Sleep functional connectivity, hyperexcitability, and cognition in Alzheimer's disease.

INTRODUCTION: Sleep disturbances are common in Alzheimer's disease (AD) and may reflect pathologic changes in brain networks. To date, no studies have examined changes in sleep functional connectivity (FC) in AD or their relationship with network hyperexcitability and cognition. METHODS: We assessed electroencephalogram (EEG) sleep FC in 33 healthy controls, 36 individuals with AD without epilepsy, and 14 individuals with AD and epilepsy. RESULTS: AD participants showed increased gamma connectivity in stage 2 sleep (N2), which was associated with longitudinal cognitive decline. Network hyperexcitability in AD was associated with a distinct sleep connectivity signature, characterized by decreased N2 delta connectivity and reversal of several connectivity changes associated with AD. Machine learning algorithms using sleep connectivity features accurately distinguished diagnostic groups and identified "fast cognitive decliners" among study participants who had AD. DISCUSSION: Our findings reveal changes in sleep functional networks associated with cognitive decline in AD and may have implications for disease monitoring and therapeutic development. HIGHLIGHTS: Brain functional connectivity (FC) in Alzheimer's disease is altered during sleep. Sleep FC measures correlate with cognitive decline in AD. Network hyperexcitability in AD has a distinct sleep connectivity signature.

Epilepsy and sleep characteristics are associated with diminished 24-h memory retention in older adults with epilepsy.

OBJECTIVE: Individuals with epilepsy often have memory difficulties, and older adults with epilepsy are especially vulnerable, due to the additive effect of aging. The goal of this study was to assess factors that are associated with 24-h memory retention in older adults with epilepsy. METHODS: Fifty-five adults with epilepsy, all aged >50 years, performed a declarative memory task involving the recall of the positions of 15 card pairs on a computer screen prior to a 24-h ambulatory electroencephalogram (EEG). We assessed the percentage of encoded card pairs that were correctly recalled after 24 h (24-h retention rate). EEGs were evaluated for the presence and frequency of scalp interictal epileptiform activity (IEA) and scored for total sleep. Global slow wave activity (SWA) power during non-rapid eye movement sleep was also calculated. RESULTS: Forty-four participants successfully completed the memory task. Two were subsequently excluded due to seizures on EEG. The final cohort (n = 42) had a mean age of 64.3 ± 7.5 years, was 52% female, and had an average 24-h retention rate of 70.9% ± 30.2%. Predictors of 24-h retention based on multivariate regression analysis when controlling for age, sex, and education included number of antiseizure medications (ß = -.20, p = .013), IEA frequency (ß = -.08, p = .0094), and SWA power (ß = +.002, p = .02). SIGNIFICANCE: In older adults with epilepsy, greater frequency of IEA, reduced SWA power, and higher burden of antiseizure medications correlated with worse 24-h memory retention. These factors represent potential treatment targets to improve memory in older adults with epilepsy.

Initial case series of a novel sensing deep brain stimulation device in drug-resistant epilepsy and consistent identification of alpha/beta oscillatory activity: A feasibility study.

OBJECTIVE: Here, we report a retrospective, single-center experience with a novel deep brain stimulation (DBS) device capable of chronic local field potential (LFP) recording in drug-resistant epilepsy (DRE) and explore potential electrophysiological biomarkers that may aid DBS programming and outcome tracking. METHODS: Five patients with DRE underwent thalamic DBS, targeting either the bilateral anterior (n = 3) or centromedian (n = 2) nuclei. Postoperative electrode lead localizations were visualized in Lead-DBS software. Local field potentials recorded over 12-18 months were tracked, and changes in power were associated with patient events, medication changes, and stimulation. We utilized a combination of lead localization, in-clinic broadband LFP recordings, real-time LFP response to stimulation, and chronic recordings to guide DBS programming. RESULTS: Four patients (80%) experienced a >50% reduction in seizure frequency, whereas one patient had no significant reduction. Peaks in the alpha and/or beta frequency range were observed in the thalamic LFPs of each patient. Stimulation suppressed these LFP peaks in a dose-dependent manner. Chronic timeline data identified changes in LFP amplitude associated with stimulation, seizure occurrences, and medication changes. We also noticed a circadian pattern of LFP amplitudes in all patients. Button-presses during seizure events via a mobile application served as a digital seizure diary and were associated with elevations in LFP power. SIGNIFICANCE: We describe an initial cohort of patients with DRE utilizing a novel sensing DBS device to characterize potential LFP biomarkers of epilepsy that may be associated with seizure control after DBS in DRE. We also present a new workflow utilizing the Percept device that may optimize DBS programming using real-time and chronic LFP recording.

Epilepsy care in nursing facilities: Knowledge gaps and opportunities.

Epilepsy in the elderly is a complex disease, often underdiagnosed, and inadequately treated. It requires a multi-disciplinary approach and care coordination especially if the patient resides in a nursing facility. Episodes of loss of consciousness falls, or amnestic events in those living in a nursing facility require a detailed description and an urgent assessment to rule out an epileptic seizure. Prompt recognition of seizures and the implementation of treatment protocols in those with recurrent seizures are needed to prevent unnecessary emergency visits. Although there is a myriad of antiseizure medications (ASM) to treat seizures, clinicians should be aware of common interactions, side effects, and changes in pharmacodynamics with age. There is a limited number of ASMs that have been properly studied in clinical trials to assess tolerability and efficacy in the elderly, and an over-reliance on enzyme-inducing ASMs. Strategies to improve the knowledge of health care providers include electronic resources, treatment protocols, and improving awareness of the efficacy, drug-drug interaction, and short-term and long-term monitoring of ASM side effects.

Generalized tonic-clonic seizures are accompanied by changes of interrelations within the autonomic nervous system.

PURPOSE: A seizure is a strong central stimulus that affects multiple subsystems of the autonomic nervous system (ANS), and results in different interactions across ANS modalities. Here, we aimed to evaluate whether multimodal peripheral ANS measures demonstrate interactions before and after seizures as compared to controls to provide the basis for seizure detection and forecasting based on peripheral ANS signals. METHODS: Continuous electrodermal activity (EDA), heart rate (HR), peripheral body temperature (TEMP), and respiratory rate (RR) calculated based on blood volume pulse were acquired by a wireless multi-sensor device. We selected 45 min of preictal and 60 min of postictal data and time-matched segments for controls. Data were analyzed over 15-min windows. For unimodal analysis, mean values over each time window were calculated for all modalities and analyzed by Friedman's two-way analysis of variance. RESULTS: Twenty-one children with recorded generalized tonic-clonic seizures (GTCS), and 21 age- and gender-matched controls were included. Unimodal results revealed no significant effect for RR and TEMP, but EDA (p = 0.002) and HR (p < 0.001) were elevated 0-15 min after seizures. The averaged bimodal correlation across all pairs of modalities changed for 15-min windows in patients with seizures. The highest correlations were observed immediately before (0.85) and the lowest correlation immediately after seizures. Overall, average correlations for controls were higher. SIGNIFICANCE: Multimodal ANS changes related to GTCS occur within and across autonomic nervous system modalities. While unimodal changes were most prominent during postictal segments, bimodal correlations increased before seizures and decreased postictally. This offers a promising avenue for further research on seizure detection, and potentially risk assessment for seizure recurrence and sudden unexplained death in epilepsy.

Association between semiologic, autonomic, and electrographic seizure characteristics in children with generalized tonic-clonic seizures.

INTRODUCTION: Generalized tonic-clonic seizures (GTCS) are associated with elevated electrodermal activity (EDA) and postictal generalized electroencephalographic suppression (PGES), markers that may indicate sudden unexpected death in epilepsy (SUDEP) risk. This study investigated the association of GTCS semiology, EDA, and PGES in children with epilepsy. METHODS: Patients admitted to the Boston Children's Hospital long-term video-EEG monitoring unit wore a sensor that records EDA. We selected patients with at least one GTCS and reviewed video-EEGs for semiology, tonic and clonic phase duration, total clinical seizure duration, electrographic onset, offset, and PGES. We grouped patients into three semiology classes: GTCS 1: bilateral symmetric tonic arm extension, GTCS 2: no specific tonic arm extension or flexion, GTCS 3: unilateral or asymmetrical arm extension, tonic arm flexion or posturing that does not fit into GTCS 1 or 2. We analyzed the correlation between semiology, EDA, and PGES, and measured the area under the curve (AUC) of the ictal EDA (seizure onset to one hour after), subtracting baseline EDA (one-hour seizure-free before seizure onset). Using generalized estimating equation (GEE) and linear regression, we analyzed all seizures and single episodes per patient. RESULTS: We included 30 patients (median age 13.8 ±â€¯3.6 years, 46.7% females) and 53 seizures. With GEE, GTCS 1 was associated with longer PGES duration compared to GTCS 2 (Estimate (ß) = -26.32 s, 95% Confidence Interval (CI): -36.46 to -16.18, p < 0.001), and the presence of PGES was associated with greater EDA change (ß = 429604 µS, 95% CI: 3550.96 to 855657.04, p = 0.048). With single-episode analysis, GTCS 1 had greater EDA change than GTCS 2 ((ß = -601339 µS, 95% CI: -1167016.56 to -35661.44, p = 0.047). EDA increased with PGES presence (ß = 637500 µS, 95% CI: 183571.84 to 1091428.16, p = 0.01) and duration (ß = 16794 µS, 95% CI: 5729.8 to 27858.2, p = 0.006). Patients with GTCS 1 had longer PGES duration compared to GTCS 2 (ß = -30.53 s, 95% CI: -44.6 to -16.46, p < 0.001) and GTCS 3 (ß = -22.07 s, 95% CI: -38.95 to -5.19, p = 0.016). CONCLUSION: In children with epilepsy, PGES correlates with greater ictal EDA. GTCS 1 correlated with longer PGES duration and may indirectly correlate with greater ictal EDA. Our study suggests potential applications in monitoring and preventing SUDEP in these patients.

Photoplethysmography: A measure for the function of the autonomic nervous system in focal impaired awareness seizures.

OBJECTIVES: Photoplethysmography (PPG) reflects variations of blood perfusion in tissues, which may signify seizure-related autonomic changes. The aim of this study is to assess the variability of PPG signals and their value in detecting peri-ictal changes in patients with focal impaired awareness seizures (FIASs). METHODS: PPG data were recorded using a wearable sensor placed on the wrist or ankle of children with epilepsy admitted for long-term video-electroencephalographic monitoring. We analyzed PPG data in four different periods: seizure-free, preictal, ictal, and postictal. Multiple features were automatically extracted from the PPG signal-frequency, duration, amplitude, increasing and decreasing slopes, smoothness, and area under the curve (AUC)-and were used to identify preictal, ictal, or postictal changes by comparing them with seizure-free periods and with each other using a linear mixed-effects model. RESULTS: We studied PPG in 11 patients (18 FIASs), including seizure-free, preictal, and postictal periods, and a subset of eight patients (12 FIASs) including the ictal period. Compared to the seizure-free period, we found significant changes in PPG (1) during the ictal period across all features; (2) during the preictal period in amplitude, duration, increasing slope, and AUC; and (3) during the postictal period in decreasing slope. SIGNIFICANCE: Specific PPG changes can be seen before, during, and after FIASs. The peri-ictal changes in the PPG features of patients with FIASs suggest potential applications of PPG monitoring for seizure detection.

Anti-N-Methyl-D-Aspartate Receptor Encephalitis: A Review of Psychiatric Phenotypes and Management Considerations: A Report of the American Neuropsychiatric Association Committee on Research.

OBJECTIVE: Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder characterized by prominent neuropsychiatric symptoms. Given the nature of its pathophysiology, psychiatrists tend to be one of the first clinicians encountering patients with the disease. METHODS: In the present review of patients described in the literature with psychiatric symptoms, the authors aimed to characterize the psychiatric symptoms of the disease and its management in adults and adolescents as well as children (≤12 years old). A total of 544 patients fulfilled the inclusion criteria. RESULTS: The authors found that 77% of patients with NMDAR encephalitis presented initially with psychiatric symptoms. These were mostly agitation (59%) and psychotic symptoms (in 54%, especially disorganized behavior and visual-auditory hallucinations), with agitation even more commonly being the presenting symptom in children (66%). Where psychotic symptoms were detailed, visual (64%) and auditory (59%) hallucinations were the most common, as well as persecutory delusions (73%). However, delusions were not clearly characterized in most cases. Catatonia was described in 42% of adult patients and 35% of children. Of the patients with documented exposure to antipsychotics, 33% were suspected to have an adverse drug reaction (notably, neuroleptic malignant syndrome in 22% of the cases). CONCLUSIONS: On the basis of these findings, it is important to consider anti-NMDAR encephalitis in the differential diagnosis of patients with an acute onset psychosis, especially in association with agitation, catatonia, or adverse response to antipsychotics. Furthermore, it is important to use antipsychotics with caution in patients with suspected or confirmed anti-NMDAR encephalitis.

Late-onset unexplained epilepsy: What are we missing?

With the aging of the US population, the incidence of epilepsy will increase, with 25 to 50% of new cases with no identifiable etiology diagnosed as late-onset unexplained epilepsy (LOUE). In the current targeted review, we discuss the possible role of cerebral small vessel ischemic disease, accumulation of amyloidß and hyperphosphorylated tau, and sleep apnea as potential pathophysiologic mechanisms explaining LOUE. We highlight the impact of these processes on cognition and avenues for diagnosis and treatment.

Sleep in psychogenic nonepileptic seizures: Time to raise a red flag.

Poor sleep is a frequent complaint in patients with psychogenic nonepileptic seizures (PNES). However, few studies have examined sleep problems in this population. We aimed to compare sleep complaints in patients with PNES with those with epilepsy. Subjects diagnosed as having PNES by experts using video-electroencephalography (vEEG) were recruited through the Brigham and Women's Hospital epilepsy monitoring unit (EMU) between 3/25/2013 and 3/29/2018. Controls were patients with epilepsy recruited through the EMU and subspecialty clinics. All subjects were given the Beck Depression Inventory, 2nd Edition (BDI-II) and the Quality of Life in Epilepsy Inventory-10 (QOLIE-10). Subjective sleep problems were identified from item 16 (changes in sleep patterns) of the BDI-II. Independent sample t-test, chi-square test, and Spearman correlation were used. A total of 149 patients with PNES and 82 patients with epilepsy completed the BDI-II and QOLIE-10. Compared with control subjects with epilepsy, patients with PNES more frequently reported moderate-severe changes in sleep patterns, notably sleeping less than usual, waking up 1-2 h too early, and having trouble returning to sleep. These changes in sleep patterns were associated with worse quality of life. Our findings suggest that sleep is more commonly reported as a problem in PNES compared with epilepsy. Because sleep plays a major role in good health, understanding the specific sleep problem in PNES may provide insight for improving quality of life for this challenging disorder.

The clinical and neurobehavioral course of Down syndrome and dementia with or without new-onset epilepsy.

BACKGROUND: Adult patients with Down syndrome (DS) are at higher risk of developing Alzheimer-type dementia and epilepsy. The relationship between developing dementia and the risk of developing seizures in DS is poorly characterized to date. In addition, treatment response and medication tolerability have not been rigorously studied. METHODS: We identified 220 patients with a diagnosis of DS and dementia. Those without a history of developing seizures (DD) were compared to patients with new-onset seizures (DD+S) after the age of 35. Electronic records were reviewed for demographics, seizure characteristics, cognitive status, and psychiatric comorbidities. RESULTS: Of the patients included for analysis, twenty-six out of 60 patients had new-onset seizures or developed seizures during the follow-up period (the DD+S group) with a median onset of 2.0years after the dementia diagnosis. Generalized tonic-clonic seizures were the most common seizure type (61.5% of DD+S). Sixteen (61.5%) patients were reported to have myoclonus. Levetiracetam was the most commonly used initial medication, with the majority (73%) of patients treated achieving partial or complete seizure control. The DD+S patients tended to have a similar burden of new-onset neuropsychiatric symptoms compared to the DD group. DISCUSSION: New-onset epilepsy seems to occur early in the course of dementia in DS patients. Patients generally respond to treatment. A great burden of neuropsychiatric symptoms is seen. Future studies need to explore the relationship between ß-amyloid accumulation and epileptiform activity and attend to the care and needs of DS patients with dementia and seizures.

Delayed Deterioration of EEG Background Rhythm Post-cardiac Arrest.

BACKGROUND: Electroencephalogram (EEG) background continuity is associated with a favorable prognosis in cardiac arrest patients post-therapeutic hypothermia. However, the continuous EEG in a subset of patients will undergo 'delayed EEG deterioration'; they will invariably have poor outcome. The aim of this study was to characterize this phenomenon. METHODS: We studied a prospectively collected cohort of consecutive cardiac arrest patients who underwent therapeutic hypothermia between July 2012 and May 2015. We identified patients with an initially favorable EEG rhythm post-cooling and characterized a subset of patients with delayed EEG deterioration. RESULTS: A total of 133 patients were included in the analysis. Of these, 69/133 (51.9%) had an initially favorable EEG. Of those patients with initially favorable EEG, 7/69 (10.1%) had a subsequent deterioration. Delayed EEG deterioration was associated with poor outcome. The median time to deterioration was 55 h. CONCLUSIONS: Delayed EEG deterioration is associated with poor clinical outcomes. We hypothesize that this is the result of delayed neuronal degeneration, the exact mechanism requiring further exploration. Identifying patients with delayed EEG deterioration post-therapeutic hypothermia is paramount as further interventions may yet salvage their outcomes, though further study is needed.

Clinical and Neurophysiologic Characteristics of Unprovoked Seizures in Patients Diagnosed With Dementia.

Seizures are a common comorbid condition in patients with dementia, but their characteristics have been poorly described. The authors performed a retrospective chart review using ICD-9 diagnosis codes consistent with seizures and with dementia. Seventy-seven patients were identified. Average age at onset was 68.1 years for cognitive symptoms, 71.5 years for dementia, and 73.9 years for seizures. Seizures preceded or followed cognitive symptoms (4.3 years before and 18.7 years after). At last follow-up, 12% of patients continued to have seizures. Findings show that unprovoked seizures can precede or follow the onset of dementia, but these seizures are controlled with medications in the majority of patients.

Neuropsychiatric and seizure outcomes in nonparaneoplastic autoimmune limbic encephalitis.

INTRODUCTION: Autoimmune limbic encephalitis is an inflammatory condition often associated with an underlying neoplasm. However, a subset of patients does not have an underlying tumor and have a nonparaneoplastic form of this condition. The focus in the literature has been on the acute phase of this illness, but long-term follow-up is lacking. METHODS: A retrospective chart review, over a period of 15 years, of patients carrying a diagnosis of encephalitis was performed. Inclusion criteria included a clinical presentation consistent with limbic encephalitis (subacute behavioral change, seizures, or anterograde memory decline) and an identifiable autoantibody, inflammatory CSF (>5 white blood cells/mm(3)), or limbic hyperintensities on MRI. Readmission rates and long-term psychiatric, psychosocial, and seizure outcomes were evaluated. RESULTS: A total of 16 patients were identified. Clinical presentation included new-onset seizures in 14 (88%), behavioral changes in 7 (44%), and memory decline in 5 (31%). Four (25%) patients presented with status epilepticus. Five patients had antibodies against NMDAR (N-methyl-D-aspartate receptor) and four against VGKC (voltage gated potassium channel) complex. An inflammatory CSF was noted in 7 (44%) and MRI changes in 9 (56%). Four were readmitted during the follow-up period. Around half the patients continued to have medically drug/treatment-refractory seizures, while 7 (44%) had a new psychiatric diagnosis (mood disorder, anxiety disorder, or impulse control disorder). The majority of the patients continued to reside at home, while 43% of previously employed patients lost employment. CONCLUSION: Nonparaneoplastic autoimmune limbic encephalitis is a neuropsychiatric condition presenting with a combination of seizures (sometimes status epilepticus), behavioral changes, and memory decline. After the acute phase, patients are at risk of readmissions, medically refractory seizures, chronic mood and anxiety disorders, and loss of employment.

Predictors of SOZ localization, subsequent surgical intervention, and seizure outcomes in iEEG.

OBJECTIVE: A third of the patients who undergo intracranial EEG (iEEG) for seizure-onset zone (SOZ) localization do not proceed to resective surgery for epilepsy, and over half of those who do continue to have seizures following treatment. To better identify candidates who are more likely to see benefits from undergoing iEEG, we investigated preoperative and iEEG peri-operative features associated with the localization of a putative SOZ, undergoing subsequent surgical treatment, and seizure outcomes. METHODS: We conducted a retrospective cohort study of consecutive patients who underwent iEEG from 2001 to 2022 at two institutions. Outcomes included SOZ identification, proceeding to surgical treatment (resection vs. neuromodulation), and subsequent seizure freedom. RESULTS: We identified 329 unique patients who were followed for a median of 3.9 (IQR:7) years, with a minimum of 2-year follow-up for seizure outcomes analyses. Multivariate analysis identified lateralized and lobar localization on scalp EEG (OR 3.8, p = 0.001) to be associated with SOZ localization. Patients with unilateral localization on scalp EEG (OR 3.0, p = 0.003), unilateral preimplantation hypothesis (OR 3.1, p = 0.001), and lesional preoperative MRI (OR 2.1, p = 0.033) were more likely to undergo resection than neuromodulation. Similarly, a unilateral pre-implantation hypothesis (OR 2.6, p < 0.001) favored seizure freedom, whereas prior neuromodulation (OR 0.3, p = 0.013) decreased the odds. Larger number of preoperative anti-seizure medications (ASMs) did not influence seizure freedom rates but did decrease favorable (Engel I, II) seizure outcomes (OR 0.7, p = 0.026). INTERPRETATION: Non-invasive localization data prior to iEEG are associated with subsequent resection and seizure freedom, independent of iEEG localization. Factors predictive of SOZ localization are not necessarily predictive of post-operative seizure freedom.

Neuropsychological and psychiatric outcomes in poorly controlled idiopathic generalized epilepsy.

The neuropsychological and psychiatric outcomes of patients with poorly controlled idiopathic generalized epilepsy (IGE) have not been well characterized. The current study aimed to compare these outcomes to a group of patients with medically refractory temporal lobe epilepsy (TLE). A retrospective review of patients admitted to the epilepsy monitoring unit identified 19 patients with IGE and 23 patients with TLE who underwent neuropsychological and psychiatric evaluations. Patients with IGE required a longer time to complete the Trail Making Tests and had lower performance IQ compared to patients with TLE. Despite a higher burden of convulsions, patients with IGE had lower depression scores on the Beck Depression Inventory-II (BDI-II) than patients with TLE. In the group with IGE, the BDI-II scores were inversely correlated with epilepsy duration. These findings indicate that patients with IGE have lower performance IQ, impaired performance on tests of executive functioning, and lower depression scores compared to patients with TLE, implicating different pathophysiological processes.

Interictal epileptiform discharges in Alzheimer's disease: prevalence, relevance, and controversies.

Alzheimer's disease (AD) is the most common type of dementia and remains an incurable, progressive disease with limited disease-modifying interventions available. In patients with AD, interictal epileptiform discharges (IEDs) have been identified in up to 54% of combined cohorts of mild cognitive impairment (MCI) or mild dementia and are a marker of a more aggressive disease course. Studies assessing the role of IEDs in AD are limited by the lack of standardization in the definition of IEDs or the different neurophysiologic techniques used to capture them. IEDs are an appealing treatment target given the availability of EEG and anti-seizure medications. There remains uncertainty regarding when to treat IEDs, the optimal drug and dose for treatment, and the impact of treatment on disease course. This review covers the state of knowledge of the field of IEDs in AD, and the steps needed to move the field forward.