There may be new hope for people who suffer from epilepsy. A recent study has shown that an experimental implant reduces seizures in epileptic rats by 93 percent, and that the effects remain after the device has been removed.
The study was conducted by a team led by Asst. Prof. Giovanna Paolone, of Italy’s University of Ferrara – she is also associated with Rhode Island-based Gloriana Therapeutics, which is developing the technology.
Implanted in the rats’ brains, the device incorporates a hollow-fiber membrane which contains encapsulated bioengineered human ARPE-19 cells. These in turn produce and secrete a protein known as glial cell line-derived neurotrophic factor (GDNF), which recent research suggests may help to suppress epileptic activity by reducing cell death in the hippocampus region of the brain.
In the study, the implant delivered GDNF directly to the animals’ hippocampus. As a result, seizures were reduced by 75 percent within two weeks, and were 93 percent less frequent after three months. Even after the device was removed, the effect persisted, suggesting that the treatment modified the manner in which the disease progressed.
It was additionally noted that the rats displayed fewer anxiety-like symptoms, and that they performed better at an object recognition task – this reportedly suggests an improvement in cognitive function.
A paper on the research was recently published in the journal JNeurosci.
Ketosis and ketoacidosis both involve the production of ketones in the body. However, while ketosis is generally safe, ketoacidosis can be life-threatening.
Sources: Society for Neuroscience via EurekAlert, Gloriana Therapeutics
Nutritional ketosis occurs when the body starts burning fat instead of glucose. Inducing ketosis is the aim of a ketogenic diet, or “keto” diet, which is a high-fat, very-low-carb diet that can help people lose weight.
Ketoacidosis occurs when the body produces dangerously high levels of ketones, and it is often a complication of type 1 diabetes.
In this article, we discuss the differences between ketosis and ketoacidosis, including their symptoms. We also explain when to see a doctor and how to treat and prevent ketoacidosis.
Ketosis vs. ketoacidosis
A doctor may recommend blood or urine tests to determine if someone is experiencing ketosis or ketoacidosis.
Nutritional ketosis occurs when the body uses fat instead of glucose as fuel. The liver breaks down this fat into chemicals called ketones and releases them into the bloodstream. The body is then able to use the ketones as an energy source.
The ketogenic diet aims to induce nutritional ketosis. People do this by eating foods that are high in fat but very low in carbohydrates. Adopting this diet has become a popular way to burn fat and lose weight.
Doctors originally developed the ketogenic diet to treat children with epilepsy. The “classic” ketogenic diet involves eating 3–4 grams (g) of fat for every 1 g of carbohydrate and protein. Studies show that more than 50 percent of children who try the diet have half the number of seizures or fewer, while 10–15 percent become seizure-free.
Doctors do not know why the ketogenic diet reduces some symptoms of epilepsy. Research suggests that this diet may also help with some other neurological disorders, such as Parkinson’s disease and Alzheimer’s disease.
In contrast, ketoacidosis occurs when the body thinks that it is starving and starts breaking down fats and proteins too quickly. It is a potential complication of type 1 diabetes.
If a person does not have enough insulin, the body cannot move glucose from the blood into cells, where it is necessary for energy. As a result, dangerous levels of both glucose and ketones can accumulate in the blood. Doctors refer to this condition as diabetic ketoacidosis.
Doctors can use blood and urine tests to determine whether a person is in ketosis or ketoacidosis.
During nutritional ketosis, it is normal to have blood ketone levels of 0.5–3.0 millimoles per liter (mmol/L). According to the American Diabetes Association, a person should check their ketone levels if their blood glucose levels are higher than 240 milligrams per deciliter (mg/dl).
People with diabetes whose blood ketone levels are high have a more significant risk of diabetic ketoacidosis.
Symptoms of ketoacidosis
Diabetic ketoacidosis is a potential complication of type 1 diabetes, and it can occur if a person does not administer enough insulin at the right times. Not eating enough food can also sometimes trigger diabetic ketoacidosis.
The symptoms of diabetic ketoacidosis include:
- high blood glucose levels
- rising levels of ketones in the urine
- thirst and frequent urination
- dry or flushed skin
As ketoacidosis progresses, symptoms can include:
- nausea and vomiting
- stomach pain
- trouble breathing
- a fruity odor in the breath
- confusion and difficulty paying attention
- loss of consciousness
Symptoms of ketosis may include fatigue, feeling cold, and general weakness.
For most people, ketosis is a short-lived metabolic state that happens when the body temporarily switches from burning glucose to burning fat. During this time, the level of ketones in the blood rises.
People on ketogenic diets aim to spend more extended periods in ketosis. Some people also enter a state of ketosis through fasting.
Ketosis can lead to bad breath and weight loss. It may also cause headaches, thirst, and stomach complaints in some people.
Although inducing ketosis is generally safe, it can lead to nutritional imbalances in some people or result in them not getting enough calories. Malnutrition can cause:
- poor concentration or memory problems
- changes in mood
- feeling cold
- getting ill more frequently
When to see a doctor
A doctor can use blood or urine tests to determine whether a person is in ketosis or ketoacidosis. These tests measure the levels of ketones, glucose, and acidity in the body.
Nutritional ketosis is not a medical condition and does not require a diagnosis. However, ketoacidosis is a life-threatening condition, and anyone with symptoms should seek immediate medical attention. People with signs of malnutrition should also see a doctor.
Doctors often provide urine test strips to people with type 1 diabetes to allow them to check their ketone levels.
Treatment of ketoacidosis
Diabetic ketoacidosis is a medical emergency that can progress quickly, but it is also highly treatable.
Doctors usually treat people with diabetic ketoacidosis in a hospital or emergency room. Treatment typically involves insulin therapy together with fluid and electrolyte replacement.
Most people with diabetic ketoacidosis will need to stay at the hospital for monitoring. As blood ketone levels return to normal, the doctor may recommend additional testing to determine whether a person has other risk factors for ketoacidosis.
Prevention of ketoacidosis
Monitoring blood glucose levels can help prevent ketoacidosis.
People with diabetes can reduce their risk of ketoacidosis by:
- monitoring blood glucose levels regularly and notifying a doctor if they are not under control
- testing the urine for ketones if blood glucose levels are above 240 mg/dl
- avoiding exercise if ketones are present in the urine and blood glucose levels are high
- taking insulin according to the doctor’s treatment plan
- eating a healthful and balanced diet
- avoiding skipping meals
Although ketosis and ketoacidosis both cause ketone levels in the body to rise, they are not the same. Nutritional ketosis is the aim of the ketogenic diet, and it is generally safe, whereas ketoacidosis is a potentially dangerous complication of type 1 diabetes.
People with diabetes should avoid ketogenic diets and follow their doctor’s treatment recommendations to prevent ketoacidosis.
Ketogenic diets can help people lose weight and may offer some health benefits. However, it is always best to talk to a doctor before trying a new diet.
OUR SOURCE: MEDICAL NEWS TODAY BY
For many of the 3 million adults and 470,000 children in the US (1.2% of the population) living with active epilepsy,1 the unpredictable nature of seizures is unsettling for both patients and caregivers. Seizures can have many immediate negative consequences; the most significant is sudden unexpected death in epilepsy (SUDEP), the most common cause of premature death among people with epilepsy.2 The pathophysiology of SUDEP often includes a terminal seizure.3,4 Interventions that reduce seizure frequency (eg, epilepsy surgery or add-on drug therapy) also reduce SUDEP rates.5,6
The seizures that cause the majority of SUDEP cases are often unattended. Most SUDEPs occur during unsupervised times, and most commonly, the decedent is found by family or caregivers in the morning.3,7Persons with a history of seizures during unsupervised times may also be more vulnerable; a history of nocturnal seizures increases SUDEP risk.8 Increased nighttime supervision appears to be protective; having a roommate or use of a nocturnal listening device is associated with reduced SUDEP risk.9 This is likely because someone may be able to provide aid and resuscitation in the vulnerable postictal period when cardiopulmonary dysfunction may be reversible.4 Even tactile stimulation and repositioning can decrease postictal respiratory dysfunction.10
There has been a growing interest in seizure detection and alerting devices for use in the home to notify caregivers of a seizure and turn unwitnessed seizures into attended seizures, as a method to reduce SUDEP risk. With the help of innovations in health technology, mobile sensors, and smartphones, many devices are in development and some have been commercialized. Recently 2 such devices were approved by the FDA for use as adjuncts to seizure monitoring.
Seizure Detection Methods
A range of biologic signals can be monitored for seizure detection (Figure), and these can be categorized as cerebral activity, seizure-related behavior (including movement and muscle contraction), and noncerebral, nonmotor physiologic changes (Tables 1 and 2).
Cerebral activity can be monitored using scalp electrodes or more invasive tools such as intracranial EEG (iEEG). The standard for seizure monitoring remains video EEG (vEEG). An advantage of monitoring cerebral activity is that seizure activity is detected early or may even be predicted before it is clinically evident.11 All types of seizures can be detected by EEG even when brief or without major motor manifestations. Devices that measure EEG signals can be useful for quantifying overall seizure burden because many patients are unaware of some or all of their seizures.12 Long-term monitoring of scalp EEG, however, requires application and maintenance of electrodes that may not be practical for long-term use. Implantable, intracranial seizure detection systems carry surgical risk that may not be acceptable and detection of subclinical or nonmotor seizures may not be necessary for SUDEP risk, as the majority of SUDEP follows generalized tonic-clonic seizure (GTCS). There has been an emphasis on developing practical noninvasive, noncerebral seizure detection methods.
Seizure activity can be detected using extracerebral (or nonEEG) devices. Video motion detectors,13-15 accelerometers,16-19 or surface EMG (sEMG)19-22 have been employed to detect the repetitive movements and muscle activity present during GTCS (Table 1). Audio recordings may be used to detect the unique sounds of GTCS such as ictal cry.23Movement detection devices are noninvasive and more widely applicable than intracerebral devices. Sensors to detect seizure-related movements include wrist-worn accelerometers, computer vision analysis of video signals, and piezo-electric mattress sensors.24
The movement signals recorded are not necessarily seizure specific; however, sophisticated algorithms are necessary to distinguish seizure-related motion from other forms of repetitive movements common in daily life (eg, running, chopping vegetables, or playing video games) to reduce false-detection rates. Some movement-detection sensors are location specific (ie, bed or mattress sensors), which can alleviate concerns for nighttime seizure detection but are not applicable to all forms of unattended seizures.
Accelerometer and Gyroscope. Accelerometers measure motion and velocity changes in more than 2 dimensions, whereas gyroscopic sensors measure angular and rotational acceleration. Both are low cost with low energy consumption. Small accelerometers can be worn easily on a limb and are much better tolerated by patients than EEG. Studies support that a wrist-worn motion detector should alert caregivers when GTCS occurs.25These units can be part of a commercially available smartwatch or an independent unit, either of which can connect to a smartphone to deliver alerts to caregivers. Accelerometers have high sensitivity for GTCS detection.17,18 False positives varied in these studies from once every 5 days17 to several times a day.18,25
Noncontact Movement Sensors. Pressure sensors can be placed under a mattress or sheet to detect patterns of abnormal movement, although sensitivity varies greatly; 1 study detected 89% of GTCS in adults,26 whereas another study detected only 30% of GTCS in children.27 There are several other problems with movement sensors such as high rates of false positives, faulty sensors, and an inability to differentiate seizures from other nighttime movements.26 An advantage is that these sensors do not require physical contact with the patients, which can be helpful in young children.
Surface EMG. Changes in the electric activity of muscles are measured in surface EMG (sEMG) with electrodes placed on the skin rather than inserted into the muscle. Tonic and tonic-clonic seizures have characteristic sEMG patterns that can be used in detection devices.28 In a prospective multicenter study, sEMG had sensitivity of 94% for GTCS detection.20 A potential disadvantage of sEMG is that incorrect placement of a surface electrode can alter seizure detection accuracy and false-positive rate significantly (76% vs 100% and 2.52 vs 1.44 per 24 hours, respectively).22
Video. Video observation is part of the standard for in-hospital monitoring of seizures; however, having a person review a live video stream is not feasible for home use. Advances in computer software have made automated detection of seizure-related behavior from a video stream a possibility.13 Advantages of video-based methods include contactless monitoring, ease of use, and the ability to watch in real-time or play back an event for review. Disadvantages include the possibility of missing small seizure-related movements and restricted location of monitoring.
Audio. Many noises accompany seizures including ictal cry, vocalizations, certain automatisms (eg, lip smacking or sniffing), stridorous respirations, and secretions. Audio devices share some of the same advantages of video monitoring, (ie, comfort [contactless] and practicality) and are also more affordable. Baby monitors are one of the most widely used device types in the pediatric population. Disadvantages include relatively low-quality sound, background noise interference, and lack of visualization. Audio detection systems can be used with other modalities.23
Noncerebral Physiological Changes
Ictal and peri-ictal cardiorespiratory events seem to play an important role in the context of SUDEP.4,29,30 Autonomic changes have also been noted peri-ictally.31,32 NonEEG seizure detection devices could employ one or a combination of these signals, including heart rate/EKG, blood pressure, O2 saturation, respirations, and electrodermal activity (EDA), a measure related to sympathetic nervous system activation. Many of these signals can be recorded noninvasively.
Electrodermal Activity. Electrodermal activity is a measure of skin conductance and resistance caused by sweat gland activity, which is a direct reflection of sympathetic activity.33 Seizures, and specifically GTCS, can lead to sympathetic activity that is reflected in peri-ictal EDA changes.31 The mechanism of seizure-related sympathetic nervous system activation is not clear, although there are direct and indirect connections between cortical structures commonly involved in seizure networks (ie, frontal cortex, orcingulate gyrus) and medullary autonomic centers.34 Electric stimulation of those structures can induce EDA changes.35
In addition to seizure detection, the EDA response amplitude has been proposed as a biomarker for SUDEP risk because it is correlated with longer EEG suppression, which is also considered a measure of SUDEP risk.31 A disadvantage is that peri-ictal EDA changes have a relatively slow time course and may need to be combined with other methods to improve detection latency for seizure-monitoring devices.36
Electrocardiogram and Pulse Rate. Heart rhythm abnormalities, persistently elevated heart rate (HR), and decreased heart rate variability (HRV) are all predictors of sudden cardiac death in healthy populations and in people with medical conditions and are associated with ictal and post-ictal phases.37 Seizure-related heart rate changes can include tachycardia, bradycardia, and asystole, and may be more associated with GTCS, temporal lobe seizures, and hypermotor frontal lobe seizures.38
Although there are advantages to this form of monitoring, such as portability and being able to monitor variables with as little as 2 leads, several important disadvantages remain. For instance, solely cardiac-based detection has failed to discriminate some types of seizures from other activities such as exercise, arousal from sleep,32 and even psychogenic nonepileptic seizures.39
Pulse Oximetry. Oxygen saturation (SpO2) uses infrared waves to detect blood-oxygen concentration (a saturometer) and a plethysmograph. It can be easily monitored by a sticker or strap on a distal extremity or even an earlobe. When combined with an HR and an EDA detector, it was found that SpO2 decrease caused an alert after HR change and before EDA change.36 When SpO2 thresholds are set to 80% to 86%, SpO2 detectors alone are able to detect 63% to 73% of generalized convulsions and 20% to 28% of focal seizures.40 Because SpO2 detection has a relatively high false alarm rate, they are usually combined with other sensors in a multimodal system.
Near-Infrared Spectroscopy. Using the near-infrared region of the electromagnetic spectrum, near-infrared spectroscopy (NIRS) measures hemodynamic changes (eg, cerebral O2 saturation) during epileptic seizures. In children with epilepsy, an association was seen between convulsive seizures and cerebral blood volume; however, the same study also showed no change to mild change in absence seizures, an initial decrease in some convulsive seizures, and an initial increase followed by decrease for tonic status epilepticus.41 Another study suggests that NIRS can distinguish patterns of cerebral oxygenation that differ in focal unaware seizures and focal to bilateral tonic-clonic seizures.42 There are still limitations including the size of the wearable device and conflicting evidence regarding low positive predictive value for seizures.43,44 More data are required to assess the sensitivity of NIRS as a reliable seizure detector.
Several commercially available seizure monitoring devices are available or in development (Table 2). Many have been tested against the standard vEEG in patients admitted to epilepsy-monitoring units. Most target GTCS with reported sensitivities of 53% to 100% and false-positive rates between 0.1 and 2.52 per 24 hours in the epilepsy-monitoring unit.
Devices differ in how caregivers are alerted. Some pair with an application on the patient’s smartphone to issue text alerts or voice calls to prespecified responders, and others use a paired receiver that issues an audio alarm. At this time, no device links directly to first responders or centralized call centers, which is a concern for patients who live alone or are socially isolated without nearby friends or family to provide peri-ictal assistance.
A survey showed that the majority of people with epilepsy are familiar with multiple digital technologies, making them a good population for wearable technology.45 There are limited data about the usefulness of wearable devices, in part because both patients and their health care providers lack knowledge of the devices.
A majority of persons with epilepsy prefer devices that are wearable, portable, and discrete.45,46 Cost is also a major factor, with a majority of patients surveyed wanting to use a device only if it was covered by insurance, and a few expressing interest if it were not covered but affordable.45 Multimodal devices for long-term use are also preferred.46
Seizure-Detection Device Caveats
Most data regarding the accuracy of seizure detection devices come from studies in the epilepsy-monitoring unit, but that is not an accurate representation of real-world use because of patients’ limited range of activity in the unit and the presence of study staff to apply and position devices.22 Little data exist for ambulatory patients and there are currently no standards for assessing accuracy. A set of outcome measures and standards for reporting have been proposed,47 but not all prior studies meet those standards. There is also the issue of patient adherence. Even if the device is readily available and applied correctly, there is no way of ensuring it is always used.
Options Limited for Those Who Live Alone
People with epilepsy are more likely to live alone after they become independent from their parents.48 For these people, seizure detection does not equate to timely intervention. A recent case report highlighted this for a patient who, despite using a device that detected a convulsive seizure and issued an alert, died before his parents (the prespecified responders) arrived 15 minutes later.53
Unknown Life-Saving Efficacy
There are no studies yet that demonstrate seizure detection and alerting devices reduce SUDEP risk and, because of the relatively infrequent occurrence of SUDEP even in the highest risk populations, these studies may be difficult to perform.9 Seizure detection may fail to prevent all SUDEP because although the majority of witnessed SUDEP occurred following GTCS, approximately 10% occurred following focal unaware seizures.3Concurrent vEEG monitoring54 and ambulatory intracranial monitoring55 has shown that SUDEP can occur without antecedent seizures. In these cases, devices that detect only GTCS would not prevent SUDEP. It is also possible for SUDEP to occur despite immediate peri-ictal intervention by trained personnel, suggesting that simple resuscitative efforts may not always be enough to reverse the cascade of events leading to death.56
Conclusions and Future Directions
Noninvasive devices to detect GTCS and alert caregivers are becoming readily available. Although performance of some of these devices is uncertain, especially in the outpatient setting, there is sufficient information available to help choose between available options and determine which device may work best for a particular patient. Despite the lack of direct evidence that seizure detection devices prevent SUDEP, they may be a good tool to augment nocturnal supervision as a SUDEP-prevention strategy. The use of these seizure detection devices should be put in the context of SUDEP risk, seizure types, independence, and patient and family preferences.
The intersection of technology and health is constantly evolving, and there are a few things that we can expect to see going forward. The most common methods for detection discussed in this review may eventually play more of a role in a closed-loop warning system able to provide rapid treatment or prevention of seizures.57 As this technology is improved upon, seizure forecasting/prediction devices will emerge for the purpose of treatment and not just alerting. This will give the patient and family even more confidence and peace of mind, improving the quality of life of all parties involved. Although many patients can achieve seizure freedom, the population of people refractory to treatment remains and they are entitled to the same quality of life as their healthy counterparts.
Cassandra Kazl, MD
Clinical Neurophysiology Fellow
Department of Neurology
NYU Comprehensive Epilepsy Center
New York, NY
Daniel Friedman, MD, MSc
Associate Professor, Department of Neurology
Co-Director, Video-EEG Laboratory
Director of Medical, Cardiac and Neurosurgical ICU Epilepsy Monitoring Services
Co-Director, Special Procedures for the Epilepsy Service
NYU Comprehensive Epilepsy Center
New York, NY
CK has no relevant disclosures.
DF serves on the executive committee of the North American SUDEP Registry. He has performed contracted research for Epitel, Empatica, and Neuropace. He holds ownership interest in Neuroview Technology. He receives salary support from the nonprofit Epilepsy Study Consortium. He has consulted or serves on advisory boards for Eisai, GW Pharmaceuticals, LivaNova, Penumbra, Supernus, and UCB. He has received an honorarium for educational materials from Neuropace. He also receives research support from NINDS, Epilepsy Foundation, the Centers for Disease Control and Prevention, and UCB Pharmaceuticals.
Researchers have mapped out a newly discovered serious disease which causes children to suffer epileptic seizures, loss of magnesium in urine and reduced intelligence.
Two children from Europe and a child from Canada suffer from a previously unknown disease that causes epileptic seizures, loss of magnesium in urine and reduced intelligence at the same time — though unfortunately without it being possible to treat or alleviate their symptoms.
But researchers in an international consortium have now discovered what is wrong with the children aged 4, 6 and 10. Professor Bente Vilsen and her research group at the Department of Biomedicine at Aarhus University, Denmark, are part of the consortium, which also includes researchers from universities in Germany, England, Austria, the Netherlands and Canada. The research results have been published in the American Journal of Human Genetics.
Using a genetic analysis, the researchers have discovered that the disease is caused by a newly occurring mutation in one of the sodium-potassium pump’s four forms, known as the Alpha-1 form. Even though the children have exactly the same three symptoms, they do not have the same genetic defect, as the amino acids in the pump protein which are genetically altered are different, explains Bente Vilsen.
“It turns out that the form of sodium-potassium pump which mutates is found in both the kidneys and the brain. The mutation leads to the kidneys, which normally absorb magnesium, instead secreting the substance in the urine; however, it is not the loss of magnesium which triggers the epileptic seizures. The convulsions occur because the sodium-potassium pump is also extremely important for the brain’s functions, meaning that giving extra magnesium supplements won’t help prevent the seizures,” says Bente Vilsen.
She adds that the third frightening sign of the disease, mental retardation, should probably be attributed to a lack of oxygen to the brain during the seizures.
The children share the common trait that the mutations have destroyed the pump functioning that Jens Christian Skou received the Nobel Prize in Chemistry in 1997 for discovering. This knowledge is important because understanding the role of the sodium-potassium pump is the first step towards developing effective treatment methods. The research group is now working towards this goal, even though the disease is most likely rare.
“But three cases have turned up in two different places in Europe and in Canada, and they’re not likely to be the only ones,” says Bente Vilsen. She explains that the new knowledge about the disease will probably mean that medical doctors will in future be more aware that loss of magnesium in combination with epilepsy may be caused by genetic defects in the sodium-potassium pump.
“I believe that we will in future find many more children with the disease, and that this is a good example of why international research cooperation is absolutely necessary — there are simply too few cases of the disease for a single country to carry out the research alone,” says Bente Vilsen.
She points out that in future, it will be possible to replace sick genes with healthy, and that it is therefore important to know precisely which gene is affected by a mutation. She also points out that the understanding of the disease mechanisms causing rare diseases often turns out to lead to better treatment of patients with related but far more commonly occurring diseases.
Jens Chr. Skou’s sodium-potassium pump is best known as the membrane pump that is needed for the normal functioning of nerve cells, kidney cells and most of the body’s other cells.
The pump works like a battery that separates sodium and potassium on either side of the membrane. This creates an electrical current across the cell membrane that drives many other processes such as e.g. electric conduction along the nerve cells and the absorption of magnesium and a range of nutrients from the urine into the kidney cells, so that they are not normally lost in the urine.
Jens Christian Skou, who died in early summer at the age of 99, originally had the idea that mutations in the sodium-potassium pump would be incompatible with life. But it has since been found that more serious diseases which are not necessarily fatal are due to genetic defects in the sodium-potassium pump — and this is precisely the case with the disease that the three children suffer from.
This is due to two factors. Firstly, that in the body’s different types of tissues there are several variants of the sodium-potassium pump which are able to supplement each other if one of the forms does not work. And, secondly, that we have genetic material from both our parents, so even in the kidneys, which in contrast to the brain only contain one variant of the sodium-potassium pump (Alpha-1), not all of the sodium-potassium pumps will be defective, but only those derived from one of the two parents.
Therefore, in both the brain and kidneys, there will be a reduced number of functioning sodium-potassium pumps, but not a total absence of pumps — because if this was the case, the children would have died before birth as predicted by Jens Christian Skou.
In the specific research project, the patients were discovered by medical doctors working in clinical practice. Bente Vilsen’s group have contributed with their expertise in examining sick sodium-potassium pumps by inserting the diseased gene in cultured cells that originally come from monkey kidneys, making it possible to measure their pump function in the laboratory. As it turned out, the three mutations each in their own way caused the pump to be unable to transport sodium and potassium.
There is a long way to go before the research results benefit the patients as the discovery is as such basic research. However, Bente Vilsen explains that Postdoc Rikke Holm from her research group recently discovered how it was possible to use an additional mutation — a so-called ‘rescue’ mutation — to nullify the effects of the disease mutations on the pump’s binding of sodium.
“This provides an insight into the molecular mechanism which we in the research group are working to utilise to improve the pump’s transport activities, meaning that we can possibly one day develop a drug with a similar ‘rescue-effect’. In any event, that’s our hope. The fact is that it’s basic research which generates the knowledge that forms the basis for the development of the vast majority of drugs and forms of treatment,” points out Bente Vilsen.
Materials provided by Aarhus University. Original written by Nanna Jespersgård. Note: Content may be edited for style and length.
- Karl P. Schlingmann, Sascha Bandulik, Cherry Mammen, Maja Tarailo-Graovac, Rikke Holm, Matthias Baumann, Jens König, Jessica J.Y. Lee, Britt Drögemöller, Katrin Imminger, Bodo B. Beck, Janine Altmüller, Holger Thiele, Siegfried Waldegger, William van’t Hoff, Robert Kleta, Richard Warth, Clara D.M. van Karnebeek, Bente Vilsen, Detlef Bockenhauer, Martin Konrad. Germline De Novo Mutations in ATP1A1 Cause Renal Hypomagnesemia, Refractory Seizures, and Intellectual Disability. The American Journal of Human Genetics, 2018; 103 (5): 808 DOI: 10.1016/j.ajhg.2018.10.004
SOURCE: SCIENCE DAILY
Pedro Irazoqui had just enjoyed a huge lobster dinner.
Then he woke up that night finding he couldn’t breathe.
Terrified, Irazoqui sat up and tried to relax. Air suddenly returned to his lungs like nothing had happened.
After grabbing his phone and Googling like crazy, Irazoqui, a professor at Purdue University, discovered that what he had experienced was acid reaching his larynx, causing it to contract and cut off air flow. Sitting up pushes the acid back down to the stomach with the help of gravity.
A few years later, this episode inspired a possible explanation of why one in 1,000 adults with epilepsy die suddenly during a seizure each year: acid reflux.
The study, led by Irazoqui’s team at Purdue, found acid in the esophagus of animal models 100 percent of the time that they experienced sudden death during a seizure.
These findings propose another potential cause of death to investigate, as well as ideas for more targeted treatment. The team intends to start clinical trials this year on whether humans with epilepsy also experience acid reflux during a seizure.
The published paper appears in the December issue of Epilepsy Research.
While the sample size was small, the researchers have seen the same correlation in animals tested since this study.
“The moral of the story isn’t just to not be a glutton: What if the mechanism of sudden death is not respiratory or cardiac – the two theories held at the moment – but all through the stomach?” said Irazoqui, who is a professor of biomedical engineering and electrical and computer engineering.
Treatment, then, could involve a cranial nerve called the vagus, which controls acid production.
The vagus nerve splits into many branches below the diaphragm. One of those is the gastric branch to the stomach. When this nerve is stimulated, such as during a seizure, the stomach overproduces acid that could hit the valve to the larynx.
Because the animals did not experience acid reflux with an empty stomach, even though their seizures triggered a lot of acid production, a short-term solution to preventing death could be not eating after a certain time of night.
“An empty stomach might hold acid down. Since seizures almost always happen during sleep, maybe just not eating after 5:00 p.m. could do the trick. We’re hoping to test this in humans,” Irazoqui said.
A more reliable and long-term solution could be an implantable device that would block electrical activity in the gastric branch of the vagus nerve only during a seizure, preventing acid production from cutting off air flow.
Irazoqui’s team has already built a prototype of this device and plans to test it in animals and humans. Their findings might also provide some insights into other unexplained mechanisms of death, such as sudden infant death syndrome.
The study was funded in part by a grant from the James Lewis Foundation through Epilepsy Research UK. This work aligns with Purdue’s Giant Leaps celebration, acknowledging the university’s global advancements made in health, longevity and quality of life as part of Purdue’s 150th anniversary. This is one of the four themes of the yearlong celebration’s Ideas Festival, designed to showcase Purdue as an intellectual center solving real-world issues.
The Purdue Research Foundation Office of Technology Commercialization has patented the implantable device technology.
Writer: Kayla Wiles
Source: Pedro Irazoqui
Acid reflux induced laryngospasm as a potential mechanism of sudden death in epilepsy
Ryan B.Budde1, Muhammad A.Arafat1, Daniel J.Pederson1, Thelma A.Lovick1,2, John G.R.Jefferys1,3, Pedro P.Irazoqui1
1Purdue University, West Lafayette, IN, USA
2University of Bristol, Bristol, UK
3Oxford University, Oxford, UK
Recent research suggests that obstructive laryngospasm and consequent respiratory arrest may be a mechanism in sudden unexpected death in epilepsy. We sought to test a new hypothesis that this laryngospasm is caused by seizures driving reflux of stomach acid into the larynx, rather than spontaneous pathological activity in the recurrent laryngeal nerve.
We used an acute kainic acid model under urethane anesthesia to observe seizure activity in Long−Evans rats. We measured the pH in the esophagus and respiratory activity. In a subset of experiments, we blocked acid movement up the esophagus with a balloon catheter.
In all cases of sudden death, terminal apnea was preceded by a large pH drop from 7 to 2 in the esophagus. In several animals we observed acidic fluid exiting the mouth, sometimes in large quantities. In animals where acid movement was blocked, sudden deaths did not occur. No acid was detected in controls.
The results suggest that acid movement up the esophagus is a trigger for sudden death in KA induced seizures. The fact that blocking acid also eliminates sudden death implies causation. These results may provide insight to the mechanism of SUDEP in humans.
Cannabinoids (CBDs) demonstrated superior efficacy to placebo and similar efficacy to that of other antiepileptic drugs for managing Dravet syndrome and Lennox–Gastaut syndrome in pediatric patients as well as for adults with epilepsy, according to review results of 3 randomized trials published in Developmental Medicine & Child Neurology.
In 3 recently published trials, all of which began with a 4-week baseline period, a subsequent 2-week escalation phase, a 12-week maintenance, and a 14-week treatment period, researchers administered CBD at 20 mg/kg/day. Only 1 of the 3 trials had an additional arm of 10 mg/kg/day CBD. The first trial, comprised of pediatric patients with Dravet syndrome, found that 43% of patients who received CBD experienced a >50% reduction in convulsive seizures vs 27% of patients who received placebo. In addition, 5% of patients treated with CBD achieved seizure freedom.
A greater percentage of parents of patients who received CBD reported improvement on the Caregiver Global Impression of Change compared with parents of those who received placebo (57% to 58% vs 38% to 44%, respectively). In a double-blind, randomized trial of adults patients with epilepsy (age 18-70 years) who received CBD, no difference was found between CBD and placebo with regard to seizure reduction.
With regard to tetrahydrocannabinol for the management of pediatric epilepsy, the researchers added, “there are concerns about the effect of [tetrahydrocannabinol] on the developing brain with well documented earlier onset of psychosis in patients who take recreational [tetrahydrocannabinol].” The researchers added that there exist “a large number of other cannabinoids with fewer side effects as suggested by animal models, some of which are under investigation and may hold promise for treatment of epilepsy in the future.”
SOURCE: Neurology Advisor by B. May
People with psychogenic nonepileptic seizures (PNES) who complete psychotherapy are more likely to improve than patients who do not, new research shows.
PNES are paroxysmal events involving involuntary movements or alterations of consciousness caused by psychological factors. They are relatively common, disabling, and tough to diagnose correctly because they can look and feel very much like epileptic seizures, Dr. Tolchin explained. “Even the person having the seizures and trained neurologists observing the seizures can easily confuse the two.”
The best way to differentiate PNES from epileptic seizures is capturing the seizure events on video-electroencephalogram (video-EEG). “Once the diagnosis of PNES is made, the evidence suggests that psychotherapy, and specifically cognitive behavioral therapy, is an effective treatment, while the anti-seizure medications used to treat epileptic seizures are not effective in treating PNES,” said Dr. Tolchin.
The new study, online January 4 in Neurology, provides more evidence that psychotherapy works, when patients adhere to it.
Dr. Tolchin and colleagues at Brigham and Women’s Hospital in Boston, MA, studied 105 patients diagnosed with documented PNES by board-certified epileptologists via video-EEG who were referred to psychotherapy. Eighty-seven patients (94%) were adherent to psychotherapy, defined as attending at least eight sessions within a 16-week period starting at the time of referral.
Adherent patients were more likely to achieve a 50% reduction in weekly seizure frequency than their non-adherent peers (84% vs 61%, P=0.021), see improvement in quality of life (P=0.044), and make fewer trips to the emergency department (P=0.040), “with medium effect sizes,” the researchers report in their paper.
The association between adherence to psychotherapy and a 50% reduction in PNES frequency persisted after controlling for potential confounders in a multivariate model, they say.
“There are many obstacles to completing psychotherapy,” said Dr. Tolchin, “including stigma, a shortage of behavioral health providers, and patient non-adherence. This study suggests that people of self-identified minority status or a history of childhood abuse are at increased risk of not completing psychotherapy.”
The researchers note that the study was done at a single center with a special interest in PNES, and with treatment resources that may not be available in other settings, which may limit the generalizability of the findings. “Our results should ideally be replicated in a multi-center study spanning different treatment environments,” they say.
“Internal validity of the study is also limited by heterogenous psychotherapy, variable follow-up time, and by subjective measurements of PNES frequency, which allows recall bias. Our study is further limited by a lack of data on the types of therapy performed by outpatient therapists, and the use of psychotropic and anti-seizure medications during the course of psychotherapy,” they add.
SOURCE By Megan Brooks for Reuters Health News
The US Food and Drug Administration (FDA) has granted 510(k) clearance to the Embrace smartband for use in children ages 6 years and older with epilepsy. The smartband detects patterns in motion as well as physiological signs that may indicate generalized tonic-clonic seizures and alerts caregivers with the information.
“The clearance of the Embrace watch to detect seizures in children ages 6 years and older is an important step forward in our ability to identify seizures rapidly and thereby allow parents or others to respond,” said Orrin Devinsky, MD, Director at NYU Comprehensive Epilepsy Center and the Saint Barnabas Institute of Neurology and Neurosurgery (INN).
A clinical trial of 141 patients with epilepsy, including 80 pediatric patients aged 6-21 years, supported the 510(k) clearance for the pediatric use of Embrace. The Embrace smartband detected with 98% accuracy, identifying 53 out of 54 generalized tonic-clonic seizures.
“We are so happy to provide Embrace with FDA’s formal clearance of its use by pediatric subjects aged 6-21. Embrace improves the likelihood that a trusted caregiver will be there during the critical moments after a seizure happens. Having somebody present is associated with better health outcomes,” said Rosalind Picard, ScD, Empatica co-founder, chief scientist, and professor at MIT.
Embrace was approved for use in adults with epilepsy in early 2018, supported by results of a clinical trial of 135 patients. Participants were monitored via video electroencephalography (EEG) as well as the Embrace smartband. The Embrace device detected 40 generalized tonic-clonic seizures with 100% accuracy.
“We are very grateful for this result,” said Matteo Lai, Empatica CEO and co-founder. “Empatica’s team worked very hard to expand the use of the Embrace for seizure monitoring, as we realized how much this would mean for the community and parents. We are continuously committed to implement the best science and technology, in order to provide better care to millions of patients living with epilepsy.”
SOURCE: MDmag.com by Cecilia Pessoa Gingerich
LINK TO EMPATICA SMART BANDS HERE
What is the risk of attention-deficit/hyperactivity disorder in children prenatally exposed to valproate (Depakote) and other antiepileptic drugs?
In a population-based study of 913,302 children in Denmark, prenatal exposure to valproate was significantly associated with a 48% increased risk of attention-deficit/hyperactivity disorder compared with children with no valproate exposure. No association was identified for other antiepileptic drugs.
The findings of this study corroborate that counseling is appropriate for the use of valproate in pregnancy and in women of childbearing potential.
Valproate is an antiepileptic drug (AED) used in the treatment of epilepsy and many other neurological and psychiatric disorders. Its use in pregnancy is associated with increased risks of congenital malformations and adverse neurodevelopment in the offspring and may be associated with an increased risk of attention-deficit/hyperactivity disorder (ADHD).
Maternal use of valproate, but not other AEDs, during pregnancy was associated with an increased risk of ADHD in the offspring. These findings have important implications for the counseling of women of childbearing potential using valproate.
“The risk of ADHD was related to valproate exposure mainly in the first trimester, but the number of cases exposed only in later trimesters was low; our findings therefore do not exclude the possibility that valproate exposure across all stages of pregnancy may be associated with an increased risk of ADHD in the offspring. When examining doses of valproate, prenatal exposure to estimated higher doses tended to be associated with higher risks of ADHD than exposure to estimated lower doses of valproate, although the difference between high and low doses was not significant.”
Maternal use of valproate during pregnancy was associated with a small but significantly increased risk of ADHD in the offspring, even after adjusting for maternal psychiatric disease, maternal epilepsy, and other potential confounding covariates. These findings have important implications for the counseling of women of childbearing potential who are undergoing treatment with valproate, and they support warnings issued by authorities. As randomized clinical trials of valproate use during pregnancy are neither feasible nor ethical, our study provides clinical information on the risk of ADHD associated with valproate use during pregnancy. Replication of our findings in large-scale observational studies of adverse drug effects is warranted as such effects have not been evaluated adequately in controlled trials (ie, during pregnancy).
SOURCE: “This is an open access article distributed under the terms of the CC-BY License. © 2019 Christensen J et al. JAMA Network Open.
The key factor leading to epileptic seizures in rats has been identified by Russian scientists who investigated the complex interaction of neural signals.
The scientists studied the complex changes in the temporal lobe cortex of a rat brain during prolonged epileptic seizes to identify the key factor leading to the seizures. The work has been published in Frontiers in Cellular Neuroscience.
Epistatus is the condition where a person subject to epilepsy experiences seizures which follow each other after a short time. The condition is considered to be particularly dangerous. Although scientists know that this is caused by an excessive excitation of neurons in the brain, the reason for such neuron activity is unclear.
The difficulty of analysing individual neuron signals
Anton Chizhov is a doctor of physical and mathematical sciences, senior researcher at the Ioffe Institute of RAS, and Leading Researcher at Sechenov Institute of Evolutionary Physiology and Biochemistry. Chizhov explained:”Neurons send each other signals that can be excitatory or inhibitory, depending on the type of target receptor on the cell membrane. For example, the first are those that react to glutamate and its analogues, the second are sensitive to gamma-aminobutyric acid or GABA. Yet GABA receptors of those suffering with the epilepsy also become exciting. There lies the main research difficulty: when several signals act on the neuron at once it is very difficult to assess their individual contribution.”
The key mechanism causing epileptic seizures
The researchers investigated the signalling processes in the cortex of the temporal lobe before and after the rat epileptic seizures. They examined the effect of amino acids on receptors of all major types. They found that each of the components of the signal after epileptic electrical discharges becomes stronger and longer.
In order to find out what happened as a result of affecting only one amplified signal on the remaining paths, the team created a mathematical model of interacting nerve cells system.
The results showed that only the conductivity of the AMPA receptors in the network of neurons significantly changes. This leads to stronger excitation of all neurons and stronger synaptic signals recorded on one nerve cell. Chizhov added: “Further studies showed that this is the mechanism of synaptic plasticity with the incorporation of new calcium-permeable AMPA receptors into the cell membranes. Under normal conditions, such a process in the brain is associated with memory and learning, but under pathological conditions it leads to an excitability increase up to tens of minutes. Therefore, the risk of a new convulsive discharge rises, which may lead to pathology fixation.”
Chizhov concluded: “Knowing that embedding calcium-permeable AMPA receptors leads to the consolidation of seizure activity, we can develop new antiepileptic drugs.”
SOURCE: SCITECH Europa
The two hemispheres of our brain — left and right — specialize in different tasks. A recent study asks how this occurs and reaches a surprising conclusion.
Exactly how do the left and right brain compete for dominance?
Hemispheric dominance, also known as lateralization of brain function, describes the tendency for either the left or the right side of the brain to carry out specific brain activities.
Even though both sides of the brain are almost identical, one hemisphere primarily carries out some functions over others.
For instance, the left hemisphere houses brain regions linked to speech (or the right hemisphere in left-handed people).
Previously, scientists thought humans were the only creatures to exhibit this phenomenon. However, recent research has found lateralized brain function throughout the animal kingdom — from insects, such as honeybees, to aquatic mammals, including killer whales.
The corpus callosum — a thick tract of nerve cells, known as commissural fibers — connects the two hemispheres. Exactly how dominance is produced remains uncertain.
Recently, researchers from Ruhr-Universität Bochum in Germany set out to investigate this question. They chose to study the visual system of pigeons, and they have published their findings in the journal Cell Reports.
Bird brains and old ideas
Previously, scientists have theorized that one side of the brain simply inhibits the other, allowing it to take dominance.
Co-lead author Prof. Onur Güntürkün explains that “[i]n the past, it had been assumed that the dominant hemisphere transmits inhibitory signals to the other hemisphere via the commissures, thus suppressing specific functions in that region.”
In effect, the dominant hemisphere is thought to overpower its neighbor. However, scientists have also noted that excitatory messages run both ways, so there must be more to this interaction.
The researchers decided to use a pigeon model because other studies have described hemispheric dominance in this species in some detail over recent years.
For instance, in pigeon brains, the left hemisphere takes the lead when it comes to visual processing of patterns and colors. Conversely, the right brain more often deals with social or emotionally charged stimuli.
The scientists trained the birds to perform a color differentiation task. In particular, this challenge involves part of the brain that uses visual information to guide motor activity. In this type of task, the left side of the brain is dominant.
To understand how cross-talk between hemispheres influences dominance, Prof. Güntürkün and co-author Dr. Qian Xiao intermittently switched off some of the neurons that run between the two sides of the brain.
Interfering in cross-talk
After blocking specific neurons running from one side, they would observe the activity of the neurons that usually receive their input on the opposite side. In this way, they could pick apart the way in which the dominant hemisphere exerts its control.
The researchers showed that, rather than merely inhibiting the right side of the brain during this task, the left brain could delay the response of the right brain, so preventing it from getting involved.
As Prof. Güntürkün explains, “The right hemisphere simply acts too late to control the response.”
Rather than merely inhibiting the response, the right brain still operates, but its signals are too late to the party to make a difference to the bird’s behavior.
“These results show that hemispheric dominance is based on a sophisticated mechanism. It does not hinge on one general inhibitory or excitatory influence; rather it is caused by minute temporal delays in the activity of nerve cells in the other hemisphere.”
Prof. Onur Güntürkün
The findings provide an entirely new way to look at hemispheric dominance. Research is bound to continue into this rather peculiar phenomenon that evolution has lovingly conserved throughout many branches of life.
However, it is likely to be quite some time before we understand why dividing tasks between the hemispheres is so evolutionarily advantageous.
SOURCE: Medical News Today by T. Newman
A high overall incidence of epilepsy in children with congenital heart disease (CHD) and a markedly higher incidence in those with perioperative clinical seizures (CS) prompted a neurocardiology team to call for increased perioperative electroencephalogram (EEG) monitoring.
“The last decades have been marked by considerable advances in perioperative care of children undergoing congenital heart surgery,” study co-author Nancy Poirier, MD, Division of Cardiac Surgery, Department of Surgery, Sainte-Justine University Hospital Center and University of Montreal, told MD Magazine®.
PHOTO: Nancy Poirier, MD
“With high survival rates, the focus of pediatric cardiac surgical teams has shifted towards improving functional outcomes with the ultimate goal of offering our tiny patients a bright cardiac and neurodevelopmental future,” Poirier said.
Poirier said this goal is only feasible with collaboration with neurologists, intensivists, developmental pediatricians, paramedical professional including physiotherapists and occupational therapists, and clinical investigators.
Such a multidisciplinary team collaborated with researchers at the Clinique d’Investigation Neuro-Cardiaque (CINC), Sainte-Justine, Montreal, Canada, and study principle investigators, Lionel Carmant, MD and Ala Birca, MD, PhD, to conduct a prospective investigation of the incidence and risk factors of perioperative clinical seizures (CS) and epilepsy in children who undergo cardiac surgery for complex CHD.
The investigators identified 128 consecutive children with CHD who underwent cardiac surgery with or without cardiopulmonary bypass at a neurocardiac clinic to follow for a period of at least 2 years. Perioperative seizures were defined as any CS occurring before the first surgery or less than 21 days after any surgery; and epilepsy as seizure recurrence more than 21 days after surgery.
Univariate logistic regression was applied to determine risk factors for perioperative CS and the development of epilepsy.
Four of the 128 patients (3.1%) developed epilepsy (median age 7.75 months; range 2 – 26 months). Among the 10 patients (7.8%) who had experienced perioperative CS, 4 (40%) developed epilepsy.
Analysis revealed that CS was most common in patients with higher Risk Adjustment for Congenital Heart Surgery (RACHS) scores, delayed sternal closure and use of extra corporeal membrane oxygenation (ECMO). These patients also required longer periods in the pediatric intensive care and durations of hospital stay.
In addition, there was higher likelihood of CS in patients with longer cardio-pulmonary bypass, aortic clamp times and deep hypothermic circulatory arrest. Use of ECMO and longer hospital stay was also associated with epilepsy.
Carmant, Birca and colleagues note that EEG monitoring had not been systematically performed in this cohort, but that it had detected 1 additional patient with preoperative EEG-only seizure. They suspect, therefore, that the reported 7.8% of children with clinically apparent seizures was an under representation of the actual incidence of seizures, and of those at highest risk for epilepsy.
“None of the patients without perioperative CS developed epilepsy,” investigators observed. “We believe that both clinical and EEG-only seizures are equally involved in epileptogenesis.”
They also assert that undiagnosed and untreated EEG-only seizures persist longer and eventually manifest clinically.
“This underscores the importance of perioperative EEG monitoring, as seizure persistence during the critical period is one of the main predictors of later epilepsy,” Carmant, Birca and colleagues indicated.
Poirer added that perioperative monitoring is critical in detecting potential brain injury and guide treatment.
“Continuous EEG monitoring of brain activity allows us to detect seizures, which are frequently not clinically manifest, but may contribute to brain injury and long-term sequelae such as epilepsy and impaired neurodevelopment,” she said.
Investigators strongly advocated for a “more liberal use” of EEG monitoring in vulnerable infants.
The study, Epilepsy and Seizures in Children with Congenital Heart Disease: A Prospective Study, was published online in Seizure: European Journal of Epilepsy.
SOURCE: MDMag.com by K. Bender, PharmD, MA
A new, smart implant that “listens” to brain signals could help treat epilepsy and other neurological conditions, such as Parkinson’s disease.
Could an innovative brain-stimulating device make a difference to the treatment of neurological conditions?
Doctors use neurostimulation to treat various conditions, including epilepsy, the effects of stroke, and even depression. This treatment involves using special devices that send electrical impulses to control the activity of the brain and central nervous system.
Doctors sometimes also use this technique to improve the symptoms of Parkinson’s disease, a neurological condition that affects physical balance and the ability to move or coordinate the movement of the limbs.
However, the neurostimulator devices that are currently available for the treatment of neurological conditions are unable to both stimulate brain activity and record it at the same time.
Now, specialists from the University of California (UC), Berkeley have developed a new, sophisticated neurostimulator that seems able to achieve this. It may have the potential to improve the treatment of epilepsy, Parkinson’s, and other conditions.
The research team has named this device “WAND,” which stands for “wireless artifact-free neuromodulation device.” WAND has two tiny external controllers, each of which monitors 64 electrodes that sit in the brain.
This device can monitor electrical activity in the brain and learn to identify abnormal signals that indicate the presence of a seizure or tremors. WAND can then help modulate electrical signals in the brain to prevent such events and symptoms.
Unlike similar existing devices, which can only record electrical activity from up to eight points in the brain, WAND can track activity from 128 different channels.
New device is cost- and time-efficient
In their study paper, which the journal Nature Biomedical Engineering has published, the researchers note that, in the future, WAND could potentially help improve the lives of people who have seizures or live with various neurological conditions.
“The process of finding the right therapy for a patient is extremely costly and can take years,” explains assistant professor Rikky Muller, one of the researchers.
“Significant reduction in both cost and duration can potentially lead to greatly improved outcomes and accessibility. We want to enable the device to figure out what is the best way to stimulate for a given patient to give the best outcomes. And you can only do that by listening and recording the neural signatures.”
Muller and team have tested WAND in an animal model, using rhesus macaques to show how the device can learn to recognize brain signals for specific arm movements and how it can then act on those same signals.
After a while, the implanted devices learned to detect the neural signals that corresponded to the macaques’ hand motions. Once they had identified these patterns, they were able to send out electrical signals that delayed the hand movements.
“While delaying reaction time is something that has been demonstrated before, this is, to our knowledge, the first time that it has been demonstrated in a closed-loop system based on a neurological recording only,” says Muller.
“In the future, we aim to incorporate learning into our closed-loop platform to build intelligent devices that can figure out how to best treat you and remove the doctor from having to constantly intervene in this process,” she adds.
WAND double-activity may boost treatment
The researchers explain that the currently available neurostimulator devices are unable to detect signature electrical signals in the brain while also modulating such signals.
This, they note, is because the electrical pulses that the neurostimulator emits “obscure” the original brain signals, thus rendering them virtually undetectable.
“In order to deliver closed-loop stimulation-based therapies, which is a big goal for people treating Parkinson’s and epilepsy and a variety of neurological disorders, it is very important to both perform neural recordings and stimulation simultaneously, which currently no single commercial device does,” says study co-author Samantha Santacruz, previously a researcher at UC Berkeley and now an assistant professor at the University of Texas in Austin.
Unlike other neurostimulators, WAND devices have a unique design with custom integrated circuits that are able to record the subtle electrical signals that the brain emits while also sending out stronger impulses to “correct” faulty signals.
Thanks to WAND, “[b]ecause we can actually stimulate and record in the same brain region, we know exactly what is happening when we are providing a therapy,” notes Muller.
Source: Medical News Today by M. Cohut
Seizures can be scary for parents and children, but researchers from the Netherlands have developed a new model that can help determine the risk of epilepsy and guide future clinical pathways.
Eric van Diessen, MD, PhD
For children who have had 1 or more seizures, the model may help to determine the risk a child has of receiving a diagnosis of epilepsy, according to the report. The study, published in Pediatrics, details how the model was developed and tested.1
Epileptic seizures can be underestimated in children because clinical symptoms vary so widely and initial interictal electroencephalogram (EEG) may have limited sensitivity, the report notes.
“Previous efforts have been made to identify prognostic clinical variables for seizure recurrence after first consultation. These studies were restricted to children with a definitive diagnose of epilepsy,” says Eric van Diessen, MD, PhD, of University Medical Center Utrecht, the Netherlands, and lead author of the report. “Diagnosing epilepsy, however, might be difficult considering the heterogeneity of a [first] paroxysmal event in children. Some of these paroxysmal events might not be epileptic in nature. To assist the clinician in the diagnostic workup, with access to an EEG, we developed this prediction model.”
Van Diessen and colleagues developed the model from retrospective data on 451 children that combined clinical data, including age at first seizure and initial EEG findings. The children involved in the study were followed for at least a year and either had been diagnosed with epilepsy or diagnoses were unconfirmed. The model was validated using case data from an additional 187 children.
Forty-five percent of children in the training cohort and 29% in the validation cohort had inconclusive epilepsy diagnoses at the start of the study, according to the report. After a year of follow-up, a definitive diagnosis was made in 94.2% of children in the training cohort and 92% in the validation cohort.
Modeling efforts were considered highly successful, according to the report, and could be used as a screening—but not necessarily diagnostic—tool to assess seizure likelihood and provide insight on when to refer a patient to a specialist.
How the model works
“Our model provides a rational approach to assist clinicians during the diagnostic process by combining routinely available clinical information in a multivariate way,” the researchers write. “More specifically, we expect our model to be useful as an ‘independent’ screening tool to assess the likelihood of a possible seizure to be epileptic in origin and to help the clinician decide on the need for ancillary investigations or refer to an epileptologist.”
The model could be especially useful in children with uncertain diagnoses of epilepsy, as a false diagnosis could result in unnecessary antiepileptic medication use or hospitalizations, the report notes.
“Our prediction tool can help the clinician to decide whether ancillary investigations or referral to an epileptologist are necessary, which is especially preferable for children where the risk is neither high nor low,” says the report. “Additionally, high-risk cases are identified quickly, and appropriate actions can be taken early in the process.”
The research team also made the model available as an Internet application to help clinicians estimate seizure probability in practice.
“To improve the implementation in clinical practice, we constructed a Web application that may assist clinicians to estimate the individualized probability of epilepsy in children who present after 1 or more possible seizures,” van Diessen says. “We do not claim to present a diagnostic tool; obviously, it is up to the clinician to finally conclude whether a child may truly have epilepsy and whether ancillary diagnostics or treatment is indicated.”
References: 1. van Diessen E, Lamberink HJ, Otte WM, et al. A prediction model to determine childhood epilepsy after 1 or more paroxysmal events. Pediatrics. 2018;142(6):e20180931.
SOURCE: contemporarypediatrics.com by R. Zimlich, RN, BSN
The body of knowledge about the human brain is growing exponentially, but questions big and small remain unanswered. Researchers have been using electrode arrays to map electrical activity in different brain regions to understand brain function. Until now, however, these arrays have only been able to detect activity over a certain frequency threshold. A new technology developed in Barcelona overcomes this technical limitation, unlocking the wealth of information found below 0.1 Hz and paving the way for future brain-computer interfaces.
Developed at the Barcelona Microelectronics Institute (IMB-CNM, CSIC), the Catalan Institute of Nanoscience and Nanotechnology and the CIBER in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), and adapted for brain recordings in collaboration with the August Pi i Sunyer Biomedical Research Institute (IDIBAPS), the technology moves away from electrodes and uses an innovative transistor-based architecture that amplifies the brain’s signals in situ before transmitting them to a receiver. Furthermore, the use of graphene to build this new architecture means the resulting implant can support many more recording sites than a standard electrode array; it is also slim and flexible enough to be used over large areas of the cortex without being rejected or interfering with normal brain function. The result is an unprecedented mapping of the kind of low-frequency brain activity known to carry crucial information about events in the brain such as the onset and progression of epileptic
Beyond epilepsy, though, this precise mapping and interaction with the brain has other exciting applications. Taking advantage of the capability of the transistor configuration to create arrays with a very large number of recording sites via a so-called multiplexing strategy, the technology is also being adapted by the researchers to restore speech and communication as part of the European project BrainCom. Led by the ICN2, this project will deliver a new generation of brain-computer interfaces able to explore and repair high-level cognitive functions with a particular focus on the kind of speech impairment caused by brain or spinal cord injuries (aphasia).
Details of the underlying technological advances can be found in Nature Materials.
The graphene microtransistors were adapted for brain recordings and tested in vivo at IDIBAPS, led by ICREA Prof. Mavi Sánchez-Vives. An imaging technique was developed in collaboration with ICFO, led by ICREA Prof. Turgut Durduran (ICFO is a center of BIST).
Source: Catalan Institute of Nanoscience and Nanotechnology Photo Credits: ICN2
One of four patients admitted to hospitals for evaluation of seizures don’t have epilepsy but rather have a debilitating and difficult to diagnose condition known as psychogenic non-epileptic seizures, or PNES.
Nearly 80 percent of these patients who suffer seizures not caused by altered electrical activity in the brain have been previously misdiagnosed as having epilepsy and prescribed anti-seizure medicines to which they do not respond. Many return to emergency rooms again and again.
But a new study by researchers at Yale University and Brigham and Women’s Hospital in Boston show that psychiatric counseling does help patients with the condition — once called hysteria — according to research published Jan. 4 in the journal Neurology.
“There’s a feeling among many physicians that there is nothing that can be done to treat these patients but our study shows that they can receive benefits from psychotherapy if they engage and complete the treatment,” said Benjamin Tolchin, assistant professor of neurology at Yale.
PNES is thought to have an underlying psychiatric cause and has been linked to PTSD, anxiety disorder, personality disorder, and depression as well as a history of sexual abuse or bullying. Diagnosing PNES typically requires a hospital stay of four days or more in a specialized epilepsy-monitoring unit.
More than half of patients end up on disability and they frequently make repeated visits to hospital emergency departments, Tolchin said. There is also substantial stigma to the disorder, which includes suspicions that people fake seizures, he adds.
PNES was once thought to be a condition that afflicts women but scientists now know it can strike men as well.
The new study of 105 patients shows that those who adhered to psychotherapy treatment were much more likely to achieve a 50 percent reduction in seizure frequency and reduction in emergency room visits.
“We want to increase visibility of the condition because it is overwhelmingly misdiagnosed,” Tolchin said.
Gaston Baslet of the Department of Psychiatry at Brigham and Women’s Hospital and Harvard Medical School is senior author of the paper, which was primarily funded by the American Academy of Neurology and a Veterans Administration VISN1 Career Development Award.
Source: news.yale.edu by B. Hathaway
“Many individuals are being treated for epilepsy who do not actually have this disorder”, so says Peter Crino, MD, PhD, Chair of the Department of Neurology at the University of Maryland School of Medicine.
Psychogenic Non-Epileptic Seizures (PNES) are common and may account for up to 20% of people being treated for epilepsy. PNES are events of psychological origin, resembling an epileptic seizure, but without the characteristic electrical discharges associated with epilepsy. Because it is often hard to distinguish between the symptoms of epilepsy and PNES some people who don’t have epilepsy will be receiving potent antiepileptic medication unnecessarily, whilst others (who do have epilepsy) wait a long time to begin treatment.
Researchers at the University of Pennsylvania decided to address this issue and have recently presented their findings suggesting that a bio-marker based blood test may be able to distinguish between epilepsy and PNES.
Psychogenic nonepileptic events are common–accounting for an estimated 20% or more of patients seeking medical care at comprehensive epilepsy centers. They resemble and are hard to distinguish from true epileptic seizures and are related to psychological factors rather than electrical disturbances in the brain. Since epilepsy is difficult to diagnose, individuals with psychogenic nonepileptic seizures are often assumed to have epilepsy and receive unnecessary testing and treatment, including powerful antiepileptic drugs. They also risk losing driver licenses and other privileges. One study found that wrongly diagnosed psychogenic patients received unnecessary antiepileptic therapy for an average of seven to 10 years.2
Peter Crino, MD, PhD, is Chair of the Department of Neurology at the University of Maryland School of Medicine and a co-author of the new study. His former laboratory at the University of Pennsylvania conducted key studies of Cognizance Biomarkers’ approach. Dr. Crino noted, “Many individuals are being treated for epilepsy who do not actually have this disorder. Individuals with psychogenic nonepileptic seizures are especially at risk for an epilepsy misdiagnosis. These results provide strong preliminary evidence that neuroinflammatory-associated biomarkers can be used to triage suspected seizure patients for expert evaluation, thereby ensuring that patients are accurately diagnosed and appropriately treated.”
Epilepsy is currently diagnosed using electroencephalograms (EEGs) and comprehensive patient assessments. The process can be subjective, cumbersome, expensive and inconclusive. Video EEGs are more informative, but they require costly hospitalization. Cognizance Biomarkers’ simple-to-administer blood test aims to accurately diagnose epileptic seizures based on proprietary methods for biomarker assessment, leveraging recent research showing that neuroinflammation is associated with epilepsy and is both a cause and consequence of seizures. Prior clinical studies have confirmed the ability of the Cognizance neuroinflammatory biomarker test to distinguish actual seizures from seizure-like events.
In the study reported today, researchers screened for levels of 51 inflammatory-associated proteins in post-event blood samples from confirmed epilepsy patients and individuals with psychogenic nonepileptic seizures. A series of analyses selected four protein biomarkers that were highly predictive in distinguishing true seizures from seizure-like events. Additional analyses identified substantial differences in clinical histories and comorbidities (i.e. risk factors) between ES and PNES patients. The selected neuroinflammatory-associated biomarkers were combined with the PNES risk factors to generate and refine a diagnostic algorithm that demonstrated strong performance in distinguishing true epileptic seizures from nonepileptic psychogenic seizures with 100% specificity, 87% sensitivity and 98% accuracy.
Todd Wallach, President and Chief Executive Officer of Evogen/Cognizance Biomarkers, commented, “These new data further confirm that our biomarker-based blood test has the potential to revolutionize the diagnosis of epilepsy. The results we are presenting today address one of the most vexing diagnostic issues in epilepsy—differentiating true epileptic seizures from similar-seeming psychogenic nonepileptic events. Our neuroinflammatory biomarker test combined with selected psychogenic risk factors accurately distinguished these two groups. Our blood-based diagnostic test will enable epilepsy to be diagnosed and treated more rapidly and accurately and has the potential to guide epilepsy clinical research and manage treatment over the lifecycle of the condition.”
This research was conducted with grant support from the National Institutes of Health.
A two-year-old boy has a rare form of epilepsy that left him in tears for 15 hours straight and triggered painful outbursts of hiccups and hysterical laughter for six months.
Jack Trotter was born in Atlanta, Georgia July 2016 – a seemingly healthy baby after a smooth birth.
But a day after his mother Leah, 30, took him home to his father and sister, things changed: he began crying consistently and as his cries intensified, he became inconsolable.
Initially Leah, a special needs advocate, wasn’t worried. Babies cry, this is normal.
But this was merely a hint of a much more serious condition that would take more than a year to diagnose.
As pediatricians insisted Jack was just ‘irritable’, the little boy endured painful episodes once a month of laughter or hiccups or tears.
At three months old, in October 2016, they thought they had found an answer – a terrifying one: a doctor misdiagnosed Jack with terminal Mitochondrial disease which usually proves fatal.
However, two months later, Jack was finally diagnosed with Pyridoxine Dependent Epilepsy (PDE), a rare cause of stubborn, difficult to control, seizures appearing in newborns, infants and occasionally older children.
It is treatable – but without care and medication it can be life-threatening, and his mother Leah is now fighting to get more kids tested at birth to avoid preventable deaths.
‘We went through six months of hell and our son almost died from a treatable condition that could be tested at birth. So, that is my first order of business,’ Leah said.
‘I try to advocate through social media platforms for PDE and I have since helped a mother in Brazil obtain access to the specialists necessary to treat her daughter with PDE.
‘I would like other mothers in similar situations to know that they control the narrative. Don’t let a doctor dictate the way you feel about the diagnosis being given to your child.
“I hope that all mothers faced with these situations won’t become overwhelmed with the heavy diagnosis and medical terminology being thrown around, but instead will use the opportunity to rise up and make the best quality of life for their child.’
Leah, says she ‘was on top of the world’ when Jack, her second child, was born.
‘He was perfect at eight pounds and three ounces, 22 inches long. He nursed perfectly right off the bat,’ Leah said.
It all went smoothly. She gave birth on a Saturday morning and was home by Monday afternoon.
‘Everything was perfect. He ate well, he slept well, he was an easy and happy baby,’ she explains.
But things shifted abruptly on Tuesday evening when Jack started cry.
Leah insists she wasn’t concerned at first (‘I rocked him, loved him and knew he would feel better soon. We had our routine follow-up with his pediatrician on Wednesday.’)
But she wasn’t aware then that they were embarking on a long arduous journey to get a diagnosis.
‘Jack had still not stopped crying by that time. No exaggeration, Jack cried for 15 hours straight. He cried the entire time at the pediatrician’s office.’
After their appointment, they went home, and the crying didn’t stop until about 8pm that evening. Jack had still been eating throughout all the crying, but when stopped crying he stopped nursing.
Then something new started – and Leah was sure it was something like a seizure.
‘I cannot explain it, although I have told the story to more doctors than I can count,’ she explains.
‘Jack did not look quite right after the crying stopped. Keep in mind, he was barely five days old at this time so it was hard to say if he was just brand new or if he was acting strange.
‘Babies are strange; they have strange movements. But something was neurologically not right, and I knew it.
‘He did not look like he was seizing (not in the sense that I thought a seizure looked like at that time at least), but something told me he was having little seizures.
‘He was slightly shaking, jittery as they called it in the hospital, and then he would startle and throw his left arm out and turn his head to the left simultaneously.
‘There is no way to explain this act, you just had to see it. I tried everything to see if I was imagining it or if something wasn’t right.
‘I was so blind to the true hardships in life and without warning, my life changed in an instant. Did I even blink? Had I been dreaming all along?’
In the morning, Leah’s mother helped her to give Jack a little sponge bath. He seemed rigid, and by that point Leah was very concerned.
‘I was done. I called the pediatrician and we went back in the next morning. Jack was just five days old.’
Despite Leah’s worry, she says the staff at the hospital didn’t take her concern very seriously, until a nurse approached them and noticed something wasn’t right.
‘Before I knew it there were six or seven nurses in the room, all crowded around Jack trying to help him and my husband and I faded into the background as they worked,’ Leah said.
‘I have never been so scared in my life.’
It was soon decided that Jack needed to be sent to Children’s Healthcare of Atlanta (CHOA), the best pediatric specialists in the state.
‘I was terrified because this confirmed that something bad was happening to our newborn son,’ Leah said.
Jack only got worse. He was in and out of the hospital with hard-to-control seizures, put on a myriad of medications, and still no answers.
When he was almost three months old, he was in status again and admitted to the PICU.
That’s when a neurologist ordered an MRI and concluded that Jack had Mitochondrial disease. The doctor told Leah her son’s brain has begun to atrophy and would continue to until he died.
‘They told us there was no hope,’ she said.
That changed a few days later when the results from their genetic tests came back.
His form of epilepsy is rare but manageable – but doctors warned that if he’d been diagnosed any later, he could have suffered sinister consequences.
‘His treatment for the first six months of his life had been all wrong, almost detrimental to him,’ Leah said.
‘We immediately saw a neurologist, genetics, nutrition, all the specialists we needed to get Jack on the right track.
‘We have been working so hard ever since with six therapies per week for Jack and lots of work at home. He still has many delays and a few new diagnoses, but he has a great quality of life.’
Jack has had numerous types of seizures in the first six months of his life such as; tonic-clonic, partial, focal, absence, gelatic, dacrystic and even some where he just has constant hiccups, but it’s under control now.
Leah says their support network has been key to making it through – and now she hopes to pay it forward.
‘Everyone has been incredibly supportive throughout the entire journey and still are. We could not have made it through any of this without our amazing support system.
‘I have a few things that I am incredibly passionate about and want to work on in the future. First and foremost, I want PDE added to the new-born screening.’
Both demographic and socioeconomic factors are associated with how often adult epilepsy patients utilize emergency departments, according to findings presented at the American Epilepsy Society (AES) Annual Meeting in New Orleans.
Investigators from UCB Pharma conducted a long-term retrospective analysis of more than 95,000 epilepsy patients in order to collect more data about how this population uses emergency departments and their healthcare outcomes.
The patients lived in California, Florida, and New York, between 2003 – 2014. They had at least 1 inpatient epilepsy diagnosis in the two-year identification period and the researchers followed up for 4 years to track their inpatient and emergency department utilization data. Then, they categorized patients into groups based on age: those less than 15 years of age and those greater than 65 years of age.
The investigators monitored impact of socioeconomic factors, such as residence zip code, insurance type, and income, and demographic factors, like gender and race, to form their analysis.
The younger cohort had two-and-a-half times the emergency department usage as the older cohort across the first year of follow up, the researchers found. The younger cohort included about 10,000 patients—a much smaller group than the adult patients. This group also had 15% lower inpatient utilization for all care compared to the older patients.
In terms of care related specifically to epilepsy, the researchers found, the younger patients had 7.5 times higher emergency department utilization and nearly 4 times as many inpatient utilizations, compared to the older patient group.
The researchers analyzed the socioeconomic factors with respect to the top income quartile of each zip code and learned that the epilepsy patients in the bottom income quartile had 3 times more initial emergency room utilization and 7% higher inpatient utilization.
Patients in the bottom quartile had 2.65 times more emergency department utilization than the top quartile as well as 19% lower inpatient utilization, the investigators determined.
The gap between under-15 and over-65 was largely consistent beyond the first year of follow up, the researchers demonstrated. The younger group had emergency room utilization across the additional 3 years 2.09 times higher, and 7.39 times higher for direct epilepsy care compared to the older cohort.
The researchers also found that the patients in the bottom income quartile zip codes had long-term emergency department utilization that was 26% higher overall and epilepsy-specific visits to the emergency department that were 24% higher when compared to the top income quartile zip codes. This was true even after the researchers took other factors into account, they said.
“For people with epilepsy, demographic and socioeconomic factors are associated with overall inpatient and ED utilization, as well as epilepsy-specific utilization,” the study authors concluded. “Patients [aged less than] 15 years old and those of lower socioeconomic status have higher baseline utilization, particularly for emergency department utilization.”
These differences across age and socioeconomic groups remain intact over time, investigators confirmed, particularly from the scope of utilization 3 years out.
The study, “Longitudinal predictors of healthcare use in adults with epilepsy,” was published online on the AES website.
According to the CDC, over 3.4 million Americans – or 1.2 percent of the U.S. population – suffer from some form of epilepsy. Medication keeps some of these people’s seizures under control. The medications’ side effects, however, often make it difficult to function normally, and at least 30 percent of patients don’t respond to anti-seizure medication at all.
Enter NeuroPace, Inc., a neuro-technology company based in Silicon Valley. It recently concluded a nine-year study on patients suffering from epilepsy using a tech gadget – not medication – to stymie the seizures.
The results? Over the course of the study, 75 percent of epileptic patients had at least a 50 percent reduction in seizures – and 33 percent had at least a 90 percent reduction! In addition, 28 percent had no seizures for over six months and 18 percent had no seizures for over a year. Patients did not report chronic stimulation side effects.
NeuroPace’s neuro-modulation study was the longest and largest for epileptics. The company evaluated 230 patients from 33 epilepsy centers across the United States. In addition to long-term seizure reduction, patients reported having a better quality of life in areas unrelated to epilepsy, and the device’s neural recordings provided doctors with critical information to better understand and, subsequently, treat seizures.
So how exactly does the technology work?
Neurons in the human brain constantly release electrical signals (otherwise known as brain activity). Misfired electrical signals can result in seizures. Anti-seizure medications remove, reduce, or alter excessive electrical activity so that faulty electrical signals aren’t “passed on” to the next batch of neurons, thus reducing the probability of seizures.
In contrast, NeuroPace’s Responsive Neurostimulation (RNS) System uses a computer interface technology device to treat the seizures at their source – and the device only goes into gear when the patient requires it. The RNS System uses a three-pronged approach. First, it detects and responds to a patient’s brain activity. Every patient’s brain is a little different, so doctors tailor the program to each patient’s unique brain activity.
Once programmed, the RNS System monitors a patient’s brainwaves and is ready to provide treatment whenever it detects unusual activity that can lead to a seizure, even if the patient is sleeping. Finally, once unusual brain activity is detected, the device responds with a series of electrical pulses or bursts of stimulation to stop the seizure and normalize the brainwaves before the seizure begins.
The RNS device, which is essentially a neuro-stimulator, is placed on the bone covering the brain. Once installed, it cannot be seen or felt. Tiny wires are positioned on one or two places atop the brain where seizure activity is likely to occur. The RNS System has a remote monitor used by patients to upload his or her data, as well as an RNS tablet and Patient Data Management System to enable doctors to better monitor patients. The device can always be turned off or removed if a patient doesn’t want it anymore.
During the course of the study, NeuroPace upgraded its RNS System. The 2.0 version has a battery life lasting 8.4 years, as opposed to the original’s 3.9 years. The amount of available memory for doctors to review patients’ brainwaves has also doubled.
The RNS System is available in epilepsy centers across the U.S. It is often used in conjunction with medication and is usually covered by insurance.
SOURCE: Article by B. Halperin for JewishPress.com