School status and its associations among children with epilepsy in the Republic of Guinea.

BACKGROUND: In low-income countries (LICs), there are multiple barriers for children with epilepsy (CWE) to attend school. We examined potentially modifiable associations with poor school performance in CWE in the West African Republic of Guinea. METHODS: Children with epilepsy of school age were recruited using public announcements and a clinical register of people with epilepsy at the Ignace Deen Hospital in Conakry in 2018. A team of Guinean and U.S. neurologists and neurologists-in-training interviewed each CWE and parent for his/her epilepsy history, household finances, educational attainment level, and perceived stigma using the Stigma Scale of Epilepsy (SSE). Each child was also tested using the Wechsler Nonverbal Scale of Ability (WNV). Low school performance was defined as either not attending school or being held back a grade level at least once. Potential predictors of low school performance were analyzed. FINDINGS: Of 128 CWE (mean age: 11.6 years, 48.4% female), 11.7% (n = 15) never attended school, 23.3% (n = 30) dropped out, and 64.8% (n = 83) were currently enrolled. Of CWE attending school, 46.9% (n = 39) were held back a grade level. Overall, 54 children were defined as low performers (LPs) (42%). ;Greater than 100 lifetime seizures (odds ratio (OR) = 8.81; 95% confidence interval (CI) = 2.51, 37.4; p = 0.001) and lower total WNV score (OR = 0.954; 95% CI = 0.926, 0.977; p < 0.001) were significantly associated with poor school performance in separate models, when controlling for potential confounders. Given the strong relationship between seizure freedom and school performance, we estimated that 38 additional CWE (33.6%) could become high performers (HPs) if all CWE were adequately treated to achieve the lifetime seizure category of <10 seizures and could be cognitively intact again. Models examining SSE and household wealth quintile were not significantly associated with school performance. CONCLUSIONS: Higher lifetime seizures and lower WNV score were significantly associated with low school performance in CWE in Guinea. In spite of our conservative definition of high school performance (attending without failing) and risk of referral bias at an academic center where patients were allowed to self-refer, we demonstrate that seizure control in this setting could increase the number of CWE who could attend and stay in school.

Quality of education impacts late-life cognition.

OBJECTIVES: Screening tests of global cognition detect racial differences in scores even after adjustment for educational attainment. Differential educational environments in adolescence may affect individual cognitive function. This study examines the impact of high school educational quality on late-life cognition among community-dwelling older adults. METHODS/DESIGN: Data were collected from community-dwelling individuals from the Philadelphia Healthy Brain Aging (PHBA) cohort at the University of Pennsylvania Health System. The present analysis included subjects from the PHBA over the age of 55 years without a diagnosis of Parkinson's disease or dementia, who had attended high school in the City of Philadelphia. Cognition was assessed using the Montreal Cognitive Assessment (MoCA); clinical information was abstracted from the subject's electronic health record. High school information was obtained from the Philadelphia Board of Education. After univariable correlations were defined, we performed stepwise multiple linear regression models to determine the most significant predictors of late-life cognitive status. RESULTS: A total of 130 subjects meeting inclusion criteria were included in the analysis. Years of education, race, educational level, school district, and financial status were all positively associated with MoCA. Significant negative associations included composite vascular risk, attendance at highly segregated schools, and historical poverty status. In stepwise multiple linear regression modeling, the impact of race on cognition remained significant when educational attainment was added to the model but was no longer significant once segregation status was added. CONCLUSIONS: This work suggests that academic and community factors beyond years of education have a marked impact on late-life cognition.

The Changing Face of Osmotic Demyelination Syndrome: A Retrospective, Observational Cohort Study.

OBJECTIVE: To describe the long-term outcomes of osmotic demyelination syndrome (ODS) in an updated cohort. METHODS: We performed a retrospective medical records review of cases of ODS at the Massachusetts General and Brigham and Women's Hospitals using International Classification of Diseases-9th edition codes and a text-based search for central pontine myelinolysis, extrapontine myelinolysis, and osmotic demyelination syndrome (1999-2018). Cases were individually selected based on patients having neuroimaging and symptoms consistent with ODS and no other potentially explanatory etiology. Modified Rankin scale (mRS) scores were extracted at prehospitalization, hospital discharge, 6 months post discharge, and the most recently available clinical visit. RESULTS: We identified 45 cases of ODS (mean age 48.4 years, range 0.07-75 years; 58% female patients). Common comorbidities included liver disease (27%, n = 12), alcoholism (44%, n = 20), and kidney failure (20%, n = 9). Twenty-nine percent of patients had a rapid correction of hyponatremia. Twenty-nine percent had other electrolyte abnormalities. Only 59% (24/41) of patients with complete electrolyte data had abnormalities that could explain their ODS. At the 6-month follow-up, 16% of the patients were dead and 60% of patients had minimal-to-no disability (mRS 0-2). CONCLUSIONS: ODS has a diverse range of clinical presentations. Not all patients have electrolyte abnormalities. The prognosis is generally favorable, although 1 in 6 patients had died at 6 months, likely because of underlying disease states.

Dual HDAC and PI3K Inhibition Abrogates NFκB- and FOXM1-Mediated DNA Damage Response to Radiosensitize Pediatric High-Grade Gliomas.

Aberrant chromatin remodeling and activation of the PI3K pathway have been identified as important mediators of pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) pathogenesis. As inhibition of these pathways are promising therapeutic avenues and radiation is the only modality to prolong survival of patients with DIPG, we sought to explore radiosensitizing functions of such inhibition and to explore mechanisms of action of such agents. Here, we demonstrate that combined treatment with radiotherapy and CUDC-907, a novel first-in-class dual inhibitor of histone deacetylases (HDAC) and PI3K, evokes a potent cytotoxic response in pHGG and DIPG models. CUDC-907 modulated DNA damage response by inhibiting radiation-induced DNA repair pathways including homologous recombination and nonhomologous end joining. The radiosensitizing effects of CUDC-907 were mediated by decreased NFκB/Forkhead box M1 (FOXM1) recruitment to promoters of genes involved in the DNA damage response; exogenous expression of NFκB/FOXM1 protected from CUDC-907-induced cytotoxicity. Together, these findings reveal CUDC-907 as a novel radiosensitizer with potent antitumor activity in pHGG and DIPG and provide a preclinical rationale for the combination of CUDC-907 with radiotherapy as a novel therapeutic strategy against pHGG and DIPG. More globally, we have identified NFκB and FOXM1 and their downstream transcriptional elements as critical targets for new treatments for pHGG and DIPG.Significance: These findings describe the radiosensitizing effect of a novel agent in pediatric high-grade gliomas, addressing a critical unmet need of increasing the radiation sensitivity of these highly aggressive tumors. Cancer Res; 78(14); 4007-21. ©2018 AACR.

Parkinsonian signs are a risk factor for falls.

BACKGROUND: Parkinsonian signs are common, non-specific findings in older adults and associated with increased rates of dementia and mortality. It is important to understand which motor outcomes are associated with parkinsonian signs. OBJECTIVES: To determine the role of parkinsonian signs on fall rates among older adults. METHODS: We conducted a longitudinal study of primary care patients from the University of Pennsylvania Health System. Adults over 55 years were assessed at baseline through surveys and a neurological examination. We recorded falls over the following 2 years. Parkinsonian signs were defined as the presence of 2 of 4 cardinal signs. Incident falls were compared between subjects with and without parkinsonian signs, and modified Poisson regression used to adjust for potential confounders in the relationship between parkinsonian signs and falls. RESULTS: 982 subjects with a mean age of 68 (s.d. 8.8) years participated. 29% of participants fell and 12% exhibited parkinsonian signs at baseline. The unadjusted RR for falls among individuals with parkinsonian signs was 1.36 (95% CI 1.05-1.76, p=0.02). After adjusting for age, cognitive function, urinary incontinence, depression, diabetes, stroke and arthritis, individuals with parkinsonian signs were still 38% more likely to fall than those without parkinsonian signs (RR 1.38, 95% CI 1.04-1.82; p=0.03). Falls among those with parkinsonian signs were more likely to lead to injury (53% vs 37%; p=0.04). CONCLUSIONS: Parkinsonian signs are a significant, independent risk factor for falls. Early detection of this clinical state is important in order to implement fall prevention programs among primary care patients.

Associations and implications of low health literacy in Parkinson's Disease.

BACKGROUND: Low health literacy (HL) indicates a limited ability to understand and use basic information to make appropriate healthcare decisions. While low HL is associated with higher morbidity, mortality, and healthcare costs in multiple chronic conditions, little is known about HL and its associations in Parkinson's disease (PD). METHODS: Cross-sectional study of non-demented adults with PD participating in the National Parkinson Foundation Parkinson's Outcomes Project at the University of Pennsylvania. Subjects were administered two brief HL assessments-the Rapid Estimate of Adult Literacy in Medicine-Short Form (REALM-SF), a word-recognition test, and the Newest Vital Sign (NVS), a test of literacy, numeracy and understanding of health information-as well as demographic and clinical questionnaires. Adverse outcomes included falls in the 3 months preceding the study visit, and hospital admissions, emergency room visits, infections, or injuries in the preceding year. Caregiver burden was measured using the Multidimensional Caregiver Strain Index. RESULTS: 168 subjects completed both HL screens (mean 65.8 years, 65.5% male, 65.2% Hoehn & Yahr Stage 2). Using the REALM-SF, 97.6% of subjects had adequate HL. Using the NVS, however, 29.8% had low HL, which was associated with older age, lower education, male gender, greater disease severity, and poorer cognition. Low HL was associated with hospital admission and increased caregiver burden. CONCLUSIONS: Low HL is common and associated with greater caregiver burden and a higher likelihood of hospitalization in patients with PD. Since HL is associated with both disease severity and adverse outcomes, it may be an important, modifiable contributor to morbidity.

Computerized assessment of goal-directed behavior in Parkinson's disease.

INTRODUCTION: Apathy is a syndrome characterized by a reduction in goal-directed behavior. Neurodegenerative diseases frequently exhibit apathy. However, we lack an objective measure of apathy. The Philadelphia Apathy Computerized Task (PACT) measures impairments in goal-directed behavior that contribute to apathy, including initiation, planning, and motivation. We sought to examine these mechanisms in Parkinson's disease (PD) patients. METHOD: PD patients and healthy controls with a caregiver were recruited for the study. Participants were administered the PACT, a novel computerized assessment of goal-directed behavior based on reaction times, and the Starkstein Apathy Scale (AS). Care partners completed the Neuropsychiatric Inventory (NPI). Baseline demographic characteristics of PD and control participants were compared using t tests and Wilcoxon rank sum tests. Linear regressions were used to compare PD patients to controls on each of the three PACT subtasks (initiation, planning, and motivation) while controlling for motor slowing. We then compared performance on each PACT subtask between PD subjects defined as apathetic using the NPI and Starkstein Apathy Scale and controls. RESULTS: We included 30 PD and 15 control participants in the analysis. When controlling for motor slowing, both all PD and PD apathetic subjects were significantly slower than controls on the planning task and on the initiation task. There were no significant differences between PD patients and controls on the motivation tasks. CONCLUSIONS: PD patients showed specific initiation and planning deficits compared to control participants. After using traditional scales to define apathy, PD apathetic patients still exhibited impaired initiation and planning behaviors. These results suggest that the PACT measures aspects of impaired goal-directed behavior that may contribute to apathy in PD.

Caregiver report of apathy predicts dementia in Parkinson's disease.

INTRODUCTION: Apathy is a common, troublesome symptom in Parkinson's disease (PD). However, little is known about its relationship with long-term cognition. We sought to determine if a caregiver-reported apathy measure predicts the development of PD dementia. METHODS: Non-demented PD patients were recruited as part of a longitudinal study of cognition. Demographics, medications, Dementia Rating Scale-2, Unified Parkinson's Disease Rating Scale, Geriatric Depression Scale and the Neuropsychiatric Inventory-Questionnaire (NPI-Q) ratings were obtained. Apathy was defined as an NPI-Q apathy score ≥1. Participants were evaluated annually with cognitive and functional assessments until the end of the study period or a physician consensus diagnosis of dementia was assigned. Cox proportional hazard models were used to assess the effects of baseline apathy on dementia development while controlling for other clinical and demographic factors. RESULTS: Of 132 PD patients 12.1% (N = 16) scored in the apathetic range at baseline. A total of 19.6% (N = 26) individuals developed dementia over the course of the study, 8 of whom (30.8% of future dementia patients) had baseline apathy. In bivariate analyses baseline apathy, older age, and worse cognitive, motor, and depressive symptom scores predicted the development of dementia. In a multivariate analysis the predictive effects of baseline apathy were still significant (HR = 3.56; 95% CI = 1.09-11.62; p = 0.04). CONCLUSIONS: A simple, caregiver-reported measure of apathy is an independent predictor of progression to dementia in PD. This highlights the importance of apathy as a clinical characteristic of PD and could prove useful for the prediction of future dementia.