Adult Inception of Ketogenic Diet Therapy Increases Sleep during the Dark Cycle in C57BL/6J Wild Type and Fragile X Mice.

Sleep problems are a significant phenotype in children with fragile X syndrome. Our prior work assessed sleep-wake cycles in Fmr1KO male mice and wild type (WT) littermate controls in response to ketogenic diet therapy where mice were treated from weaning (postnatal day 18) through study completion (5-6 months of age). A potentially confounding issue with commencing treatment during an active period of growth is the significant reduction in weight gain in response to the ketogenic diet. The aim here was to employ sleep electroencephalography (EEG) to assess sleep-wake cycles in mice in response to the Fmr1 genotype and a ketogenic diet, with treatment starting at postnatal day 95. EEG results were compared with prior sleep outcomes to determine if the later intervention was efficacious, as well as with published rest-activity patterns to determine if actigraphy is a viable surrogate for sleep EEG. The data replicated findings that Fmr1KO mice exhibit sleep-wake patterns similar to wild type littermates during the dark cycle when maintained on a control purified-ingredient diet but revealed a genotype-specific difference during hours 4-6 of the light cycle of the increased wake (decreased sleep and NREM) state in Fmr1KO mice. Treatment with a high-fat, low-carbohydrate ketogenic diet increased the percentage of NREM sleep in both wild type and Fmr1KO mice during the dark cycle. Differences in sleep microstructure (length of wake bouts) supported the altered sleep states in response to ketogenic diet. Commencing ketogenic diet treatment in adulthood resulted in a 15% (WT) and 8.6% (Fmr1KO) decrease in body weight after 28 days of treatment, but not the severe reduction in body weight associated with starting treatment at weaning. We conclude that the lack of evidence for improved sleep during the light cycle (mouse sleep time) in Fmr1KO mice in response to ketogenic diet therapy in two studies suggests that ketogenic diet may not be beneficial in treating sleep problems associated with fragile X and that actigraphy is not a reliable surrogate for sleep EEG in mice.

Ketogenic Diet Affects Sleep Architecture in C57BL/6J Wild Type and Fragile X Mice.

Nearly half of children with fragile X syndrome experience sleep problems including trouble falling asleep and frequent nighttime awakenings. The goals here were to assess sleep-wake cycles in mice in response to Fmr1 genotype and a dietary intervention that reduces hyperactivity. Electroencephalography (EEG) results were compared with published rest-activity patterns to determine if actigraphy is a viable surrogate for sleep EEG. Specifically, sleep-wake patterns in adult wild type and Fmr1KO littermate mice were recorded after EEG electrode implantation and the recordings manually scored for vigilance states. The data indicated that Fmr1KO mice exhibited sleep-wake patterns similar to wild type littermates when maintained on a control purified ingredient diet. Treatment with a high-fat, low-carbohydrate ketogenic diet increased the percentage of non-rapid eye movement (NREM) sleep in both wild type and Fmr1KO mice during the dark cycle, which corresponded to decreased activity levels. Treatment with a ketogenic diet flattened diurnal sleep periodicity in both wild type and Fmr1KO mice. Differences in several sleep microstructure outcomes (number and length of sleep and wake bouts) supported the altered sleep states in response to a ketogenic diet and were correlated with altered rest-activity cycles. While actigraphy may be a less expensive, reduced labor surrogate for sleep EEG during the dark cycle, daytime resting in mice did not correlate with EEG sleep states.

Dual orexin antagonist normalized sleep homeostatic drive, enhanced GABAergic inhibition, and suppressed seizures after traumatic brain injury.

STUDY OBJECTIVES: Traumatic brain injury (TBI) can result in posttraumatic epilepsy (PTE) and sleep disturbances. We hypothesized that treatment with sleep aids after TBI can ameliorate PTE. METHODS: CD-1 mice underwent controlled cortical impact (CCI), sham injury, or no craniotomy. Sham and CCI groups underwent a monthlong daily treatment with sleep aids including a dual orexin antagonist (DORA-22) or THIP (gaboxadol) or a respective vehicle starting on the day of CCI. We performed continuous EEG (electroencephalography) recordings at week 1 and months 1, 2, and 3 for ~1 week each time. Seizure analysis occurred at all-time points and sleep analysis occurred in week 1 and month-1/2 in all groups. Subsets of CCI and sham groups were subjected to voltageclamp experiments in hippocampal slices to evaluate GABAergic synaptic inhibition. RESULTS: DORA-22 treatment suppressed seizures in month 1-3 recordings. TBI reduced the amplitude and frequency of miniature inhibitory synaptic currents (mIPSCs) in dentate granule cells and these changes were rescued by DORA-22 treatment. Sleep analysis showed that DORA-22 increased nonrapid eye movement (NREM) sleep during lights-off whereas THIP increased REM sleep during lights-on in week 1. Both treatments displayed subtle changes in time spent in NREM or REM at month-1/2 as well. TBI not only increased normalized EEG delta power (NΔ) at week-1 and month-1 but also resulted in the loss of the homeostatic diurnal oscillation of NΔ, which was restored by DORA-22 but not THIP treatment. CONCLUSIONS: Dual orexin antagonists may have a therapeutic potential in suppressing PTE potentially by enhancing GABAergic inhibition and impacting sleep homeostatic drive.

Deficits in Behavioral and Neuronal Pattern Separation in Temporal Lobe Epilepsy.

In temporal lobe epilepsy, the ability of the dentate gyrus to limit excitatory cortical input to the hippocampus breaks down, leading to seizures. The dentate gyrus is also thought to help discriminate between similar memories by performing pattern separation, but whether epilepsy leads to a breakdown in this neural computation, and thus to mnemonic discrimination impairments, remains unknown. Here we show that temporal lobe epilepsy is characterized by behavioral deficits in mnemonic discrimination tasks, in both humans (females and males) and mice (C57Bl6 males, systemic low-dose kainate model). Using a recently developed assay in brain slices of the same epileptic mice, we reveal a decreased ability of the dentate gyrus to perform certain forms of pattern separation. This is because of a subset of granule cells with abnormal bursting that can develop independently of early EEG abnormalities. Overall, our results linking physiology, computation, and cognition in the same mice advance our understanding of episodic memory mechanisms and their dysfunction in epilepsy.SIGNIFICANCE STATEMENT People with temporal lobe epilepsy (TLE) often have learning and memory impairments, sometimes occurring earlier than the first seizure, but those symptoms and their biological underpinnings are poorly understood. We focused on the dentate gyrus, a brain region that is critical to avoid confusion between similar memories and is anatomically disorganized in TLE. We show that both humans and mice with TLE experience confusion between similar situations. This impairment coincides with a failure of the dentate gyrus to disambiguate similar input signals because of pathologic bursting in a subset of neurons. Our work bridges seizure-oriented and memory-oriented views of the dentate gyrus function, suggests a mechanism for cognitive symptoms in TLE, and supports a long-standing hypothesis of episodic memory theories.

Sleep Deprivation Exacerbates Seizures and Diminishes GABAergic Tonic Inhibition.

Patients with epilepsy report that sleep deprivation is a common trigger for breakthrough seizures. The basic mechanism of this phenomenon is unknown. In the Kv1.1-/- mouse model of epilepsy, daily sleep deprivation indeed exacerbated seizures though these effects were lost after the third day. Sleep deprivation also accelerated mortality in ~ 52% of Kv1.1-/- mice, not observed in controls. Voltage-clamp experiments on the day after recovery from sleep deprivation showed reductions in GABAergic tonic inhibition in dentate granule cells in epileptic Kv1.1-/- mice. Our results suggest that sleep deprivation is detrimental to seizures and survival, possibly due to reductions in GABAergic tonic inhibition. ANN NEUROL 2021;90:840-844.

Proceedings of the Sleep and Epilepsy Workshop: Section 3 Mortality: Sleep, Night, and SUDEP.

Sudden unexpected death in epilepsy (SUDEP) is the leading cause of death in patients with refractory epilepsy. Likely pathophysiological mechanisms include seizure-induced cardiac and respiratory dysregulation. A frequently identified feature in SUDEP cases is that they occur at night. This raises the question of a role for sleep state in regulating of SUDEP. An association with sleep has been identified in a number of studies with patients and in animal models. The focus of this section of the Sleep and Epilepsy Workshop was on identifying and understanding the role for sleep and time of day in the pathophysiology of SUDEP.

Sleep-wake characteristics in a mouse model of severe traumatic brain injury: Relation to posttraumatic epilepsy.

Study objectives: Traumatic brain injury (TBI) results in sequelae that include posttraumatic epilepsy (PTE) and sleep-wake disturbances. Here, we sought to determine whether sleep characteristics could predict development of PTE in a model of severe TBI. Methods: Following controlled cortical impact (CCI) or sham injury (craniotomy only), CD-1 mice were implanted with epidural electroencephalography (EEG) and nuchal electromyography (EMG) electrodes. Acute (1st week) and chronic (months 1, 2, or 3) 1-week-long video-EEG recordings were performed after the injury to examine epileptiform activity. High-amplitude interictal events were extracted from EEG using an automated method. After scoring sleep-wake patterns, sleep spindles and EEG delta power were derived from nonrapid eye movement (NREM) sleep epochs. Brain CTs (computerized tomography) were performed in sham and CCI cohorts to quantify the brain lesions. We then employed a no craniotomy (NC) control to perform 1-week-long EEG recordings at week 1 and month 1 after surgery. Results: Posttraumatic seizures were seen in the CCI group only, whereas interictal epileptiform activity was seen in CCI or sham. Sleep-wake disruptions consisted of shorter wake or NREM bout lengths and shorter duration or lower power for spindles in CCI and sham. NREM EEG delta power increased in CCI and sham groups compared with NC though the CCI group with posttraumatic seizures had lower power at a chronic time point compared with those without. Follow-up brain CTs showed a small lesion in the sham injury group suggesting a milder form of TBI that may account for their interictal activity and sleep changes. Significance: In our TBI model, tracking changes in NREM delta power distinguishes between CCI acutely and animals that will eventually develop PTE, but further work is necessary to identify sleep biomarkers of PTE. Employing NC controls together with sham controls should be considered in future TBI studies.

Untangling a Web: Basic Mechanisms of the Complex Interactions Between Sleep, Circadian Rhythms, and Epilepsy.

Seizures have sleep-wake and circadian patterns in various epilepsies and, in turn, disrupt sleep and circadian rhythms. The resultant sleep deprivation (SD) is an exacerbating factor for seizures that sets up a vicious cycle that can potentially lead to disease progression and even to epilepsy-related mortality. A variety of cellular or network electrophysiological changes and changes in expression of clock-controlled genes or other transcription factors underlie sleep-wake and circadian distribution of seizures, as well as the disruptions seen in both. A broad understanding of these mechanisms may help in designing better treatments to prevent SD-induced seizure exacerbation, disrupt the vicious cycle of disease progression, and reduce epilepsy-related mortality.

Sleep and diurnal rest-activity rhythm disturbances in a mouse model of Alzheimer's disease.

STUDY OBJECTIVES: Accumulating evidence suggests a strong association between sleep, amyloid-beta (Aß) deposition, and Alzheimer's disease (AD). We sought to determine if (1) deficits in rest-activity rhythms and sleep are significant phenotypes in J20 AD mice, (2) metabotropic glutamate receptor 5 inhibitors (mGluR5) could rescue deficits in rest-activity rhythms and sleep, and (3) Aß levels are responsive to treatment with mGluR5 inhibitors. METHODS: Diurnal rest-activity levels were measured by actigraphy and sleep-wake patterns by electroencephalography, while animals were chronically treated with mGluR5 inhibitors. Behavioral tests were performed, and Aß levels measured in brain lysates. RESULTS: J20 mice exhibited a 4.5-h delay in the acrophase of activity levels compared to wild-type littermates and spent less time in rapid eye movement (REM) sleep during the second half of the light period. J20 mice also exhibited decreased non-rapid eye movement (NREM) delta power but increased NREM sigma power. The mGluR5 inhibitor CTEP rescued the REM sleep deficit and improved NREM delta and sigma power but did not correct rest-activity rhythms. No statistically significant differences were observed in Aß levels, rotarod performance, or the passive avoidance task following chronic mGluR5 inhibitor treatment. CONCLUSIONS: J20 mice have disruptions in rest-activity rhythms and reduced homeostatic sleep pressure (reduced NREM delta power). NREM delta power was increased following treatment with a mGluR5 inhibitor. Drug bioavailability was poor. Further work is necessary to determine if mGluR5 is a viable target for treating sleep phenotypes in AD.

An automated, machine learning-based detection algorithm for spike-wave discharges (SWDs) in a mouse model of absence epilepsy.

OBJECTIVE: Manual detection of spike-wave discharges (SWDs) from electroencephalography (EEG) records is time intensive, costly, and subject to inconsistencies/biases. In addition, manual scoring often omits information on SWD confidence/intensity, which may be important for the investigation of mechanistic-based research questions. Our objective is to develop an automated method for the detection of SWDs in a mouse model of absence epilepsy that is focused on the characteristics of human scoring of preselected events to establish a confidence-based, continuous-valued scoring. METHODS: We develop a support vector machine (SVM)-based algorithm for the automated detection of SWDs in the γ2R43Q mouse model of absence epilepsy. The algorithm first identifies putative SWD events using frequency- and amplitude-based peak detection. Four humans scored a set of 2500 putative events identified by the algorithm. Then, using predictors calculated from the wavelet transform of each event and the labels from human scoring, we trained an SVM to classify (SWD/nonSWD) and assign confidence scores to each event identified from 60, 24-hour EEG records. We provide a detailed assessment of intra- and interrater scoring that demonstrates advantages of automated scoring. RESULTS: The algorithm scored SWDs along a continuum that is highly correlated with human confidence and that allows us to more effectively characterize ambiguous events. We demonstrate that events along our scoring continuum are temporally and proportionately correlated with abrupt changes in spectral power bands relevant to normal behavioral states including sleep. SIGNIFICANCE: Although there are automated and semi-automated methods for the detection of SWDs in humans and rats, we contribute to the need for continued development of SWD detection in mice. Our results demonstrate the value of viewing detection of SWDs as a continuous classification problem to better understand "ground truth" in SWD detection (ie, the most reliable features agreed upon by humans that also correlate with objective physiologic measures).

Histone deacetylase inhibitors restore normal hippocampal synaptic plasticity and seizure threshold in a mouse model of Tuberous Sclerosis Complex.

Abnormal synaptic plasticity has been implicated in several neurological disorders including epilepsy, dementia and Autism Spectrum Disorder (ASD). Tuberous Sclerosis Complex (TSC) is an autosomal dominant genetic disorder that manifests with seizures, autism, and cognitive deficits. The abnormal intracellular signaling underlying TSC has been the focus of many studies. However, nothing is known about the role of histone modifications in contributing to the neurological manifestations in TSC. Dynamic regulation of chromatin structure via post translational modification of histone tails has been implicated in learning, memory and synaptic plasticity. Histone acetylation and associated gene activation plays a key role in plasticity and so we asked whether histone acetylation might be dysregulated in TSC. In this study, we report a general reduction in hippocampal histone H3 acetylation levels in a mouse model of TSC2. Pharmacological inhibition of Histone Deacetylase (HDAC) activity restores histone H3 acetylation levels and ameliorates the aberrant plasticity in TSC2+/- mice. We describe a novel seizure phenotype in TSC2+/- mice that is also normalized with HDAC inhibitors (HDACis). The results from this study suggest an unanticipated role for chromatin modification in TSC and may inform novel therapeutic strategies for TSC patients.

A predictive epilepsy index based on probabilistic classification of interictal spike waveforms.

Quantification of interictal spikes in EEG may provide insight on epilepsy disease burden, but manual quantification of spikes is time-consuming and subject to bias. We present a probability-based, automated method for the classification and quantification of interictal events, using EEG data from kainate- and saline-injected mice (C57BL/6J background) several weeks post-treatment. We first detected high-amplitude events, then projected event waveforms into Principal Components space and identified clusters of spike morphologies using a Gaussian Mixture Model. We calculated the odds-ratio of events from kainate- versus saline-treated mice within each cluster, converted these values to probability scores, P(kainate), and calculated an Hourly Epilepsy Index for each animal by summing the probabilities for events where the cluster P(kainate) > 0.5 and dividing the resultant sum by the record duration. This Index is predictive of whether an animal received an epileptogenic treatment (i.e., kainate), even if a seizure was never observed. We applied this method to an out-of-sample dataset to assess epileptiform spike morphologies in five kainate mice monitored for ~1 month. The magnitude of the Index increased over time in a subset of animals and revealed changes in the prevalence of epileptiform (P(kainate) > 0.5) spike morphologies. Importantly, in both data sets, animals that had electrographic seizures also had a high Index. This analysis is fast, unbiased, and provides information regarding the salience of spike morphologies for disease progression. Future refinement will allow a better understanding of the definition of interictal spikes in quantitative and unambiguous terms.

Altered circadian rhythms and oscillation of clock genes and sirtuin 1 in a model of sudden unexpected death in epilepsy.

OBJECTIVES: Circadian rhythms are affected in many neurological disorders. Although sleep disturbances are known in epilepsy, data on circadian rhythm disturbances in epilepsy are sparse. Here, we examined diurnal and circadian rest-activity and sleep-wake patterns in Kcna1-null mice, which exhibit spontaneous recurrent seizures and are a model of sudden unexpected death in epilepsy. Furthermore, we sought to determine whether seizures or aberrant oscillation of core clock genes and a regulator, sirtuin 1 (Sirt1), is associated with disrupted rhythms. METHODS: We used passive infrared actigraphy to assess rest-activity patterns, electroencephalography for seizure and sleep analysis, and reverse transcription polymerase chain reaction and Western blotting to evaluate expression of clock genes and Sirt1 in Kcna1-null and wild-type mice. RESULTS: Epileptic Kcna1-null animals have disrupted diurnal and circadian rest-activity patterns, tending to exhibit prolonged circadian periods. Electroencephalographic analysis confirmed disturbances in sleep architecture, with more time spent awake and less asleep. Although all epileptic mice manifested disrupted diurnal and circadian rest-activity patterns, we found no correlation between actual seizure burden and degree of sleep disruption. However, we found attenuated oscillations of several clock genes (ie, Clock, Bmal1, Per1, and Per2) and diurnal Sirt1 mRNA in the anterior hypothalamus. SIGNIFICANCE: Attenuated oscillation of several core clock genes correlates with, and may underlie, aberrant diurnal and circadian rest-activity and sleep-wake patterns observed in Kcna1-null mice. This could contribute to late complications in epilepsy, such as sudden unexpected death in epilepsy. Sirt1 may represent a useful therapeutic target for rescuing circadian clock gene rhythmicity and sleep patterns in epilepsy.

EEG and epilepsy monitoring.

PURPOSE OF REVIEW: This article reviews the utility of EEG and prolonged video-EEG telemetry in the diagnosis and management of a patient with epilepsy. RECENT FINDINGS: The EEG can be the most helpful test to determine a diagnosis of epilepsy; it can also distinguish focal and generalized neurophysiologic correlates of epilepsy. Furthermore, when paired with video monitoring, EEG can not only define epileptic and nonepileptic events but also aid in localization of seizures in patients with epilepsy. Finally, when history and other imaging modalities are considered with the EEG, the epileptic syndrome can usually be defined and the treatment can be focused. In critically ill patients, continuous EEG monitoring can define subclinical seizures, although a variety of periodic patterns may also be identified. SUMMARY: EEG is an invaluable tool in the diagnosis and management of a patient with epilepsy, and continuous EEG monitoring is useful in identifying subclinical seizures and nonconvulsive status epilepticus in critically ill patients.

Plasma exchange in cryptogenic new onset refractory status epilepticus.

OBJECTIVE: New onset refractory status epilepticus (NORSE) is a recently described entity and has been difficult to treat because the etiology is often cryptogenic. Our aim in each case was to stop status epilepticus while simultaneously searching for the etiology. METHODS: We describe three patients who presented with NORSE, who were refractory to multiple anticonvulsants and general anesthetics for at least 5 days. All patients had an extensive evaluation including MRI brain, CSF studies, radiologic scans for malignancy and serological autoimmune and infectious investigations. RESULTS: Each patient responded dramatically to the use of plasma exchange therapy with cessation of status epilepticus by the fourth day of treatment. Although an etiology was sought after, no appropriate cause for NORSE could be found. CONCLUSION: We propose early use of plasma exchange therapy (Class IV evidence) in hopes to prevent the complications of status epilepticus and prolonged hospitalization.

Neurotoxic effects associated with antibiotic use: management considerations.

The clinical manifestations of antibiotic-induced neurotoxic effects, the underlying mechanisms and management strategies have been reviewed. PubMed and OVID searches (January 1960-June 2010) were conducted using search terms such as antibiotics, side effects, neurotoxicity and encephalopathy which yielded approximately 300 articles. All relevant case reports, case series, letters and retrospective reviews describing neurotoxic effects and those discussing mechanisms of neurotoxicity were included. Antibiotic-induced neurotoxic side effects can have a myriad of neurologic presentations. Patients with prior central nervous system (CNS) disease, renal insufficiency and advanced age may be particularly vulnerable. Treatment consists of discontinuation of the offending agent, use of antiepileptic drugs in the case of seizures or status epilepticus and haemodialysis in certain cases. The risk of CNS toxicity may be reduced via dosage adjustments in high risk populations. Awareness of the potential neurotoxic clinical manifestations of various antibiotics and high degree of vigilance in critically ill patients is essential in identifying a potentially serious, though reversible complications of antibiotic therapy particularly with the advent of newer antimicrobial agents.

Best practice guide for the treatment of nightmare disorder in adults.

Prazosin is recommended for treatment of Posttraumatic Stress Disorder (PTSD)-associated nightmares. Level A. Image Rehearsal Therapy (IRT) is recommended for treatment of nightmare disorder. Level A. Systematic Desensitization and Progressive Deep Muscle Relaxation training are suggested for treatment of idiopathic nightmares. Level B. Venlafaxine is not suggested for treatment of PTSD-associated nightmares. Level B. Clonidine may be considered for treatment of PTSD-associated nightmares. Level C. The following medications may be considered for treatment of PTSD-associated nightmares, but the data are low grade and sparse: trazodone, atypical antipsychotic medications, topiramate, low dose cortisol, fluvoxamine, triazolam and nitrazepam, phenelzine, gabapentin, cyproheptadine, and tricyclic antidepressants. Nefazodone is not recommended as first line therapy for nightmare disorder because of the increased risk of hepatotoxicity. Level C. The following behavioral therapies may be considered for treatment of PTSD-associated nightmares based on low-grade evidence: Exposure, Relaxation, and Rescripting Therapy (ERRT); Sleep Dynamic Therapy; Hypnosis; Eye-Movement Desensitization and Reprocessing (EMDR); and the Testimony Method. Level C. The following behavioral therapies may be considered for treatment of nightmare disorder based on low-grade evidence: Lucid Dreaming Therapy and Self-Exposure Therapy. Level C No recommendation is made regarding clonazepam and individual psychotherapy because of sparse data.

Best practice guide for the treatment of REM sleep behavior disorder (RBD).

SUMMARY OF RECOMMENDATIONS: Modifying the sleep environment is recommended for the treatment of patients with RBD who have sleep-related injury. Level A Clonazepam is suggested for the treatment of RBD but should be used with caution in patients with dementia, gait disorders, or concomitant OSA. Its use should be monitored carefully over time as RBD appears to be a precursor to neurodegenerative disorders with dementia in some patients. Level B Clonazepam is suggested to decrease the occurrence of sleep-related injury caused by RBD in patients for whom pharmacologic therapy is deemed necessary. It should be used in caution in patients with dementia, gait disorders, or concomitant OSA, and its use should be monitored carefully over time. Level B Melatonin is suggested for the treatment of RBD with the advantage that there are few side effects. Level B Pramipexole may be considered to treat RBD, but efficacy studies have shown contradictory results. There is little evidence to support the use of paroxetine or L-DOPA to treat RBD, and some studies have suggested that these drugs may actually induce or exacerbate RBD. There are limited data regarding the efficacy of acetylcholinesterase inhibitors, but they may be considered to treat RBD in patients with a concomitant synucleinopathy. Level C.

Status epilepticus associated with subtentorial posterior fossa lesions.

BACKGROUND: Nonconvulsive status epilepticus (SE) is a frequent complication in critically ill patients in the intensive care unit. While seizures have been reported in association with subtentorial posterior fossa lesions, the frequency of occurrence of SE among these patients is not known. OBJECTIVES: To examine prevalence, clinical features, potential risk factors, and outcome of SE among patients presenting with subtentorial posterior fossa lesions. DESIGN: Retrospective review of our hospital database was conducted to identify patients with posterior fossa lesions complicated by SE over 1 year between April 1, 2007, and May 1, 2008. SETTING: Tertiary care setting. PATIENTS: Patients with subtentorial posterior fossa lesions admitted to the hospital for neurological or neurosurgical care. MAIN OUTCOME MEASURES: Prevalence of SE, potential risk factors, and eventual neurological outcome. RESULTS: Over 1 year, 13 of 501 patients (2.6%) admitted to the hospital with posterior fossa lesions had SE. Some patients had risk factors for SE such as sepsis, use of particular drugs, or intracranial bleeding, while others had no other clear identifiable cause. CONCLUSIONS: Status epilepticus can be a potential complication in patients with posterior fossa cranial lesions and can be seen in up to 2.6% of such patients. Most have unfavorable outcome.

Ketogenic diet treatment abolishes seizure periodicity and improves diurnal rhythmicity in epileptic Kcna1-null mice.

INTRODUCTION: Seizures are known to perturb circadian rhythms in humans as well as in animal models of epilepsy. However, it is unknown whether treatment of the underlying epilepsy restores normal biologic rhythms. We asked whether: (1) seizure activity is characterized by diurnal rhythmicity, (2) chronically epileptic mice exhibit impaired rest-activity rhythms, and (3) treatment with the anticonvulsant ketogenic diet (KD) improves such perturbations. METHODS: Chronically epileptic Kcna1-null mice were fed either a standard diet (SD) or KD for 4 weeks and subjected to continuous video-EEG (electroencephalography) and actigraphy monitoring for 3-5 days to assess seizure activity and rest-activity cycles. RESULTS: Seizure activity in Kcna1-null mice demonstrated diurnal rhythmicity, peaking at zeitgeber (ZT)2.30 +/- 1.52. Rest-activity rhythms of epileptic mice were significantly disrupted. Whereas locomotor activity for wild-type mice peaked at ZT15.45 +/- 0.28 (ZT14:26-ZT16:51), peak activity of epileptic mice was more unpredictable, occurring over a 12.4 h range (ZT06:33-ZT18:57). In six of nine epileptic mice, peak activity was delayed to ZT17.42 +/- 0.38, whereas peak activity was advanced to ZT10.00 +/- 1.26 in the remaining mice. Treatment with the KD abolished seizure periodicity and restored the rest-activity rhythm to values resembling those of wild-type mice (i.e., activity peaking at ZT16.73 +/- 0.67). CONCLUSIONS: Kcna1-null mice experience seizures with 24-h periodicity and impaired circadian behavior. KD reduces the number and periodicity of seizures and restores normal behavioral rhythms, suggesting that this nonpharmacologic therapy may benefit biologic rhythm disturbances in epileptic patients.