Effects of exercise on sleep in patients with epilepsy: A systematic review.

Exercise interventions in epilepsy have been shown to improve seizure frequency, physical capacity, quality of life, mood, and cognitive functioning. However, the effectiveness of exercise in improving sleep in epilepsy is less clear. The purpose of this report is to identify the published literature regarding exercise interventions in people with epilepsy to determine 1) what proportion of published clinical trials assess sleep as an outcome, and 2) what benefits of exercise interventions on sleep have been observed. We searched the PubMed, PsycINFO, and SCOPUS electronic databases using the search terms "epilepsy AND [exercise OR physical activity]" and identified 23 articles reporting on 18 unique clinical trials. Nine studies were conducted in adults, five in children, and four in adults and children with active seizures, controlled seizures, or both. Exercise modalities included aerobic exercise, strength training, walking, and yoga, among others, and some also included educational and motivational components. Exercise effects on sleep were tested in four studies, two of which only included indirect measures of sleep- and rest-related fatigue, with mixed results. Of the two reports assessing sleep directly, one reported marginal non-significant improvements in subjective sleep quality and no improvements in objective sleep quality in children after twelve weeks of walking, and the other reported no benefits in subjective sleep quality after twelve weeks of combined aerobic, strength, and flexibility training in adults. Given the health benefits of sleep and detrimental effects of sleep deprivation in epilepsy, epilepsy researchers need to assess the effects of exercise interventions on sleep.

Surgically treatable adult epilepsy: a changing patient population. Experience from a level 4 epilepsy center.

OBJECTIVE: Invasive monitoring has long been utilized in the evaluation of patients for epilepsy surgery, providing localizing information to guide resection. Stereoelectroencephalography (SEEG) was introduced at the authors' level 4 epilepsy surgery program in 2013, with responsive neurostimulation (RNS) becoming available the following year. The authors sought to characterize patient demographics and epilepsy-related variables before and after SEEG introduction to understand whether differences emerged in their patient population. This information will be useful in understanding how SEEG, possibly in conjunction with RNS availability, may have changed practice patterns over time. METHODS: This is a retrospective cohort study of consecutive patients who underwent surgery for epilepsy from 2006 to 2018, comprising 7 years before and 5 years after the introduction of SEEG. The authors performed univariate analyses of patient characteristics and outcomes and used generalized estimating equations logistic regression for predictive analysis. RESULTS: A total of 178 patients were analyzed, with 109 patients in the pre-SEEG cohort and 69 patients in the post-SEEG cohort. In the post-SEEG cohort, more patients underwent invasive monitoring for suspected bilateral seizure onsets (40.6% vs 22.0%, p = 0.01) and extratemporal seizure onsets (68.1% vs 8.3%, p < 0.0001). The post-SEEG cohort had a higher proportion of patients with seizures arising from eloquent cortex (14.5% vs 0.9%, p < 0.001). Twelve patients underwent RNS insertion in the post-SEEG group versus none in the pre-SEEG group. Fewer patients underwent resection in the post-SEEG group (55.1% vs 96.3%, p < 0.0001), but there was no significant difference in rates of seizure freedom between cohorts for those patients having undergone a follow-up resection (53.1% vs 59.8%, p = 0.44). CONCLUSIONS: These findings demonstrate that more patients with suspected bilateral, eloquent, or extratemporal epilepsy underwent invasive monitoring after adoption of SEEG. This shift occurred coincident with the adoption of RNS, both of which likely contributed to increased patient complexity. The authors conclude that their practice now considers invasive monitoring for patients who likely would not previously have been candidates for surgical investigation and subsequent intervention.

FMRI response to acute psychological stress differentiates patients with psychogenic non-epileptic seizures from healthy controls - A biochemical and neuroimaging biomarker study.

We investigated psychological stress response in the brain regions involved in emotion-motor-executive control in psychogenic non-epileptic seizures (PNES). 12 PNES patients and 12 healthy controls (HCs) underwent stress task and resting state functional MRI (fMRI), mood and quality of life (QOL) assessments, and measurements of salivary cortisol, alpha-amylase, and heart rate. Group differences were assessed, and we correlated beta values from a priori selected brain regions showing stress task fMRI group differences with other stress response measures. We also used the regions showing stress task fMRI group differences as seeds for resting state functional connectivity (rs-FC) analysis. Mood and QOL were worse in PNES versus HCs. Physiological and assessment measures were similar except 'Planful Problem Solving' coping that was greater for HCs (p = .043). Perceived stress associated negatively with heart rate change (rs = -0.74, p = .0063). There was stress fMRI hyporeactivity in left/right amygdala and left hippocampus in PNES versus HCs (corrected p < .05). PNES exhibited a positive association between alpha-amylase change and right amygdala activation (rs = 0.71, p = .010). PNES versus HCs exhibited greater right amygdala rs-FC to left precentral and inferior/middle frontal gyri (corrected p < .05). Our findings of fMRI hyporeactivity to psychological stress, along with greater emotion-motor-executive control network rs-FC in PNES when compared to HCs suggest a dysregulation in stress response circuitry in PNES.

Sleep, Circadian Rhythms, and Epilepsy.

PURPOSE OF REVIEW: There is a known interrelationship between sleep and epilepsy. This review highlights the recent findings regarding interactions between sleep and circadian rhythms and the manifestations of epilepsy and surgical treatments for refractory epilepsy. RECENT FINDINGS: CLOCK gene expression may be reduced within the epileptogenic focus in patients with refractory epilepsy. Interictal epileptiform discharges during NREM and especially REM sleep may lateralize to the epileptogenic hemisphere. Intracranial video EEG monitoring and EEG from implanted responsive neurostimulator devices confirm scalp video EEG findings of a nocturnal peak for interictal epileptiform discharges. Successful epilepsy surgery may improve sleep macrostructure and quality. Sleep outcomes in people with epilepsy undergoing epilepsy surgery and neurostimulator implantation may provide innovative understandings into the associations between sleep and epilepsy. These associations may then provide novel therapeutic options targeting sleep and circadian pathways to improve seizure control and improve the quality of life for patients with this debilitating disorder.

Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study.

The objective of this study was to characterize the changes in adverse events, seizure severity, and frequency in response to a pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex®) in a large, prospective, single-center, open-label study. We initiated CBD in 72 children and 60 adults with treatment-resistant epilepsy (TRE) at 5 mg/kg/day and titrated it up to a maximum dosage of 50 mg/kg/day. At each visit, we monitored treatment adverse events with the adverse events profile (AEP), seizure severity using the Chalfont Seizure Severity Scale (CSSS), and seizure frequency (SF) using seizure calendars. We analyzed data for the enrollment and visits at 12, 24, and 48 weeks. We recorded AEP, CSSS, and SF at each follow-up visit for the weeks preceding the visit (seizures were averaged over 2-week periods). Of the 139 study participants in this ongoing study, at the time of analysis, 132 had 12-week, 88 had 24-week, and 61 had 48-week data. Study retention was 77% at one year. There were no significant differences between participants who contributed all 4 data points and those who contributed 2 or 3 data points in baseline demographic and AEP/SF/CSSS measures. For all participants, AEP decreased between CBD initiation and the 12-week visit (40.8 vs. 33.2; p < 0.0001) with stable AEP scores thereafter (all p ≥ 0.14). Chalfont Seizure Severity Scale scores were 80.7 at baseline, decreasing to 39.2 at 12 weeks (p < 0.0001) and stable CSSS thereafter (all p ≥ 0.19). Bi-weekly SF decreased from a mean of 144.4 at entry to 52.2 at 12 weeks (p = 0.01) and remained stable thereafter (all p ≥ 0.65). Analyses of the pediatric and adult subgroups revealed similar patterns. Most patients were treated with dosages of CBD between 20 and 30 mg/kg/day. For the first time, this prospective, open-label safety study of CBD in TRE provides evidence for significant improvements in AEP, CSSS, and SF at 12 weeks that are sustained over the 48-week duration of treatment.

Facial emotion processing in patients with seizure disorders.

Studies of emotion processing are needed to better understand the pathophysiology of psychogenic nonepileptic seizures (PNES). We examined the differences in facial emotion processing between 12 patients with PNES, 12 patients with temporal lobe epilepsy (TLE), and 24 matched healthy controls (HCs) using fMRI with emotional faces task (EFT) (happy/sad/fearful/neutral) and resting state connectivity. Compared with TLE, patients with PNES exhibited increased fMRI response to happy, neutral, and fearful faces in visual, temporal, and/or parietal regions and decreased fMRI response to sad faces in the putamen bilaterally. Regions showing significant differences between PNES and TLE were used as functional seed regions of interest (ROIs), in addition to amygdala structural seed ROIs for resting state functional connectivity analyses. Whole brain analyses showed that compared with TLE and HCs, patients with PNES exhibited increased functional connectivity of the functional seed ROIs to several brain regions, particularly to cerebellar, visual, motor, and frontotemporal regions. Connectograms showed increased functional connections between left parahippocampal gyrus/uncus ROIs and right temporal ROIs in PNES compared with both the TLE and HC groups. Resting state functional connectivity of the left and right amygdala to various brain regions including emotion regulation and motor control circuits was increased in PNES when compared with those with TLE. This study provides preliminary evidence that patients with PNES exhibit altered facial emotion processing compared with patients with TLE and HCs and increased amygdala functional connectivity compared with TLE. These findings identify potential key differences in facial emotion processing reflective of neurophysiologic markers of neural circuitry alterations that can be used to generate further hypotheses for developing studies that examine the contributions of emotion processing to the development and maintenance of PNES.

Effects of subthalamic nucleus deep brain stimulation on objective sleep outcomes in Parkinson's disease.

BACKGROUND: Sleep dysfunction is a common and disabling non-motor symptom in Parkinson's disease. Deep brain stimulation (DBS) of the subthalamic nucleus (STN) improves motor symptoms and subjective sleep in PD, but alternative stimulation parameters to optimize sleep have not been explored. We hypothesized that low frequency STN DBS would improve objective sleep more than conventional settings. METHODS: Twenty PD subjects with STN DBS (18 unilateral, 2 bilateral) underwent 3 non-consecutive nights of polysomnography: DBS off; DBS high frequency (≥130 Hz); and DBS low frequency (60 Hz). Motor symptom tolerability was assessed 30 minutes after resumption of baseline settings the morning following polysomnography. The primary outcome was change in sleep efficiency between high and low frequency nights measured with repeated measures ANOVA. RESULTS: There was no difference in sleep efficiency between nights at high frequency (82.1% (72.6-90.1)) (median (IQR)), low frequency (81.2% (56.2-88.8)), or DBS off (82.8% (75.7-87.4)), p=0.241. Additionally, there was no difference in sleep stage percent, arousals, limb movements, subjective sleep quality, or objective vigilance measures. These outcomes did not change after adjusting for age, sex, disease duration, or side of surgery. No residual adverse motor effects were noted. CONCLUSIONS: Although well tolerated, low frequency STN DBS did not improve objective sleep in PD. Remarkably, objective measures of sleep were not worse with DBS off. These observations point to the potential for adaptive stimulation approaches, through which DBS settings could be optimized during sleep to meet individual needs. Additionally, these changes could preserve battery life without compromising patient outcomes.

Statistical modeling of ICEEG features that determine resection planning.

OBJECT: The interpretation of intracranial EEG (ICEEG) recordings is a complex balance of the significance of specific rhythms and their relative timing to seizure onset. Ictal and interictal findings are evaluated in light of findings from cortical stimulation of eloquent cortex to determine the area of resection. PATIENTS AND METHODS: Patients with ICEEG electrodes and subsequent surgical resection were retrospectively identified. Only the first 15s of ictal activity, which was divided into five 3-s epochs, was considered. Every electrode in each patient was considered a separate observation in a logistic regression model to predict whether the cortex under a given electrode was included in the planned resection. RESULTS: 19 included patients had a total of 37 unique seizures. Recordings from a total of 1306 electrodes were analyzed. The strongest predictors of resection of cortex underlying a given electrode was the presence of low-voltage fast activity in Epoch 1, rhythmic spikes in Epoch 1, interictal paroxysmal fast activity, and low-voltage fast activity in Epoch 2. High-amplitude beta spikes and rhythmic slow waves were also significant predictors in Epoch 1. Interictal spikes had a higher odds ratio of affecting the planned resection if described as "continuous" or "very frequent". The presence of motor or language cortex were the strongest negative predictors of resecting underlying cortex. CONCLUSIONS: Here we describe a novel model of ictal and interictal patterns significantly associated with the inclusion of cortex underlying a given ICEEG electrode in the surgical resection plan.

Personalities of patients with nonepileptic psychogenic status.

The purposes of this study were to determine whether personalities of patients with nonepileptic psychogenic status (NEPS) are different from those of patients with typical intermittent psychogenic nonepileptic seizures (iPNES) using the Personality Assessment Inventory (PAI) and to compare their PAI profiles with the population norms. We hypothesized that patients with NEPS have more psychopathology compared with patients with iPNES and that, as a group, patients with PNES (iPNES+NEPS) would have more psychopathology compared with healthy individuals. We first compared the PAI profiles of patients with iPNES and NEPS and then the profiles of patients with NEPS, iPNES, and PNES with population norms in order to assess which PAI specific scales differed between groups in order to better characterize the psychopathology of PNES. All patients admitted for diagnostic evaluation to the epilepsy monitoring unit (EMU) were prospectively approached for participation. All patient/family interviews were conducted by an epileptologist, and the diagnosis of iPNES or NEPS was confirmed in all cases through video/EEG and/or family interview. The population norms for PAI were obtained from the manual. Of the 224 approached patients, 130 completed the PAI, and included 43 iPNES and 11 with NEPS. There were no significant differences between the two groups in regard to demographic or PAI profiles. Comparison with population norms revealed the presence of abnormal personality profiles on all scales in patients with iPNES, NEPS, or PNES. We conclude that while the occurrence of NEPS is relatively common in patients with PNES, the demographic characteristics and personality profiles of patients with NEPS are not different from those of patients with iPNES. We also confirmed the presence of significant psychopathology in the group with PNES when compared with population norms.

New-onset refractory status epilepticus (NORSE)--The potential role for immunotherapy.

New-onset refractory status epilepticus (NORSE) is defined as a state of persistent seizures with no identifiable etiology in patients without preexisting epilepsy that lasts longer than 24h despite optimal therapy. Management of NORSE is challenging, and the role of immunotherapy (IT) is unclear. We identified patients fulfilling the criteria for NORSE at a single institution. These patients were described, analyzed, and compared with NORSE cases available from the literature. Finally, a pooled analysis of available case series was conducted to compare the outcomes in patients who received IT with those not treated with IT during the course of NORSE in order to generate hypotheses for further research. In our case series, NORSE was diagnosed in 11 patients (9 females) with a mean age of 48 years and a mean duration of 54.4 days. Autoantibodies were identified in 7 patients, of which anti-GAD (glutamic acid decarboxylase) and anti-NMDAR (N-methyl-D-aspartate receptor) were most frequent. Of the 11 patients, 8 were treated with IT (intravenous steroids, immunoglobulins, plasmapheresis, or a combination), and 4 received chemotherapy. Of the 8 patients treated with IT, 6 had favorable outcomes (defined as any outcome other than death, vegetative state, or inability to take care of oneself) compared with 0 out of 3 patients who did not receive IT. Difference in outcomes was significant (p=0.026). Pooled analysis of all identified case series, including ours, showed a statistically significant effect (p=0.022), with favorable outcomes in 42% of the patients who received any IT compared with 20% in those who did not. In all patients with refractory SE and negative comprehensive investigations, a diagnosis of NORSE should be considered. This would aid planning for early immunotherapy. Currently, only Class IV evidence for the use of immunotherapy in NORSE is available. Prospective multicenter studies are necessary to assess the true efficacy of IT in NORSE.

Levetiracetam use in the critical care setting.

Intravenous (IV) levetiracetam (LEV) is currently approved as an alternative or replacement therapy for patients unable to take the oral form of this antiepileptic drug (AED). The oral form has Food and Drug Administration (FDA) indications for adjunctive therapy in the treatment of partial onset epilepsy ages 1 month or more, myoclonic seizures associated with juvenile myoclonic epilepsy starting with the age of 12 and primary generalized tonic-clonic seizures in people 6 years and older. Since the initial introduction, oral and IV LEV has been evaluated in various studies conducted in the critical care setting for the treatment of status epilepticus, stroke-related seizures, seizures following subarachnoid or intracerebral hemorrhage, post-traumatic seizures, tumor-related seizures, and seizures in critically ill patients. Additionally, studies evaluating rapid infusion of IV LEV and therapeutic monitoring of serum LEV levels in different patient populations have been performed. In this review we present the current state of knowledge on LEV use in the critical care setting focusing on the IV uses and discuss future research needs.

Safety and tolerability of early noninvasive ventilatory correction using bilevel positive airway pressure in acute ischemic stroke.

BACKGROUND AND PURPOSE: Hypercapnia can induce intracranial blood-flow steal from ischemic brain tissues, and early initiation of noninvasive ventilator correction (NIVC) may improve cerebral hemodynamics in acute ischemic stroke. We sought to determine safety and tolerability of NIVC initiated on hospital admission without polysomnography study. SUBJECTS AND METHODS: Consecutive acute ischemic stroke patients were evaluated for the presence of a proximal arterial occlusion, daytime sleepiness, or history of obstructive sleep apnea, and acceptable pulse oximetry readings while awake (96%-100% on 2 to 4 L supplemental oxygen delivered by nasal cannula). NIVC was started on hospital admission as standard of care when considered necessary by treating physicians. NIVC was initiated using bilevel positive airway pressure at 10 cmH(2)O inspiratory positive airway pressure and 5 cmH(2)O expiratory positive airway pressure in combination with 40% fraction of inspired oxygen. All potential adverse events were prospectively documented. RESULTS: Among 356 acute ischemic stroke patients (median NIHSS score, 5; interquartile range, 2-13), 64 cases (18%) received NIVC (median NIHSS score, 12; interquartile range, 6-17). Baseline stroke severity was higher and proximal arterial occlusions were more frequent in NIVC patients compared to the rest (P<0.001). NIVC was not tolerated by 4 patients (7%). Adverse events in NIVC included vomiting (n=1), aspiration pneumonia (n=1), respiratory failure/intubation (n=1), hypotension requiring pressors (n=1), and facial skin breakdown (n=3). The in-hospital mortality rate was 13% in NIVC patients and 8% in the rest (P=0.195). Neurological improvement during hospitalization tended to be greater in the NIVC group (median NIHSS score decrease, 2 points; interquartile range, 0-4) compared to the rest (median NIHSS score decrease, 1; interquartile range, 0-2; P=0.078). CONCLUSIONS: In acute ischemic stroke patients with proximal arterial occlusion and excessive sleepiness or obstructive sleep apnea, NIVC can be initiated early with good tolerability and a relatively small risk of serious complications.

Prevalence and risk factors associated with reversed Robin Hood syndrome in acute ischemic stroke.

BACKGROUND AND PURPOSE: Early deterioration can occur after acute stroke for a variety of reasons. We describe a hemodynamic steal and associated neurological deterioration, the reversed Robin Hood syndrome (RRHS). We aimed to investigate the frequency and factors associated with RRHS. METHODS: Consecutive patients with acute cerebral ischemia underwent serial National Institutes of Health Stroke Scale and bilateral transcranial Doppler monitoring with breathholding. Steal magnitude (%) was calculated from transient mean flow velocity reduction in the affected arteries at the time of velocity increase in normal vessels. Excessive sleepiness and likelihood of sleep apnea were evaluated by the Epworth Sleepiness Scale and Berlin Questionnaire. RESULTS: Among 153 patients (age, 61+/-14 years; 48% women; 21% transient ischemic attack) admitted within 48 hours from symptom onset, 21 (14%) had steal phenomenon (median steal magnitude, 20%; interquartile range, 11%; range, 6% to 45%), and 11 (7%) had RRHS. RRHS was most frequent in patients with proximal arterial occlusions (17% versus 1%; P<0.001). The following factors were independently (P<0.05) associated with RRHS (multivariate logistic regression model): male gender, younger age, persisting arterial occlusions, and excessive sleepiness (P<0.001). A 1-point increase in the Epworth Sleepiness Scale was independently related to an increased likelihood of RRHS of 36% (95% CI, 7% to 73%). CONCLUSIONS: RRHS and hemodynamic steal can be found in 7% and 14%, respectively, of consecutive patients with stroke without other known causes for deterioration. Patients with persisting arterial occlusions and excessive sleepiness can be particularly vulnerable to the steal.

Hyperammonemia following intravenous valproate loading.

BACKGROUND: Valproic acid (VPA) has been associated with hyperammonemia with and without encephalopathy. We report the frequent but transient nature of hyperammonemia following intravenous (IV) administration of loading doses of VPA. METHODS: Forty participants received a VPA loading dose (20 or 30 mg/kg) at 6 or 10mg/kg/min. All participants were monitored for signs of systemic and local intolerance. Serum VPA level, ammonia, complete blood count, bilirubin, transaminases, pancreatic enzymes, and level of consciousness were obtained at baseline, 1 and 24h after administration. Changes in ammonia levels were assessed using repeated-measures ANOVA. RESULTS: Asymptomatic hyperammonemia occurred in 30 of 40 participants at 1h post-VPA infusion. Majority of the participants (66%) demonstrated decreasing ammonia concentrations at 24h post-infusion. Multivariable repeated-measures analysis indicates the lack of influence of VPA dose (p=0.8), VPA levels (p>0.24, all time points), infusion rate (p=0.41) and gender (0.68) on ammonia levels across time. Age (p=0.015), time since dosing (p=0.017) and co-therapy with enzyme-inducing antiepileptic drugs (p=0.035) were significant predictors of changes in ammonia levels. CONCLUSIONS: Hyperammonemia is a frequent but transient finding following intravenous administration of loading doses of VPA. Hyperammonemia was not associated with alteration in consciousness or hepatic transaminases.

A family with a tau P301L mutation presenting with parkinsonism.

We report a sib-pair with a tau P301L mutation. Unlike most previous cases with this mutation, parkinsonism, rather than dementing features were the predominant and presenting feature. We have also observed that the P301L mutation has occurred on the H1 tau haplotype background. The haplotype background may influence the disease phenotype since in many previous Caucasian families with the P301L mutation, the haplotype background has been H2.