Transient targeting of hypothalamic orexin neurons alleviates seizures in a mouse model of epilepsy.

Lateral hypothalamic (LH) hypocretin/orexin neurons (HONs) control brain-wide electrical excitation. Abnormally high excitation produces epileptic seizures, which affect millions of people and need better treatments. HON population activity spikes from minute to minute, but the role of this in seizures is unknown. Here, we describe correlative and causal links between HON activity spikes and seizures. Applying temporally-targeted HON recordings and optogenetic silencing to a male mouse model of acute epilepsy, we found that pre-seizure HON activity predicts and controls the electrophysiology and behavioral pathology of subsequent seizures. No such links were detected for HON activity during seizures. Having thus defined the time window where HONs influence seizures, we targeted it with LH deep brain stimulation (DBS), which inhibited HON population activity, and produced seizure protection. Collectively, these results uncover a feature of brain activity linked to seizures, and demonstrate a proof-of-concept treatment that controls this feature and alleviates epilepsy.

Hypothalamic deep brain stimulation as a strategy to manage anxiety disorders.

Fear is essential for survival, but excessive anxiety behavior is debilitating. Anxiety disorders affecting millions of people are a global health problem, where new therapies and targets are much needed. Deep brain stimulation (DBS) is established as a therapy in several neurological disorders, but is underexplored in anxiety disorders. The lateral hypothalamus (LH) has been recently revealed as an origin of anxiogenic brain signals, suggesting a target for anxiety treatment. Here, we develop and validate a DBS strategy for modulating anxiety-like symptoms by targeting the LH. We identify a DBS waveform that rapidly inhibits anxiety-implicated LH neural activity and suppresses innate and learned anxiety behaviors in a variety of mouse models. Importantly, we show that the LH DBS displays high temporal and behavioral selectivity: Its affective impact is fast and reversible, with no evidence of side effects such as impaired movement, memory loss, or epileptic seizures. These data suggest that acute hypothalamic DBS could be a useful strategy for managing treatment-resistant anxiety disorders.

Aggressive cytoreduction and multiple subpial cortical transections may obtain good surgical outcomes in refractory epilepsy with multiple epileptic foci.

BACKGROUNDS: Epilepsy surgery is the most efficacious therapeutic modality for patients with medical refractory epilepsy, especially resective surgery. However, the variable etiologies and multiple epileptic foci are usually associated with the outcomes. The aim of this study was to demonstrate that combination of different intervention procedures might be an alternative option for patients of refractory epilepsy. METHODS: We retrospectively analyzed pre-operative and post-surgical outcomes in 30 patients who received epilepsy surgery between January 1, 2010 and December 31, 2014 at Chang Gung Memorial Hospital (CGMH), Linkou, according to Engel's classification. RESULTS: Twenty-six of the 30 patients (86.7%) had good outcomes, sum of class I and class II after epilepsy surgery. The good outcome rate of our complicated group was 80.0% (12/15), compared to 93.3% (14/15) in the simple group, but no significant differences between the two groups (p = 0.569). Four patients whose epileptic foci involved eloquent area and received multiple subpial cortical transection, and good outcome rate was 75% (3/4). At last, six patients had previously failed epilepsy surgery and received a reoperation, with a good outcome rate of 83.3% (5/6). CONCLUSION: After complete pre-surgical evaluation and combined interventional procedures, the patients with refractory epilepsy had satisfactory outcomes and few neurological complications. Moreover, re-operation can improve the outcome in some patients who previously failed epilepsy surgery.

Role of spontaneous and sensory orexin network dynamics in rapid locomotion initiation.

Appropriate motor control is critical for normal life, and requires hypothalamic hypocretin/orexin neurons (HONs). HONs are slowly regulated by nutrients, but also display rapid (subsecond) activity fluctuations in vivo. The necessity of these activity bursts for sensorimotor control and their roles in specific phases of movement are unknown. Here we show that temporally-restricted optosilencing of spontaneous or sensory-evoked HON bursts disrupts locomotion initiation, but does not affect ongoing locomotion. Conversely, HON optostimulation initiates locomotion with subsecond delays in a frequency-dependent manner. Using 2-photon volumetric imaging of activity of >300 HONs during sensory stimulation and self-initiated locomotion, we identify several locomotion-related HON subtypes, which distinctly predict the probability of imminent locomotion initiation, display distinct sensory responses, and are differentially modulated by food deprivation. By causally linking HON bursts to locomotion initiation, these findings reveal the sensorimotor importance of rapid spontaneous and evoked fluctuations in HON ensemble activity.

Effectiveness and safety of perampanel in adults with mesial temporal epilepsy: A single-center postmarketing study in Taiwan.

Mesial temporal lobe epilepsy (MTLE) is a common epilepsy syndrome often refractory to antiepileptic drug (AED) treatment. The purpose of this study was to evaluate the effectiveness and tolerability of perampanel (PER) as add-on treatment for patients of MTLE.We pooled retrospective data from adult patients with MTLE, from a tertiary center in Taiwan, who were prescribed PER between March 2016 and December 2016. The retention, responder, and seizure-free rate as well as the treatment emergent adverse events were assessed after 6 months of PER adjunctive treatment in this single-center postmarketing study.Review of medical records revealed that adequate data were available for 44 patients who were being administered PER (mean age: 42.0 ±â€Š13.3 years, 24 females; baseline mean seizure frequency: 5.4 per 28 days). Twelve patients exhibited hippocampal sclerosis (HS). Open-label PER was added to ongoing medications. Twelve patients withdrew because of ineffectiveness (n = 6) or adverse effects (n = 6). The retention rate was 72.7% at 6 months. On final evaluation, with a mean PER dose of 5.7 mg/day for 6 months, a ≥50% reduction in seizure frequency was observed in 46.9% of the patients, and 5 patients became seizure-free. The effectiveness was similar for patients with or without HS. Twenty-three patients (52.3%) experienced adverse effects. The most common adverse effects were dizziness, ataxia, and irritability.Our results suggest that PER, at doses of 2 to 12 mg/day, reduces seizure frequency effectively with acceptable safety profiles for adults with MTLE.

Clinical, Electroencephalographic Features and Prognostic Factors of Cefepime-Induced Neurotoxicity: A Retrospective Study.

BACKGROUND: The incidence of cefepime-induced neurotoxicity (CIN) has been previously underestimated, and there have only been sporadic reports from critical neurological settings. The present study aimed to investigate the potential factors associated with disease development, electroencephalography (EEG) sub-classification, and outcome measures. METHODS: The 10-year medical records of patients who underwent EEG between 2007 and 2016 at a tertiary medical center in Taiwan, and developed encephalopathy after cefepime therapy were retrospectively reviewed. Age- and sex-matched controls were included for further analysis. Demographic data, the occurrence of clinical seizures, non-convulsive status epilepticus (NCSE), use of antiepileptic drugs (AEDs), receiving maintenance or urgent hemodialysis, EEG findings, and functional outcomes were analyzed. The Chi-square test and a logistic regression model were applied to survey significant prognostic factors relating to mortality. RESULTS: A total of 42 CIN patients were identified, including 25 patients from wards and 17 from intensive care units; their mean age was 75.8 ± 11.8 years. Twenty-one patients (50%) had chronic kidney disease, and 18 (43%) had acute kidney injury. Among these patients, 32 (76%) received appropriate cefepime dose adjustment. Three patients had a normal renal function at the time of CIN onset. The logistic regression model suggested that maintenance hemodialysis and longer duration of cefepime use were independently associated with the development of CIN, with odds ratios of 3.8 and 1.2, respectively. NCSE was frequently noted in the CIN patients (64%). Generalized periodic discharge with or without triphasic morphology was the most common EEG pattern (38%), followed by generalized rhythmic delta activity and generalized spike-and-waves. AEDs were administered to 86% of the patients. A total of 17 patients (40%) did not survive to hospital discharge. Adequate cefepime dose adjustment and early cefepime discontinuation led to a better prognosis. CONCLUSIONS: CIN was associated with high mortality and morbidity rates. Neurotoxic symptoms could still occur when the cefepime dose was adjusted, or in patients with normal renal function. Patients with maintenance hemodialysis or a longer duration of cefepime therapy tended to develop CIN. Early recognition of abnormal EEG findings allowed for the withdrawal of the offending agent, resulting in clinical improvements and a better prognosis at discharge.

Different routes of heroin intake cause various heroin-induced leukoencephalopathies.

OBJECTIVE: Toxic leukoencephalopathy is a rare but critical neurological disorder in heroin abusers. Our aim is to compare the clinical manifestations, brain MRIs and prognoses of heroin-induced leukoencephalopathy by different intake routes. METHODS: We present two patients with toxic leukoencephalopathy caused by intravenous (IV) injection of heroin and 48 additional cases from systematic reviews of the literature published between 1994 and 2018. RESULTS: Among the 50 heroin abusers who developed leukoencephalopathy, inhalation was the most popular route (60%), followed by IV injection (30%) and snorting (10%). Mental changes, mutism and urine/fecal incontinence were the major symptoms in patients who IV injected heroin, while cerebellar ataxia and dysarthria were more common among those who inhaled heroin. Delayed-onset encephalopathy uniquely occurred in those who IV injected heroin, whereas progressive encephalopathy was more commonly observed in those who inhaled heroin. Clinical improvement was observed in 60% of patients, the overall mortality rate was 12%, and higher mortality was observed in patients who used the inhalation route (16.7%). The hallmarks on the MRIs of those who inhaled heroin were posterior to anterior involvement of the cerebral white matter and lesions in the posterior limbs of the internal capsules, cerebellum and brainstem. In contrast, those who IV injected heroin had more frequent lesions in the subcortical U fibers and the genu of the internal capsules. CONCLUSION: These data could help physicians make an early diagnosis and predict prognosis and suggest that prompt antioxidative or symptomatic treatments might reduce the long-term consequences and mortality of heroin-induced leukoencephalopathy.

Efficacy of limited hippocampal radiofrequency thermocoagulation for mesial temporal lobe epilepsy.

OBJECTIVE: Radiofrequency thermocoagulation (RFTC), which has been developed for drug-resistant epilepsy patients, involves less brain tissue loss due to surgery, fewer surgical adverse effects, and generally good seizure control. This study demonstrates the effectiveness of RFTC performed at limited hippocampal locations. METHODS: Daily seizure diaries were prospectively maintained for at least 6 months by 9 patients (ages 30-59 years) with drug-resistant mesial temporal lobe epilepsy (MTLE) before treatment with RFTC. The limited target for stereotactic RFTC was chosen based on intraoperative electroencephalography (EEG) recording and was initially tested with a Radionics electrode at a low temperature, 45°C, for 60 seconds. The therapeutic RFTC heating parameters were 78°C-80°C for 90 seconds. All patients who received the RFTC treatment underwent both MRI and EEG recording immediately postoperatively and at the 3-month follow-up. Monthly outpatient clinic visits were arranged over 6 months to document seizure frequency and severity to clarify the changes noted in imaging studies and EEG patterns. RESULTS: Two patients were excluded from our analysis because one had undergone multiple seizure surgeries and the other had a poor recording of seizure frequency, before the RFTC surgery. Five and two patients underwent left-sided and right-sided RFTC, respectively. None of the patients had generalized tonic-clonic attacks postoperatively, and no adverse effects or complications occurred. According to MRI data, the effect of coagulation was limited to less than 1.0 cm in diameter and perifocal edema was also in limited range. The seizure frequency within 6 months decreased postoperatively with a mean reduction in seizures of 78% (range 36%-100%). Only two patients had a temporary increase in seizure frequency within 2 weeks of the surgery, and over 50% of all patients showed a decrease in average seizure frequency. CONCLUSIONS: The study results confirm that limited RFTC provides a more effective surgery with similar seizure control but fewer complications than resective surgery for drug-resistant MTLE patients.

Predictive Factors for Early Initiation of Artificial Feeding in Patients With Sporadic Creutzfeldt-Jakob Disease.

Background: Akinetic mutism has often been used as the predictor of sporadic Creutzfeldt-Jacob disease (sCJD) endpoints, but it may be difficult for general physcians to assess. Nasogastric (NG) tube insertion is indicated for many neurodegenerative diseases with a clinical course of swallowing failure, and can be more easily identified than akinetic mutism by general physicians. Therefore, the aim of this study was to identify whether there are predictive factors for early initiation of artificial feeding in patients with sCJD who require enteral nutrition due to swallowing failure. Methods: We retrospectively reviewed the medical records of all patients diagnosed with probable sCJD who were admitted to the neurology ward at a medical center in Taiwan from January 2002 to July 2017. We used Pearson's chi-squared test to detect the correlation of initial symptoms, neurological signs, brain magnetic resonance imaging (MRI), electroencephalography (EEG), and increased levels of 14-3-3 protein in cerebrospinal fluid (CSF) analysis. The Cox proportional hazards model was used to detect prognostic factors for early initiation of NG tube insertion in sCJD patients. Results: The onset age ranged from 51 to 83 years, and mostly ranged from 60 to 79 years. Akinetic mutism was correlated with pyramidal tract signs, myoclonus, and extrapyramidal signs. Furthermore, myoclonus was revealed to be associated with pyramidal tract signs. Multivariate Cox regression analysis showed that myoclonus and elevated CSF levels of 14-3-3 protein are predictive of early NG insertion. Conclusions: Increased levels of 14-3-3 protein in CSF and the presence of myoclonus at diagnosis are predictive of early swallowing difficulty and indicate rapid deterioration in probable sCJD. In addition to akinetic mutism, early initiation of artificial feeding can be used to predict early deterioration in sCJD.

Correlation of vocals and lyrics with left temporal musicogenic epilepsy.

Whether the cognitive processing of music and speech relies on shared or distinct neuronal mechanisms remains unclear. Music and language processing in the brain are right and left temporal functions, respectively. We studied patients with musicogenic epilepsy (ME) that was specifically triggered by popular songs to analyze brain hyperexcitability triggered by specific stimuli. The study included two men and one woman (all right-handed, aged 35-55 years). The patients had sound-triggered left temporal ME in response to popular songs with vocals, but not to instrumental, classical, or nonvocal piano solo versions of the same song. Sentimental lyrics, high-pitched singing, specificity/familiarity, and singing in the native language were the most significant triggering factors. We found that recognition of the human voice and analysis of lyrics are important causal factors in left temporal ME and provide observational evidence that sounds with speech structure are predominantly processed in the left temporal lobe. A literature review indicated that language-associated stimuli triggered ME in the left temporal epileptogenic zone at a nearly twofold higher rate compared with the right temporal region. Further research on ME may enhance understanding of the cognitive neuroscience of music.

Clinical correlation and prognostic implication of periodic EEG patterns: A cohort study.

OBJECTIVE: Despite increasing amounts of research on periodic discharges (PDs), large clinical studies regarding their prognostic value are lacking. The aim of the current study was to evaluate the clinical implications and prognostic value of PDs. METHODS: In this single-center retrospective cohort study, we included patients who underwent electroencephalographic recording either during hospitalization or from our outpatient clinics. Demographic data, associated seizure events, use of antiepileptic drugs, and outcomes at discharge were analyzed. Multivariate logistic regression analysis was used to evaluate associations between clinical factors and functional outcomes. RESULTS: Four hundred and twenty patients were enrolled during a 17-year period, with a mean age of 66 years. The main etiologies included systemic infection (24%), anoxia (15%), and ischemic stroke (12%). Recent seizures were identified in 283 patients (67%), of whom 84 (30%) had status epilepticus. One hundred and fifty-four patients (37%) did not survive to hospital discharge. In multivariate analysis, old age (>65years; OR=2.55; 95% CI=1.57-4.16; P<0.001) was the strongest predictor of mortality, followed by systemic infection, anoxic encephalopathy, cefepime encephalopathy, and the occurrence of status epilepticus. Conversely, the use of antiepileptic drugs was negatively associated with mortality (OR=0.50; 95% CI=0.28-0.87; P=0.02). CONCLUSIONS: PDs were associated with high rates of comorbidities and recent seizures, while the use of antiepileptic drugs was associated with a lower rate of mortality.

Preliminary Asian experience of using perampanel in clinical practice.

BACKGROUND: To analyze the efficacy and safety of perampanel over a 3-month period in a sample of Asian people with epilepsy. METHODS: The efficacy and safety of perampanel as an adjunctive therapy for patients with epilepsy were retrospectively reviewed and analyzed. Patients were categorized according to seizure type, concomitant antiepileptic drug usage, and perampanel dosage. RESULTS: A total of 210 patients were included in the study and 131 patients completed 3 months of perampanel treatment. The average dosage of perampanel was 5.31 mg/day, and the 50% responder rate (≥50% seizure frequency reduction) in all patients was 45.8%, with a 27.5% seizure-free rate. For focal seizures, focal to bilateral tonic-clonic seizures, and primary generalized seizures, the 50% responder rates were respectively 29.4%, 49.5%, and 36.4%. In total, 39.5% of patients experienced adverse events within 3 months of observation period, and the rate of drug withdrawal due to adverse events was 8.6%. Dizziness, ataxia, irritability/aggression were the most common adverse events. CONCLUSIONS: The efficacy and safety of perampanel in a real-world setting with Asian patients is comparable to that in clinical trials that have included fewer Asian patients.

Seizure Freedom After Limited Hippocampal Radiofrequency Thermocoagulation.

BACKGROUND: Surgical interventions are often used for freedom from seizure in patients with drug-resistant mesial temporal lobe epilepsy. A patient with seizure foci in the left mesiotemporal region underwent limited-size stereotactic radiofrequency thermocoagulation (RF-TC) over the left hippocampus. CASE DESCRIPTION: A 37-year-old woman with febrile convulsion in her childhood was admitted to our neurologic department with complex partial seizure with secondary generalization. Electroencephalography showed epileptogenic focus mainly from the left mesiotemporal region, and magnetic resonance imaging confirmed a left hippocampal atrophy. Because of failure to control seizure after use of several antiepileptic drugs, drug-resistant mesial temporal lobe epilepsy was diagnosed. RF-TC was done in the left hippocampus. Unique features of our technique include intraoperative electroencephalography recordings directly from electrodes on the left hippocampus, an aura sensation provoked during the low-temperature test thermocoagulation, and therapeutic thermocoagulation performed via a Radionics radiofrequency lead. In the 16-week period following the surgery, the patient experienced no seizure attacks and no significant postoperative adverse effects or memory impairments. Compared with other reports using RF-TC, our case demonstrates a 1-step minimally invasive surgery that reduces hippocampal volume loss, shortens the length of hospital stay, decreases the occurrence of postoperative infection, and achieves good outcomes for epilepsy control. CONCLUSIONS: Favorable seizure control was achieved with minimally invasive RF-TC. Further use of this technique is warranted in cases of drug-resistant mesial temporal lobe epilepsy.

Clinical and electrodiagnostic characteristics of nitrous oxide-induced neuropathy in Taiwan.

OBJECTIVE: Nitrous oxide-induced neuropathy is toxic neuropathy occasionally encountered in Taiwanese neurological clinics. Only several case reports described their electrodiagnostic features. We used a case-control design to investigate the detailed electrodiagnostic characteristics and possible factors relating to severe nerve injury. METHODS: We retrospectively reviewed 33 patients with nitrous oxide-induced neuropathy over a 10-year period and reported their demographic data, spinal cord MRI, laboratory examinations and nerve conduction studies. 56 healthy controls' nerve conduction studies were collected for comparison analysis. RESULTS: We noted significant motor and sensory amplitudes reduction, conduction velocities slowing, and latencies prolongation in most tested nerves compared to the controls. Similar nerve conduction study characteristics with prominent lower limbs' motor and sensory amplitudes reduction was observed in patient groups with or without abnormal vitamin B12 and/or homocysteine levels. Among those with lower limbs' motor or sensory amplitudes reduction <20% of the lower limit of normal, higher homocysteine levels were detected. CONCLUSIONS: Severe impairments of the lower limbs' sensory and motor amplitudes were frequently noted in patients with nitrous oxide exposure. Nitrous oxide exposure itself is an important factor for the development of neuropathy. SIGNIFICANCE: Our study contributes to the understanding of electrodiagnostic features underlying the nitrous oxide-induced neuropathy.