagnosis. We compared cross-sectional scores on standardized measures for groups of youth evaluated at three time periods related to the COVID-19 pandemic: (a) prior to onset (PRIOR; N = 198), (b) during Year 1 (Y1; N = 149), and (c) during Year 2 (Y2; N = 227). Relative to overall cognitive ability, math scores were lower in Y1 and Y2 and reading scores were lower in Y2. Additionally, relative to overall cognitive ability, youth showed lower working memory in Y1 and lower processing speed in Y1 and Y2. Graphomotor skill and parent-rated executive functions (EF) did not vary significantly across the three time periods. ADHD status did not moderate psychometric test scores but did moderate parent-rated EF. These data suggest that the COVID-19 pandemic has negatively impacted academic and executive functions in child psychiatry outpatients. More research is needed to understand the long-term implications for development. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Reforming learning disorder diagnosis following COVID-19 educational disruption.

Current diagnostic criteria for learning disorders are insufficient because of ongoing COVID-19-related educational disruption. Diagnostic criteria for learning disorders should be modified to reduce the risk of misdiagnosis and ensure timely intervention.

The impact of COVID-19 related educational disruption on children and adolescents: An interim data summary and commentary on ten considerations for neuropsychological practice.

OBJECTIVE: The coronavirus 19 (COVID-19) pandemic resulted in educational disruption of historic breadth and duration. The authors describe early studies and interim standardized assessment reports to highlight effects of educational disruption and present critical questions for neuropsychologists. METHOD: A summary of pre-pandemic and interim literature was compiled, including analyses of national and local assessment data and preliminary studies on academic gains related to remote learning, educational and school services disruption, chronic absenteeism, and child and adolescent mental and physical health during 2020-2021. Ten major themes were identified in the early reports on impacts of educational disruption. RESULTS: Preliminary information indicates prolonged educational disruption has resulted in attenuated learning gains, most remarkably for those already at risk for educational disparities: students of color, students with disabilities, English learners, and students from low-income households. There have also been increased mental and physical health challenges for some youth during the pandemic. Other literature highlights challenges such as diagnosis of learning disabilities, reliance on normative data and development of academic recovery programs. CONCLUSION: The effects of prolonged educational disruption and psychological stressors on learning and mental health should be considered in the neuropsychological evaluation of children and adolescents, especially marginalized students. Normative data collected prior to the pandemic may be insufficient for interpretation of scores, and evaluation and treatment may be delayed due to backlog and increased demand. Clinical practice considerations are presented.

Distinct patterns of emotional and behavioral change in child psychiatry outpatients during the COVID-19 pandemic.

BACKGROUND: Studies are documenting the impact of the COVID-19 pandemic on youth mental health. We extended this literature by characterizing a child psychiatric outpatient sample in the United States during the middle of the 2020-2021 school year. We also used a computational strategy to identify distinct patterns of psychopathology symptom change and examined correlates and predictors of such change. Among potential predictors were cognition and clinical diagnoses, which have not been studied in this context previously. METHODS: Participants were 171 youth (aged 10.6 ± 3.1) referred for neuropsychiatric evaluation who enrolled in research and whose parents filled out a survey on COVID-19. The questionnaire included eight psychiatric and six psychosocial domains rated retrospectively prior to the pandemic and currently at the time of evaluation. We examined change in severity of individual domains with Wilcoxon signed-rank tests. We used a latent profile analysis (LPA) to identify groups with distinct symptom change profiles. Using multinomial logistic regression, we examined potential predictors and correlates of LPA-derived groups. Models controlled for age, sex, and assessment date and corrected for multiple testing. RESULTS: Although the majority of individual psychopathology domains were worse on average during the 2020-2021 school year, youth showed distincive patterns of symptom change. In addition to a large group (72.2%) with relatively stable symptoms and a small group (6.4%) that improved on most symptoms, there were two groups with different constellations of worsening symptoms. These latter groups both showed increased sadness, anxiety and oppositionality; however, one had increased hyperactivity/impulsivity and no change in hopelessness while the other showed greater hopelessness and no change in hyperactivity. Symptoms related to the distinguishable domains of these groups predicted group membership, and changes in screen time, conflict with parents and social isolation were correlates of worsening. Cognition and lifetime clinical diagnoses failed to predict group membership. CONCLUSIONS: In youth outpatients, psychiatric and psychosocial difficulties were worse on average during the school year following the spring 2020 COVID-19 lockdown; yet, some youth experienced greater and distinctive symptom change. A personalized approach to support may be needed as youth emerge from this period.

Considering learning disabilities and attention-deficit hyperactivity disorder when assessing for neurodegenerative disease.

PURPOSE OF REVIEW: When evaluating an older adult for a possible neurodegenerative disease, the role of premorbid specific learning disabilities or attention-deficit hyperactivity disorder (ADHD) should be considered. These neurodevelopmental conditions can manifest as lifelong weaknesses and variability in cognitive functions that complicate assessment of cognitive decline. There is also accumulating evidence that certain neurodevelopmental disorders may entail greater risk for specific neurodegenerative disorders. RECENT FINDINGS: We describe clinical cases where diagnosis of neurodegenerative disease was influenced by preexisting neurodevelopmental disorders. We also present a questionnaire to assist with screening for premorbid learning disabilities and ADHD in older adults. SUMMARY: This article offers clinical guidance for practicing neurologists in the identification and assessment of neurodevelopmental disorders in older adult patients, which informs management and treatment. Consideration of lifetime functioning has become increasingly important with research linking neurodevelopmental disabilities to increased risk of specific neurodegenerative diseases.

Long-term outcomes and late adverse effects of a prospective study on proton radiotherapy for patients with low-grade glioma.

BACKGROUND: Patients with low-grade gliomas (LGG) can survive years with their illness. Proton radiotherapy (PRT) can reduce off-target dose and decrease the risk of treatment-related morbidity. We examined long-term morbidity following proton therapy in this updated prospective cohort of patients with LGG. METHODS: Twenty patients with LGG were enrolled prospectively and received PRT to 54 Gy(RBE) in 30 fractions. Comprehensive baseline and longitudinal assessments of toxicity, neurocognitive and neuroendocrine function, quality of life, and survival outcomes were performed up to 5 years following treatment. RESULTS: Six patients died (all of disease) and six had progression of disease. Median follow-up was 6.8 years for the 14 patients alive at time of reporting. Median progression-free survival (PFS) was 4.5 years. Of tumors tested for molecular markers, 71% carried the IDH1-R132H mutation and 29% had 1p/19q co-deletion. There was no overall decline in neurocognitive function; however, a subset of five patients with reported cognitive symptoms after radiation therapy had progressively worse function by neurocognitive testing. Six patients developed neuroendocrine deficiencies, five of which received Dmax ≥20 Gy(RBE) to the hypothalamus-pituitary axis (HPA). Most long-term toxicities developed within 2 years after radiation therapy. CONCLUSIONS: The majority of patients with LGG who received proton therapy retained stable cognitive and neuroendocrine function. The IDH1-R132H mutation was present in the majority, while 1p/19q loss was present in a minority. A subset of patients developed neuroendocrine deficiencies and was more common in those with higher dose to the HPA.

Cerebellar cognitive affective syndrome: insights from Joubert syndrome.

BACKGROUND: Joubert syndrome (JS) is a rare, autosomal recessively inherited genetic disorder characterized morphologically by unique developmental malformations of the cerebellum and brainstem (the molar tooth sign), and clinically by impaired motor functions and intellectual disability. Patients with JS often face multiple cognitive challenges, but the neuropsychological profile of this condition has not been well characterized. METHODS: We performed comprehensive neurological and neuropsychological evaluations in three adult brothers with JS, ages 32, 27, and 25 years. RESULTS: They all exhibited impaired motor control, global developmental delay most evident in executive function, affect regulation, and social skill set, and similar patterns of neuropsychiatric symptoms. CONCLUSIONS: These findings provide new insights into the intellectual and neurobehavioral phenotype of JS, which we regard as a developmental form of the cerebellar cognitive affective / Schmahmann syndrome (CCAS). These observations have direct clinical relevance for the diagnosis and care of patients with JS, and they help further the understanding of the multiple manifestations of atypical cerebrocerebellar development.