Progressive multifocal leukoencephalopathy secondary to idiopathic CD4 lymphocytopenia treated with pembrolizumab.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a rare demyelinating disease due to a lytic infection of oligodendrocytes caused by John Cunningham polyoma virus (JCV) infection. Idiopathic CD4+ T-cell lymphocytopenia (ICL) is a very rare cause of PML. METHODS: We present an individual with PML secondary to ICL treated with 3 doses of pembrolizumab, a Programmed-Death-1 Immune Checkpoint Inhibitor following with complete resolution of symptoms and conduct a review of the literature. CONCLUSION: This report illustrates the objective clinical and radiological improvement in a patient with PML due to ICL and suggests further study of immune checkpoint inhibitors as potential treatment for patients with PML.

Neuropsychological Function Response to Nocturnal Blue Light Blockage in Individuals With Symptoms of Insomnia: A Pilot Randomized Controlled Study.

OBJECTIVES: Insomnia is associated with neuropsychological dysfunction. Evidence points to the role of nocturnal light exposure in disrupted sleep patterns, particularly blue light emitted through smartphones and computers used before bedtime. This study aimed to test whether blocking nocturnal blue light improves neuropsychological function in individuals with insomnia symptoms. METHODS: This study used a randomized, placebo-controlled crossover design. Participants were randomly assigned to a 1-week intervention with amber lenses worn in wrap-around frames (to block blue light) or a 1-week intervention with clear lenses (control) and switched conditions after a 4-week washout period. Neuropsychological function was evaluated with tests from the NIH Toolbox Cognition Battery at three time points: (1) baseline (BL), (2) following the amber lenses intervention, and (3) following the clear lenses intervention. Within-subjects general linear models contrasted neuropsychological test performance following the amber lenses and clear lenses conditions with BL performance. RESULTS: Fourteen participants (mean(standard deviation, SD): age = 46.5(11.4)) with symptoms of insomnia completed the protocol. Compared with BL, individuals performed better on the List Sorting Working Memory task after the amber lenses intervention, but similarly after the clear lenses intervention (F = 5.16; p = .014; η2 = 0.301). A similar pattern emerged on the Pattern Comparison Processing Speed test (F = 7.65; p = 0.002; η2 = 0.370). Consideration of intellectual ability indicated that treatment with amber lenses "normalized" performance on each test from approximately 1 SD below expected performance to expected performance. CONCLUSIONS: Using a randomized, placebo-controlled crossover design, we demonstrated improvement in processing speed and working memory with a nocturnal blue light blocking intervention among individuals with insomnia symptoms. (JINS, 2019, 25, 668-677).

Sleep-disordered breathing, neuroendocrine function, and clinical SUDEP risk in patients with epilepsy.

INTRODUCTION: Sudden unexpected death in epilepsy (SUDEP) is a major contributor to epilepsy-related mortality. It is associated with nocturnal seizures and centrally mediated postictal cardiorespiratory dysfunction (CRD), but mechanisms and contributors remain poorly understood. METHODS: We performed a prospective, cross-sectional, observational pilot study in the Columbia University Medical Center (CUMC) adult epilepsy monitoring unit (EMU) to explore relationships between periictal CRD, sleep-disordered breathing (SDB), neuroendocrine function, and clinical SUDEP risk. Thirty patients (twenty women, ten men) underwent video-electroencephalogram (EEG) with electrocardiogram (EKG) and digital pulse oximetry, inpatient or outpatient polysomnography (PSG), and comprehensive laboratory evaluation of sex steroid hormones. Sudden unexpected death in epilepsy risk was defined as Low (0-2) or High (≥3) using the revised SUDEP-7 Inventory. Sleep-disordered breathing was defined using standard criteria. Neuroendocrine dysfunction was defined as ≥1 laboratory abnormality. RESULTS: Cardiorespiratory dysfunction occurred more frequently in high-risk patients (60% vs. 27%, p = 0.018). Endocrine dysfunction was seen in 35% of patients, more in men (p = 0.018). Sleep-disordered breathing was found in 88% of fully scoreable PSGs. CONCLUSIONS: There was no significant relationship between CRD, SDB, and neuroendocrine status, though all PSGs in those with high SUDEP risk or neuroendocrine dysfunction revealed SDB. Larger studies are needed to further elucidate relationships between CRD, SDB, neuroendocrine factors, and SUDEP.

Blocking nocturnal blue light for insomnia: A randomized controlled trial.

The use of light-emitting electronic devices before bedtime may contribute to or exacerbate sleep problems. Exposure to blue-wavelength light in particular from these devices may affect sleep by suppressing melatonin and causing neurophysiologic arousal. We aimed to determine if wearing amber-tinted blue light-blocking lenses before bedtime improves sleep in individuals with insomnia. Fourteen individuals (n = 8 females; age ± SD 46.6 ± 11.5 y) with insomnia symptoms wore blue light-blocking amber lenses or clear placebo lenses in lightweight wraparound frames for 2 h immediately preceding bedtime for 7 consecutive nights in a randomized crossover trial (4-wk washout). Ambulatory sleep measures included the Pittsburgh Insomnia Rating Scale (PIRS) completed at the end of each intervention period, and daily post-sleep questionnaire and wrist-actigraphy. PIRS total scores, and Quality of Life, Distress, and Sleep Parameter subscales, were improved in amber vs. clear lenses condition (p-values <0.05). Reported wake-time was significantly delayed, and mean subjective total sleep time (TST), overall quality, and soundness of sleep were significantly higher (p-values <0.05) in amber vs. clear lenses condition over the 7-d intervention period. Actigraphic measures of TST only were significantly higher in amber vs. clear lenses condition (p = 0.035). Wearing amber vs. clear lenses for 2-h preceding bedtime for 1 week improved sleep in individuals with insomnia symptoms. These findings have health relevance given the broad use of light-emitting devices before bedtime and prevalence of insomnia. Amber lenses represent a safe, affordable, and easily implemented therapeutic intervention for insomnia symptoms. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov Identifier: NCT02698800.

Revised Framingham Stroke Risk Profile to Reflect Temporal Trends.

BACKGROUND: Age-adjusted stroke incidence has decreased over the past 50 years, likely as a result of changes in the prevalence and impact of various stroke risk factors. An updated version of the Framingham Stroke Risk Profile (FSRP) might better predict current risks in the FHS (Framingham Heart Study) and other cohorts. We compared the accuracy of the standard (old) and of a revised (new) version of the FSRP in predicting the risk of all-stroke and ischemic stroke and validated this new FSRP in 2 external cohorts, the 3C (3 Cities) and REGARDS (Reasons for Geographic and Racial Differences in Stroke) studies. METHODS: We computed the old FSRP as originally described and a new model that used the most recent epoch-specific risk factor prevalence and hazard ratios for individuals ≥55 years of age and for the subsample ≥65 years of age (to match the age range in REGARDS and 3C studies, respectively) and compared the efficacy of these models in predicting 5- and 10-year stroke risks. RESULTS: The new FSRP was a better predictor of current stroke risks in all 3 samples than the old FSRP (calibration χ2 of new/old FSRP: in men: 64.0/12.1, 59.4/30.6, and 20.7/12.5; in women: 42.5/4.1, 115.4/90.3, and 9.8/6.5 in FHS, REGARDS, and 3C, respectively). In the REGARDS, the new FSRP was a better predictor among whites compared with blacks. CONCLUSIONS: A more contemporaneous, new FSRP better predicts current risks in 3 large community samples and could serve as the basis for examining geographic and racial differences in stroke risk and the incremental diagnostic utility of novel stroke risk factors.

Prolonged sleep duration as a marker of early neurodegeneration predicting incident dementia.

OBJECTIVE: To evaluate the association between sleep duration and the risk of incident dementia and brain aging. METHODS: Self-reported total hours of sleep were examined in the Framingham Heart Study (n = 2,457, mean age 72 ± 6 years, 57% women) as a 3-level variable: <6 hours (short), 6-9 hours (reference), and >9 hours (long), and was related to the risk of incident dementia over 10 years, and cross-sectionally to total cerebral brain volume (TCBV) and cognitive performance. RESULTS: We observed 234 cases of all-cause dementia over 10 years of follow-up. In multivariable analyses, prolonged sleep duration was associated with an increased risk of incident dementia (hazard ratio [HR] 2.01; 95% confidence interval [CI] 1.24-3.26). These findings were driven by persons with baseline mild cognitive impairment (HR 2.83; 95% CI 1.06-7.55) and persons without a high school degree (HR 6.05; 95% CI 3.00-12.18). Transitioning to sleeping >9 hours over a mean period of 13 years before baseline was associated with an increased risk of all-cause dementia (HR 2.43; 95% CI 1.44-4.11) and clinical Alzheimer disease (HR 2.20; 95% CI 1.17-4.13). Relative to sleeping 6-9 hours, long sleep duration was also associated cross-sectionally with smaller TCBV (ß ± SE, -1.08 ± 0.41 mean units of TCBV difference) and poorer executive function (ß ± SE, -0.41 ± 0.13 SD units of Trail Making Test B minus A score difference). CONCLUSIONS: Prolonged sleep duration may be a marker of early neurodegeneration and hence a useful clinical tool to identify those at a higher risk of progressing to clinical dementia within 10 years.

Sleep Disordered Breathing and White Matter Hyperintensities in Community-Dwelling Elders.

STUDY OBJECTIVES: To examine the association between markers of sleep-disordered breathing (SDB) and white matter hyperintensity (WMH) volume in an elderly, multiethnic, community-dwelling cohort. METHODS: This is a cross-sectional analysis from the Washington Heights-Inwood Columbia Aging Project (WHICAP), a community-based epidemiological study of older adults. Structural magnetic resonance imaging was obtained starting in 2004; the Medical Outcomes Study-Sleep Scale (MOS-SS) was administered to participants starting in 2007. Linear regression models were used to assess the relationship between the two MOS-SS questions that measure respiratory dysfunction during sleep and quantified WMH volume among WHICAP participants with brain imaging. RESULTS: A total of 483 older adults had both structural magnetic resonance imaging and sleep assessment. Self-reported SDB was associated with WMH. After adjusting for demographic and vascular risk factors, WMH volumes were larger in individuals with frequent snoring (ß = 2.113, P = 0.004) and among those who reported waking short of breath or with headache (ß = 1.862, P = 0.048). CONCLUSIONS: In community-dwelling older adults, self-reported measures of SDB are associated with larger WMH volumes. The cognitive effects of SDB that are increasingly being recognized may be mediated at the small vessel level.

Sleep in the neurological intensive care unit: feasibility of quantifying sleep after melatonin supplementation with environmental light and noise reduction.

PURPOSE: Sleep deprivation may be particularly detrimental to intensive care unit (ICU) patients. Polysomnography has demonstrated abnormal sleep in medical and surgical ICU populations. Both environmental factors and circadian disruption have been implicated. We hypothesized that patients in a neurologic ICU would demonstrate similar sleep disturbances and that a combination of sleep-promoting interventions would increase sleep time. METHODS: Twelve patients were enrolled in this pilot-randomized, controlled, study in a neurologic ICU. For adult patients undergoing continuous EEG for clinical purposes, noise-cancelling headphones and eye masks were worn, and an oral dose of melatonin was administered for 3 days, or until EEG was stopped. Sleep was scored according to standard criteria; EEG was characterized and analyzed quantitatively. RESULTS: Sixty-five percent of the patients' recordings were unscorable based on accepted standardized criteria; therefore, sleep measures could not be compared. For those with sleep that could be scored, total sleep time was normal, although sleep was fragmented and time spent in slow-wave or rapid eye movement sleep was notably decreased. Patients with unscorable recordings had worse injury severity measures, absent or significantly slower posterior dominant rhythm, and less coherence of posterior faster frequencies. Clinical outcomes were similar between intervention and control groups. CONCLUSIONS: Although sleep-promoting interventions were feasible, sleep quantification based on currently accepted criteria limited the ability to score sleep. Similar to other ICUs, sleep in the neurologic ICU is abnormal; patients with unscorable sleep-like states have greater injury severity. This study was limited by strict enrollment criteria. A reliable method to quantify sleep and sleep-like states in the ICU is needed.

CPAP treats muscle cramps in patients with obstructive sleep apnea.

We describe a case series of 4 patients with varying degrees of obstructive sleep apnea who incidentally had a history of nocturnal leg cramps. None of the patients had periodic limb movements during the study and denied symptoms consistent with restless legs syndrome. In 3 of the 4 patients, nocturnal leg cramps resolved with CPAP treatment for OSA, while the fourth patient noted near-resolution of cramping after starting CPAP. In patients presenting with muscle cramps, obstructive sleep apnea should be considered.

Insulin-like growth factor-1 and risk of Alzheimer dementia and brain atrophy.

OBJECTIVE: To relate serum insulin-like growth factor-1 (IGF-1) to risk of Alzheimer disease (AD) dementia and to brain volumes in a dementia-free community sample spanning middle and older ages. METHODS: Dementia-free Framingham participants from generation 1 (n = 789, age 79 ± 4 years, 64% women) and generation 2 (n = 2,793, age 61 ± 9 years, 55% women; total = 3,582, age 65 ± 11 years, 57% women) had serum IGF-1 measured in 1990-1994 and 1998-2001, respectively, and were followed prospectively for incident dementia and AD dementia. Brain MRI was obtained in stroke- and dementia-free survivors of both generations 1 (n = 186) and 2 (n = 1,867) during 1999-2005. Baseline IGF-1 was related to risk of incident dementia using Cox models and to total brain and hippocampal volumes using linear regression in multivariable models adjusted for age, sex, APOE ε4, plasma homocysteine, waist-hip ratio, and physical activity. RESULTS: Mean IGF-1 levels were 144 ± 60 µg/L in generation 1 and 114 ± 37 µg/L in generation 2. We observed 279 cases of incident dementia (230 AD dementia) over a mean follow-up of 7.4 ± 3.1 years. Persons with IGF-1 in the lowest quartile had a 51% greater risk of AD dementia (hazard ratio = 1.51, 95% confidence interval: 1.14-2.00; p = 0.004). Among persons without dementia, higher IGF-1 levels were associated with greater total brain volumes (ß/SD increment in IGF-1 was 0.55 ± 0.24, p = 0.025; and 0.26 ± 0.06, p < 0.001, for generations 1 and 2, respectively). CONCLUSION: Lower serum levels of IGF-1 are associated with an increased risk of developing AD dementia and higher levels with greater brain volumes even among middle-aged community-dwelling participants free of stroke and dementia. Higher levels of IGF-1 may protect against subclinical and clinical neurodegeneration.

Relations of arterial stiffness and endothelial function to brain aging in the community.

OBJECTIVE: To determine the association of arterial stiffness and pressure pulsatility, which can damage small vessels in the brain, with vascular and Alzheimer-type brain aging. METHODS: Stroke- and dementia-free Framingham Offspring Study participants (n = 1,587, 61 ± 9 years, 45% male) underwent study of tonometric arterial stiffness and endothelial function (1998-2001) and brain MRI and cognition (1999-2002). We related carotid-femoral pulse wave velocity (CFPWV), mean arterial and central pulse pressure, and endothelial function to vascular brain aging by MRI (total cerebral brain volume [TCBV], white matter hyperintensity volume, silent cerebral infarcts) and vascular and Alzheimer-type cognitive aging (Trails B minus Trails A and logical memory-delayed recall, respectively). RESULTS: Higher CFPWV was associated with lower TCBV, greater white matter hyperintensity volume, and greater prevalence of silent cerebral infarcts (all p < 0.05). Each SD greater CFPWV was associated with lower TCBV equivalent to 1.2 years of brain aging. Mean arterial and central pulse pressure were associated with greater white matter hyperintensity volume (p = 0.005) and lower TCBV (p = 0.02), respectively, and worse verbal memory (both p < 0.05). Associations of tonometry variables with TCBV and white matter hyperintensity volume were stronger among those aged 65 years and older vs those younger than 65 years (p < 0.10 for interaction). Brachial artery endothelial function was unrelated to MRI measures (all p > 0.05). CONCLUSIONS: Greater arterial stiffness and pressure pulsatility are associated with brain aging, MRI vascular insults, and memory deficits typically seen in Alzheimer dementia. Future investigations are warranted to evaluate the potential impact of prevention and treatment of unfavorable arterial hemodynamics on neurocognitive outcomes.

Somato-dendritic nicotinic receptor responses recorded in vitro from the medial septal diagonal band complex of the rodent.

The medial septal diagonal band area (MS/DB), made up of GABAergic and cholinergic neurones, plays an essential role in the generation and modulation of the hippocampal theta rhythm. To understand the part that the cholinergic neurones might play in this activity, we sought to determine whether postsynaptic nicotinic receptor responses can be detected in slices of the rodent MS/DB by puffing on acetylcholine (ACh). Neurones were characterized electrophysiologically into GABAergic and cholinergic neurones according to previous criteria. Responses of the MS/SB neurones to ACh were various combinations of fast depolarizations (1.5-2.5 s), fast hyperpolarizations (3-4 s) and slow depolarizations (20-30 s), the latter two being blocked by atropine. The fast depolarizations were partially or not blocked with cadmium and low calcium, tetrodotoxin, and antagonists of other ionotropic receptors, and were antagonized with 25 microm mecamylamine. Pharmacological investigation of the responses showed that the alpha 7* nicotinic receptor type is associated with cholinergic neurones and 10% of the GABAergic neurones, and that non alpha 7* nicotinic receptor subtypes are associated with 50% of the GABAergic neurones. Pharmacological dissection of evoked and spontaneous postsynaptic responses, however, did not provide evidence for synaptic nicotinic receptor transmission in the MS/DB. It was concluded that nicotinic receptors, although prevalent on the somatic and/or dendritic membrane compartments of neurones in the MS/DB, are on extrasynaptic sites where they presumably play a neuromodulatory role. The presence of alpha 7* nicotinic receptors on cholinergic neurones may also render these cells specifically vulnerable to degeneration in Alzheimer's disease.