Hypothermia associated with clobazam use in adult epilepsy

AbstractClobazam, a 1,5-benzodiazepine FDA-approved in 2011, is commonly used to treat anxiety and epilepsy. It has not been associated with hypothermia until very recently, in a case report involving two pediatric patients. Here, we report the first case of hypothermia development in an adult patient with epilepsy associated with clobazam use. A couple months after starting clobazam, the patient started developing episodes of hypothermia every several weeks, with temperatures ranging from 90°F–95°F. Normothermia was achieved with Bair Hugger therapy. Thyroid-stimulating hormone and cortisol levels were normal, and there was no evidence of infection in most instances. After 11 total episodes of hypothermia over a year of clobazam use, the drug was discontinued. It has now been 7months after discontinuation, and the patient has not experienced any more episodes of hypothermia. Early recognition of the link between clobazam and hypothermia may prevent avoidable Emergency Department visits and hospitalizations

Electrical cortical stimulation can impair production of the alphabet without impairing counting

Neurosurgery has the potential to cure patients with drug-resistant focal epilepsy, but carries the risk of permanent language impairment when surgery involves the dominant hemisphere of the brain. This risk can be estimated and minimized using electrical stimulation mapping (ESM), which uses cognitive and linguistic tasks during cortical ESM to differentiate "eloquent" and "resectable" areas in the brain. One such task, counting, is often used to screen and characterize language during ESM in patients whose language abilities are limited. Here we report a patient with drug-resistant epilepsy arising from the language-dominant hemisphere using fMRI. Our patient experienced loss of the ability to recite or write the alphabet, but not to count, during ESM of the dominant left posterior superior temporal gyrus. This selective impairment extended to both spoken and written production. We suggest the need for caution when using counting as a sole means to screen language function and as a method of testing low functioning patients using ESM

Disease-causing Slack potassium channel mutations produce opposite effects on excitability of excitatory and inhibitory neurons

Summary: The KCNT1 gene encodes the sodium-activated potassium channel Slack (KCNT1, KNa1.1), a regulator of neuronal excitability. Gain-of-function mutations in humans cause cortical network hyperexcitability, seizures, and severe intellectual disability. Using a mouse model expressing the Slack-R455H mutation, we find that Na+-dependent K+ (KNa) and voltage-dependent sodium (NaV) currents are increased in both excitatory and inhibitory cortical neurons. These increased currents, however, enhance the firing of excitability neurons but suppress that of inhibitory neurons. We further show that the expression of NaV channel subunits, particularly that of NaV1.6, is upregulated and that the length of the axon initial segment and of axonal NaV immunostaining is increased in both neuron types. Our study on the coordinate regulation of KNa currents and the expression of NaV channels may provide an avenue for understanding and treating epilepsies and other neurological disorders

Impairment of consciousness induced by bilateral electrical stimulation of the frontal convexity

We report a case of impairment of consciousness (IOC) induced by electrical cortical stimulation (ECS) of homologous regions within the lateral frontal convexities in a patient with medically intractable epilepsy. The patient had mixed features of idiopathic generalized and focal epilepsy. On intracranial EEG recording, interictal and ictal discharges showed a high degree of synchrony across widespread bilateral fronto-parietal areas. We identified regions in the lateral frontal lobes that reliably and produced loss of consciousness by ECS. This was accompanied by evoked EEG activity of admixed frequencies over the fronto-parietal, mesial frontal and temporal regions during stimulation and was not associated with after-discharges. Symptoms were immediately reversible upon cessation of stimulation. This finding suggests that focal cortical stimulation can disrupt widespread networks that underlie consciousness. Individuals with high degrees of speculated thalamo-frontal cortical connectivity might be more susceptible to this effect, and the findings highlight the importance of standardizing the testing of level of consciousness during mapping sessions. Although consciousness is commonly impaired in epileptic seizures, limited literature is available on loss of consciousness induced by electrical cortical stimulation (ECS) in humans undergoing intracranial EEG evaluations for localization of epileptic focus. One theory advocates the presence of consciousness ‘switch’ in subcortical structures. While this model is novel and simplistic, it has its inherent limitations. In this case study, we propose an alternative approach on the entity and discuss the complex circuits underlying it and correlate that with the electrophysiological findings and the pathophysiology of the phenotype of the disease and discuss potential causes for rarity of reports on the subject

Nonquantal transmission at the vestibular hair cell–calyx synapse: K_LV currents modulate fast electrical and slow K⁺ potentials

Vestibular hair cells transmit information about head position and motion across synapses to primary afferent neurons. At some of these synapses, the afferent neuron envelopes the hair cell, forming an enlarged synaptic terminal called a calyx. The vestibular hair cell–calyx synapse supports a mysterious form of electrical transmission that does not involve gap junctions, termed nonquantal transmission (NQT). The NQT mechanism is thought to involve the flow of ions from the presynaptic hair cell to the postsynaptic calyx through low-voltage-activated channels driven by changes in cleft [K+] as K+ exits the hair cell. However, this hypothesis has not been tested with a quantitative model and the possible role of an electrical potential in the cleft has remained speculative. Here, we present a computational model that captures experimental observations of NQT and identifies features that support the existence of an electrical potential (ϕ) in the synaptic cleft. We show that changes in cleft ϕ reduce transmission latency and illustrate the relative contributions of both cleft [K+] and ϕ to the gain and phase of NQT. We further demonstrate that the magnitude and speed of NQT depend on calyx morphology and that increasing calyx height reduces action potential latency in the calyx afferent. These predictions are consistent with the idea that the calyx evolved to enhance NQT and speed up vestibular signals that drive neural circuits controlling gaze, balance, and orientation

Prevalence of atrial fibrillation in patients taking TSH suppression therapy for management of thyroid cancer

Background: Suppression of thyroid stimulating hormone (TSH) below the normal range with administration of L-thyroxine has been shown to improve survival in patients treated for thyroid cancer (TC). Although most TC patients require long-term TSH suppression therapy, the effect of this treatment on cardiac rhythm remains unknown. A cross-sectional study was conducted to determine the prevalence of atrial fibrillation (AF) in TC patients on TSH suppressive therapy. Methods: All TC patients seen between June 2009 and March 2010 through a multidisciplinary thyroid oncology clinic, Halifax, Nova Scotia, Canada, for whom TSH suppressive therapy had previously been recommended, were recruited into the study. Each patient underwent an electrocardiogram and filled out a questionnaire relevant to causes, signs/symptoms of AF and/or its complications. The prevalence of AF in this population then was compared against the published prevalence of AF in general populations. Results: A total of 351 patients were seen in the thyroid clinic of which 136 patients met the inclusion criteria for the study. The mean age was 52 years, 85% were female, and mean follow-up duration prior to recruitment was 11 years. The mean TSH was 0.17 mIU/L (Normal: 0.35 – 5.5 mIU/L). There were 14 patients found to have AF (two patients had long-standing persistent AF and 12 patients had paroxysmal AF). The mean ages of patients with and without AF were 61.6 years and 51.4 years, respectively (P = 0.01). Prevalence of AF in the study group was 10.3%; the rate of AF in the TC patients aged 60 years and over (17.5%) was higher than the rate of AF in published data in people 60 years and over (P < 0.001). AF was diagnosed after the initiation of the TSH suppression therapy in all except one patient. Conclusion: TSH suppression in thyroid cancer is associated with a high prevalence of AF, particularly in older individuals

Human Slack Potassium Channel Mutations Increase Positive Cooperativity between Individual Channels

Summary: Disease-causing mutations in ion channels generally alter intrinsic gating properties such as activation, inactivation, and voltage dependence. We examined nine different mutations of the KCNT1 (Slack) Na+-activated K+ channel that give rise to three distinct forms of epilepsy. All produced many-fold increases in current amplitude compared to the wild-type channel. This could not be accounted for by increases in the intrinsic open probability of individual channels. Rather, greatly increased opening was a consequence of cooperative interactions between multiple channels in a patch. The degree of cooperative gating was much greater for all of the mutant channels than for the wild-type channel, and could explain increases in current even in a mutant with reduced unitary conductance. We also found that the same mutation gave rise to different forms of epilepsy in different individuals. Our findings indicate that a major consequence of these mutations is to alter channel-channel interactions. : Slack KCNT1 channels regulate how neurons respond to sustained stimulation. Kim et al. characterized nine KCNT1 mutations found in epilepsy patients with severe intellectual disabilities and showed that, in isolation, channel behavior is unaltered. However, in groups, mutant channels interact with each other abnormally, increasing current that flows through the channels

A multicenter retrospective study of patients treated in the thalamus with responsive neurostimulation

IntroductionFor drug resistant epilepsy patients who are either not candidates for resective surgery or have already failed resective surgery, neuromodulation is a promising option. Neuromodulatory approaches include responsive neurostimulation (RNS), deep brain stimulation (DBS), and vagal nerve stimulation (VNS). Thalamocortical circuits are involved in both generalized and focal onset seizures. This paper explores the use of RNS in the centromedian nucleus of the thalamus (CMN) and in the anterior thalamic nucleus (ANT) of patients with drug resistant epilepsy.MethodsThis is a retrospective multicenter study from seven different epilepsy centers in the United States. Patients that had unilateral or bilateral thalamic RNS leads implanted in the CMN or ANT for at least 6 months were included. Primary objectives were to describe the implant location and determine changes in the frequency of disabling seizures at 6 months, 1 year, 2 years, and &gt; 2 years. Secondary objectives included documenting seizure free periods, anti-seizure medication regimen changes, stimulation side effects, and serious adverse events. In addition, the global clinical impression scale was completed.ResultsTwelve patients had at least one lead placed in the CMN, and 13 had at least one lead placed in the ANT. The median baseline seizure frequency was 15 per month. Overall, the median seizure reduction was 33% at 6 months, 55% at 1 year, 65% at 2 years, and 74% at &gt;2 years. Seizure free intervals of at least 3 months occurred in nine patients. Most patients (60%, 15/25) did not have a change in anti-seizure medications post RNS placement. Two serious adverse events were recorded, one related to RNS implantation. Lastly, overall functioning seemed to improve with 88% showing improvement on the global clinical impression scale.DiscussionMeaningful seizure reduction was observed in patients who suffer from drug resistant epilepsy with unilateral or bilateral RNS in either the ANT or CMN of the thalamus. Most patients remained on their pre-operative anti-seizure medication regimen. The device was well tolerated with few side effects. There were rare serious adverse events. Most patients showed an improvement in global clinical impression scores