Deep Brain Stimulation as a Treatment for Refractory Epilepsy: Review of the Current State-of-the-Art.

Epilepsy affects ∼ 1% of the global population, and 33% of patients are nonresponsive to medication and must seek alternative treatment options. Alternative options such as surgery and ablation exist but are not appropriate treatment plans for some patients. Neurostimulation methods such as vagal nerve stimulation, responsive neural stimulation, and deep brain stimulation (DBS) are viable alternatives for medically refractory patients. DBS stimulation has been used in the treatment of Parkinson's disease, dystonia, and pain management. For the treatment of epilepsy, DBS has been found to be an effective treatment plan, with promising results of reduced seizure frequency and intensity. In this review, we discuss DBS surgery and equipment, mechanisms of DBS for epilepsy, and efficacy, technological specifications, and suggestions for future research. We also review a historical summary of experiments involving DBS for epilepsy. Our literature review suggests that further studies are warranted for medically refractory epilepsy using DBS.

Electrostimulation for Refractory Epilepsy: A Review.

Epilepsy is a neurological disorder that has been diagnosed in approximately 1% of the world's population. In North America alone, more than 3 million individuals suffer from epilepsy. Antiepileptic drugs are not fully effective in some patients, and most drugs have adverse side effects. Recently, several stimulation techniques (responsive neural, vagal nerve, transcranial magnetic, and deep brain) have been used as adjunct therapies to treat medically refractive seizures. Since its Food and Drug Administration approval in 2013, responsive neural stimulation (RNS), a closed-loop electrical stimulation system, has emerged as a potential therapeutic alternative to treat patients with epilepsy (PWE). RNS consists of a cranially implantable neurostimulator that sends electrical pulses using depth electrodes to epileptic foci/focus after the device senses irregular electrical activity, thus avoiding the onset of a seizure. In a long-term study that lasted 7 yr and involved more than 245 patients using RNS, results showed that16% of patients were seizure free, 60% had 50% or greater seizure reduction, and 84% had some improvement. Quality of life improved in 44% of the patients by the end of the second year. There is a need for more, larger, well-designed, randomized, controlled trials to validate and optimize efficacy and safety of invasive intracranial neurostimulation treatments in PWE. This article highlights the effects of treating patients with medically refractive seizures using RNS.

Transcranial Magnetic Stimulation in Migraine: A New Therapy and New Insights into Pathogenesis.

Transcranial magnetic stimulation (TMS) was first found to be effective in acute migraine 12 years ago, and subsequent studies have confirmed this benefit in approximately two -thirds of treated patients. High response rate, ease of application, and freedom from adverse effects combine to make TMS a natural front-line treatment for migraine, and its use should therefore be encouraged. In relation to the pathogenesis of migraine, the prompt relief of symptoms often observed with TMS is considered incompatible with an underlying neuroinflammatory process and with spreading depression as a cause of aura. Instead, the available evidence points to hyperexcitability of cortical neurons as the immediate cause of headache and any associated symptoms, although the factor(s) leading up to the hyperexcitability remain unclear.

Air Pollution and Cardiovascular Disease: A Review.

Air pollution is comprised of different compounds and particulate matter (PM) of sizes 2.5 and 10 µm, with the former size posing the greatest danger to humans. Evidence suggests that the global rise in air pollution levels during the past century is correlated with the increased incidence of diseases of the cardiovascular system. On a global scale, 7 million individuals died as a result of the effects of air pollution in 2012. Air pollution leads to tremendous amounts of financial burden (in 2010, $16 trillion in the US and Europe) on the health-care system. The severity of effects experienced by varying populations due to air pollution can differ due to locale, length of exposure, weather conditions, residential proximity to major highways or factories, and soil aridity. Pollutants affect the heart, blood vessels, and blood at a molecular level through proinflammatory or oxidative stress response, autonomic nervous system imbalance, and the direct permeation of harmful compounds into the tissue. The dysfunction of cells and biological processes of the cardiovascular system due to PM leads to an increased prevalence of cardiovascular diseases (CVDs) such as atherosclerosis, hypertension, myocardial infarction, thrombosis, and restricted valve motion. Studies in countries such as China have shown an increase of 0.25% in ischemic heart disease (IHD) mortality and a 0.27% increase in IHD morbidity due to a 10 µg/m3 increase in PM. In a study conducted in the US, PM2.5 concentrations ranged from 9.2-22.6 µg/m3, and every 5-µg/m3 increase in PM2.5 caused coronary calcification to increase by 4.1 Agatston units/yr. Studies on traffic-related air pollution found that nonhypertensive participants residing within 100 m of major roadways experienced an increase in systolic (0.35 mmHg) and diastolic (0.22 mmHg) blood pressure as a result of increases in traffic. The progression of CVD due to pollution has been found to fluctuate within individuals based on age, gender, location of exercise, smoking, pregnancy, diabetes, preexisting cardiovascular or pulmonary diseases, and other factors. Considering the number of individuals affected by pollution on a daily basis and the burden that this places on society through the health-care system, immediate preventive measures are needed to address these problems. Increased knowledge about the widespread effects of pollution on human physiological systems should aid in remediating the problem across the globe. Biomedical engineers can have a great positive impact in developing better instrumentation to measure discrete pollutants and characterizing their harmful effects on physiological systems.

The Migraine Aura: A Problem for Vision Theory?

The scintillating zigzag pattern that a migraine patient may see as an illusion before the onset of headache offers a unique investigative approach to visual mechanisms. The likeliest interpretation of these zigzags is that they are the spontaneous discharges of the orientation-selective neurons first described in the striate cortex by Hubel and Wiesel (Hubel DH, Wiesel TN. Receptive fields, binocular interaction and functional architecture in the cat's visual cortex. J Physiol (Lond). 1962 Jan;160:106-54; and Hubel DH, Wiesel TN. Receptive fields and functional architecture of monkey striate cortex. J Physiol (London). 1968 Mar;195(1):215-43). Although these cells appear to lie in rows in V1, as Hubel and Wiesel found, very few angles in the visual field are represented; this, and the coarseness of the representation, makes it unlikely that the cells act as feature detectors. The orientation-selective cells could, however, monitor the amount of light falling on the retina and thereby enable color constancy to be achieved. The cells may also serve as coarse movement detectors. The new model of cell organization in human V1 enables us to determine the approximate sizes of the receptive fields of the orientation-selective cells.

Air Pollution's Effects on the Human Respiratory System.

The World Health Organization defines air pollution as "any chemical, physical or biological agent that modifies the natural characteristics of the atmosphere." The most common pollutants include particulate matter, carbon monoxide, ozone, nitrogen oxide, and sulfur dioxide. The two types of air pollution, indoor and ambient, both contribute to a host of cardiac and respiratory illnesses. Exposure to excess levels of air pollution is significantly associated with a variety of acute and chronic respiratory illnesses, such as chronic obstructive pulmonary disease, asthma, respiratory allergies, and lung cancer. The effects of air pollution disproportionately impact the extremes of the age distribution, perhaps due to altered immune responses. Athletes and those who exercise outdoors are at greater risk for the respiratory effects of air pollution. This article discusses the epidemiology, types of respiratory diseases, and mechanisms involved in exposure to excess levels of air pollution. Biomedical engineering can contribute to the identification of air pollutants through the design of novel instrumentation using materials based on nanotechnology. Mathematical models can also be developed to characterize the physiological effects of air pollution.

Cortical spreading depression in migraine-time to reconsider? / Depressão alastrante cortical na enxaqueca – hora de reconsiderar?

New evidence concerning the pathophysiology of migraine has come from the results of therapeutic transcranial magnetic stimulation (tTMS). The instantaneous responses to single pulses applied during the aura or headache phase, together with a number of other observations, make it unlikely that cortical spreading depression is involved in migraine. tTMS is considered to act by abolishing abnormal impulse activity in cortical pyramidal neurons and a suggestion is made as to how this activity could arise.

Novas evidências referentes à fisiopatologia da enxaqueca são o resultado de estimulação magnética transcraniana terapêutica (tTMS). As respostas imediatas a pulsos simples aplicados durante as fases de aura ou de cefaleia, em associação a diversas outras observações, tornam improvável a ideia de que a depressão alastrante esteja envolvida na enxaqueca. Considera-se que tTMS tenha sua ação abolindo atividade anormal de impulsos em neurônios corticais piramidais, sugerindo que esta atividade tenha um papel desencadeante.

Cortical spreading depression in migraine-time to reconsider?

New evidence concerning the pathophysiology of migraine has come from the results of therapeutic transcranial magnetic stimulation (tTMS). The instantaneous responses to single pulses applied during the aura or headache phase, together with a number of other observations, make it unlikely that cortical spreading depression is involved in migraine. tTMS is considered to act by abolishing abnormal impulse activity in cortical pyramidal neurons and a suggestion is made as to how this activity could arise.

GERD and obesity: is the autonomic nervous system the missing link?

Gastroesophageal reflux disease (GERD) is a common chronic condition that not only impairs the quality of life of those who are affected by it but also poses a significant economic burden. It encompasses a wide spectrum of symptoms as a result of gastric content moving into the esophagus. The most common cause of GERD, other than a hiatus hernia, is considered to be transient lower esophageal sphincter relaxation. The lower esophageal sphincter (LES) normally has a higher resting tone than the stomach, thus preventing the reflux of gastric contents into the esophagus. The greater prevalence of GERD and GERD symptoms in obese individuals has generated significant interest in understanding the association between these 2 conditions and the underlying physiological mechanisms. The potential relationship between GERD and obesity and the exact mechanism by which obesity may cause reflux, however, remains uncertain. It has been proposed that patients with GERD have altered autonomic nervous function and, more specifically, have reduced parasympathetic activity. Obese individuals also have shown diminished parasympathetic activity, which may be reversed after weight reduction through exercise, diet control, and bariatric surgery. Given that contraction and relaxation of the LES are vagally mediated, the question that arises is whether the autonomic nervous system is, in fact, the missing link between obesity and GERD. In this article we examine the current evidence and hypothesize that the potential imbalance in sympathovagal stimulation to the LES is a key contributing factor to the increased prevalence of GERD symptoms in obese individuals.

Meta-analysis of randomized trials on first line and adjunctive levetiracetam.

CONTEXT: New evidence suggests that levetiracetam may be as effective as traditional agents, with better safety profile. OBJECTIVE: To synthesize evidence regarding efficacy and tolerability of levetiracetam as first line, adjunctive or prophylactic antiepileptic agent. Study Selection & Data Extraction: Eligible studies were randomized controlled trials (RCTs) of levetiracetam used in adults with epilepsy. MEDLINE, EMBASE, CENTRAL, CINHAL, PAPERSFIRST, PROCEEDINGSFIRST, PROQUEST and conference proceedings identified studies (to September 30, 2010). Two investigators independently selected, appraised studies, collected and analyzed data. RESULTS: Of ten eligible randomized trials, eight investigated adjunctive levetiracetam for refractory seizures, one as monotherapy for newly diagnosed seizures, one as monotherapy for prophylaxis. Eight RCTs of adjunctive levetiracetam were of moderate quality (GRADE criteria), with two showing lack of allocation concealment. Meta-analyses showed adjunctive levetiracetam was more effective than placebo in achieving at least 50% reduction of seizure frequency, when added to baseline antiepileptic regimen (pooled RR 2.15 [1.65,2.82], I2 = 45%, p value (heterogeneity) = 0.08, p value (overall effect) < 0.01). Likelihood of serious adverse events necessitating withdrawal from study was not significantly different between levetiracetam and control (pooled RR 1.37 [0.88,2.13], I2 = 0%, p value (heterogeneity) = 0.84, p value (overall effect) = 0.17). Subgroup analyses suggested similar effects across different dosages. Sensitivity analysis of studies with adequate concealment showed similar effects. CONCLUSIONS: Levetiracetam is an effective adjunctive agent for refractory epilepsy. More studies are needed to establish whether it is effective as monotherapy for newly diagnosed seizures, and for prophylaxis in traumatic brain injury.

Evaluation of the efficacy and performance of medical implants: a review.

An implant can be defined, in a medical context, as biological or artificial materials inserted or grafted into the body. Implants may be sensory devices (cochlear, ocular), mechanical devices that are 'passive' (orthopedic joint replacements and fixation plates, dental implants, coronary artery stents and vascular grafts) or 'active' (left ventricular assist devices, heart valves) electrophysiological stimulation devices (cardiac or gastric pacemakers, implantable cardiac defibrillators, functional electrical stimulators for epilepsy or Parkinson's disease) or medication administration devices (insulin or analgesic delivery pumps) or intra-ocular sustained drug release implants. Implantation has had a long history in several subspecialties of medicine. Evaluation of the efficacy of implants is a multifactorial issue. Several variables need to be considered while studying the rejection of the implants such as pathophysiological mechanisms, malfunction, design shortcomings and improper implementation/implantation by a medical team. This paper identifies a variety of modes of failure and how they affect the overall efficacy of the device technologies. Suggestions for improvement, as outlined in the literature, will be examined.

Longer-term effects of implanted vagal nerve stimulation.

Vagal nerve stimulation (VNS) is a non-pharmacologic therapeutic intervention approved in adults and children with neuropsychiatric disorders. Studies conducted over the past 20 years have demonstrated that VNS results in immediate and longer-term changes in brain regions implicated in neuropsychiatric disorders, such as the thalamus, cerebellum, orbitofrontal cortex, limbic system, hypothalamus, and medulla with vagus innervations. This review summarizes the effects of longer-term implanted VNS and how the incorporation of this non-pharmacologic therapeutic management in the treatment regime can be beneficial to address the needs of patients who are unable to tolerate medications and/or undergo surgery and do not respond to pharmacologic therapies. We also highlight the therapeutic efficacy of longer-term implanted VNS, safety, tolerability, patient acceptance, adherence, and adverse events, if any, in adults and children in this modality of treatment.

Identification of ataxia-associated mtDNA mutations (m.4052T>C and m.9035T>C) and evaluation of their pathogenicity in transmitochondrial cybrids.

The potential pathogenicity of two homoplasmic mtDNA point mutations, 9035T>C and 4452T>C, found in a family afflicted with maternally transmitted cognitive developmental delay, learning disability, and progressive ataxia was evaluated using transmitochondrial cybrids. We confirmed that the 4452T>C transition in tRNA(Met) represented a polymorphism; however, 9035T>C conversion in the ATP6 gene was responsible for a defective F(0)-ATPase. Accordingly, mutant cybrids had a reduced oligomycin-sensitive ATP hydrolyzing activity. They had less than half of the steady-state content of ATP and nearly an 8-fold higher basal level of reactive oxygen species (ROS). Mutant cybrids were unable to cope with additional insults, i.e., glucose deprivation or tertiary-butyl hydroperoxide, and they succumbed to either apoptotic or necrotic cell death. Both of these outcomes were prevented by the antioxidants CoQ(10) and vitamin E, suggesting that the abnormally high levels of ROS were the triggers of cell death. In conclusion, the principal metabolic defects, i.e., energy deficiency and ROS burden, resulted from the 9035T>C mutation and could be responsible for the development of clinical symptoms in this family. Furthermore, antioxidant therapy might prove helpful in the management of this disease.

Transcranial magnetic stimulation for migraine: clinical effects.

The objective was to assess the impact of transcranial magnetic stimulation (TMS) on pain and the autonomic nervous system (ANS) in migraine. Forty-two people [mean age 41.43+/-11.69 (SD) years, 36 females] were randomised into high vs. low TMS stimulation groups and received 2 brief pulses of TMS. Thirty-three (33/42) individuals had heart-rate variability assessed, before and after stimulation. No group effects were found. Pain decreased by 75%; 32% of people after 1 treatment reported no headache after 24 h. Mean heart rate decreased from 79.05+/-10.27 to 72.89+/-11.35 beats/min. The low-frequency (LF) and the high-frequency (HF) areas derived from power spectral analyses increased [mean 6522+/-1277 to 8315+/-1009 beats/min(2) (LF) (p=0.001) and mean 5600+/-1568 to 8755+/-3071 beats/min(2) (HF) (p=0.001)]. The LF:HF ratio decreased from mean 1.31+/-0.51 to 1.13+/-0.48 (NS). TMS produces immediate, sustained reductions in pain and modification of the ANS.

Optimal electrical stimulation modality for cortical esophageal evoked potentials: transmural or intraesophageal?

Esophageal electrical stimulation using short and a relatively small number of (200 micros, 0.2 Hz, n = 25) electrical pulses generates a characteristic and well defined cortical evoked potential response (EP). There are two methods of stimulation: either through intraesophageal electrodes or with transmural electrodes. The objective of this paper is to compare EP response, sensations and heart rate variability power spectra elicited by both stimulation modalities in healthy volunteers. Our results suggest that transmural stimulation is more accurately perceived and at lower intensities, produces more reproducible peaks of higher amplitude than during intraesophageal stimulation. During either mode of esophageal stimulation, power within the high-frequency component of the heart rate variability power spectrum is enhanced.

A comparison of algorithms for detection of spikes in the electroencephalogram.

Identification of the short transient waveform, called a spike, in the cortical electroencephalogram (EEG) plays an important role during diagnosis of neurological disorders such as epilepsy. It has been suggested that artificial neural networks (ANN) can be employed for spike detection in the EEG, if suitable features are provided as input to an ANN. In this paper, we explore the performance of neural network-based classifiers using features selected by algorithms suggested by four previous investigators. Of these, three algorithms model the spike by mathematical parameters and use them as features for classification while the fourth algorithm uses raw EEG to train the classifier. The objective of this paper is to examine if there is any inherent advantage to any particular set of features, subject to the condition that the same data are used for all feature selection algorithms. Our results suggest that artificial neural networks trained with features selected using any one of the above three algorithms as well as raw EEG directly fed to the ANN will yield similar results.

Vagal stimulation for intractable seizures.

Vagal stimulation has recently been approved for use in North America. Dr. Upton discusses the findings of a study conducted at the McMaster Medical Centre.