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.

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.

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.

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.