New guidance has been issued for clinicians on the determination of brain death, also known as death by neurologic criteria. A new consensus practice guideline, developed through a collaboration between the American Academy of Neurology (AAN), the American Academy of Pediatrics (AAP), the Child Neurology Society (CNS), and the Society of Critical Care Medicine (SCCM) is published in Neurology, the medical journal of the American Academy of Neurology.
This guideline updates the 2010 AAN adult practice guidelines and the 2011 AAP/CNS/SCCM paediatric practice guidelines on the determination of brain death. Because of a lack of high-quality evidence on the subject, the experts used an evidence-informed consensus process to develop the guideline.
“Until now, there have been two separate guidelines for determining brain death, one for adults and one for children,” said author Matthew P. Kirschen, MD, PhD, FAAN, of the Children’s Hospital of Philadelphia, and a member of the Child Neurology Society and the Society of Critical Care Medicine. “This update integrates guidance for adults and children into a single guideline, providing clinicians with a comprehensive and practical way to evaluate someone who has sustained a catastrophic brain injury to determine if they meet the criteria for brain death.”
Brain death is a state in which there is complete and permanent cessation of function of the brain in a person who has suffered catastrophic brain injury.
“Brain death means that clinicians cannot observe or elicit any clinical signs of brain function,” said author David M. Greer, MD, FAAN, FCCM, of Boston University in Massachusetts. “Brain death is different from comatose and vegetative states. People do not recover from brain death. Brain death is legal death.”
The consensus practice guideline outlines the standardised procedure for trained clinicians to evaluate people for brain death. As part of this procedure, clinicians perform an evaluation to determine whether there is any clinical functioning of the brain and brainstem, including whether the person breathes on their own. Brain death is declared if a person has a catastrophic brain injury, has no possibility of recovering any brain function, is completely unresponsive, does not demonstrate any brain or brainstem function, and does not breathe on their own.
This guideline includes updates on the prerequisites for brain death determination, the examination and the examiners, apnoea testing and ancillary testing.
In the early 1900s, Japanese scientist Kikunae Ikeda first proposed umami as a basic taste in addition to sweet, sour, salty and bitter. About eight decades later, the scientific community officially agreed with him. Now, scientists led by researchers at the USC Dornsife College of Letters, Arts and Sciences have evidence of a sixth basic taste, which fans of salt licorice will recognise.
In research published in Nature Communications, USC Dornsife neuroscientist Emily Liman and her team found that the tongue responds to ammonium chloride through the same protein receptor that signals sour taste.
Salt licorice has been a popular sweet in northern European countries since at least since the early 20th century, and also appears on South African shelves. The treat counts among its ingredients salmiak salt, or ammonium chloride.
Scientists have for decades recognised that the tongue responds strongly to ammonium chloride. However, despite extensive research, the specific tongue receptors that react to it remained elusive.
Liman and the research team thought they might have an answer. In recent years, they uncovered the protein responsible for detecting sour taste. That protein, called OTOP1, sits within cell membranes and forms a channel for hydrogen ions moving into the cell.
Hydrogen ions are the key component of acids, and as foodies everywhere know, the tongue senses acid as sour, such as the citric acid in lemon juice. Hydrogen ions from these acidic substances move into taste receptor cells through the OTOP1 channel.
Because ammonium chloride can affect the concentration of acid – that is, hydrogen ions – within a cell, the team wondered if it could somehow trigger OTOP1.
To answer this question, they introduced the Otop1 gene into lab-grown human cells so the cells produce the OTOP1 receptor protein. They then exposed the cells to acid or to ammonium chloride and measured the responses.
“We saw that ammonium chloride is a really strong activator of the OTOP1 channel,” Liman said. “It activates as well or better than acids.”
Ammonium chloride gives off small amounts of ammonia, which moves inside the cell and raises the pH, meaning fewer hydrogen ions.
“This pH difference drives a proton influx through the OTOP1 channel,” explained Ziyu Liang, a PhD student in Liman’s lab and first author on the study.
To confirm that their result was more than a laboratory artifact, they turned to a technique that measures electrical conductivity, simulating how nerves conduct a signal. Using taste bud cells from normal mice and from mice the lab previously genetically engineered to not produce OTOP1, they measured how well the taste cells generated electrical responses called action potentials when ammonium chloride is introduced.
Taste bud cells from wildtype mice showed a sharp increase in action potentials after ammonium chloride was added while taste bud cells from the mice lacking OTOP1 failed to respond to the salt. This confirmed their hypothesis that OTOP1 responds to the salt, generating an electrical signal in taste bud cells.
The same was true when another member of the research team, Courtney Wilson, recorded signals from the nerves that innervate the taste cells. She saw the nerves respond to addition of ammonium chloride in normal mice but not in mice lacking OTOP1.
Then the team went one step further and examined how mice react when given a choice to drink either plain water or water laced with ammonium chloride. For these experiments, they disabled the bitter cells that also contribute to the taste of ammonium chloride. Mice with a functional OTOP1 protein found the taste of ammonium chloride unappealing and did not drink the solution, while mice lacking the OTOP1 protein did not mind the alkaline salt, even at very high concentrations.
“This was really the clincher,” Liman said. “It shows that the OTOP1 channel is essential for the behavioral response to ammonium.”
But the scientists weren’t done. They wondered if other animals would also be sensitive to and use their OTOP1 channels to detect ammonium. They found that the OTOP1 channel in some species seems to be more sensitive to ammonium chloride than in other species. And human OTOP1 channels were also sensitive to ammonium chloride.
So, what is the advantage in tasting ammonium chloride and why is it evolutionarily so conserved?
Liman speculates that the ability to taste ammonium chloride might have evolved to help organisms avoid eating harmful biological substances that have high concentrations of ammonium.
“Ammonium is found in waste products – think of fertiliser – and is somewhat toxic,” she explained, “so it makes sense we evolved taste mechanisms to detect it. Chicken OTOP1 is much more sensitive to ammonium than zebra fish.” Liman speculates that these variations may reflect differences in the ecological niches of different animals. “Fish may simply not encounter much ammonium in the water, while chicken coops are filled with ammonium that needs to be avoided and not eaten.”
But she cautions that this is very early research and further study is needed to understand species differences in sensitivity to ammonium and what makes OTOP1 channels from some species sensitive and some less sensitive to ammonium.
Towards this end, they have made a start. “We identified a particular part of the OTOP1 channel – a specific amino acid – that’s necessary for it to respond to ammonium,” Liman said. “If we mutate this one residue, the channel is not nearly as sensitive to ammonium, but it still responds to acid.”
Moreover, because this one amino acid is conserved across different species, there must have been selective pressure to maintain it, she says. In other words, the OTOP1 channel’s ability to respond to ammonium must have been important to the animals’ survival.
In the future, the researchers plan to extend these studies to understand whether sensitivity to ammonium is conserved among other members of the OTOP proton family, which are expressed in other parts of the body, including in the digestive tract.
And who knows? Perhaps ammonium chloride will join the other five basic tastes to bring the official count to six.
Scientists have uncovered why night shift work is associated with changes in appetite in a new University of Bristol-led study. The study shows that circadian disruption can disrupt the brain’s regulation of appetite hormones. The findings, published in Communications Biology, could help the millions of people that work through the night and struggle with weight gain.
Scientists from Bristol and the University of Occupational and Environmental Health in Japan, sought to understand how ‘circadian misalignment’ – a phenomenon commonly associated with ‘jet-lag’ whereby the body’s biological clock is disrupted – affects the hormones responsible for regulating appetite.
Prevalent in night shift workers, in this new study, the international team reveal how circadian misalignment can profoundly alter the brain’s regulation of hormones controlling hunger to the detriment of metabolic health.
The team focused on glucocorticoid hormones in the adrenal gland which regulate many physiological functions including metabolism and appetite. Glucocorticoids are known to directly regulate a group of brain peptides controlling appetitive behaviour, with some increasing appetite (orexigenic) and some decreasing appetite (anorexigenic).
In an experiment using animal models, comprising a control group and a out-of-phase ‘jet-lagged’ group, the team found misalignment between light and dark cues led the out-of-phase group’s orexigenic hypothalamic neuropeptides (NPY) to become dysregulated, driving an increased desire to eat significantly more during the inactive phase of the day.
Strikingly, the team discovered that rats in the control group ate 88.4% of their daily intake during their active phase, and only 11.6% during their inactive phase. In contrast, the ‘jet-lagged’ group consumed 53.8% of their daily calories during their inactive phase (without an increase in activity during this time). This equated to nearly five-times more (460% more) than what the control group consumed during the inactive phase. These results show that it is timing of consumption that has been affected.
This new discovery revealed how completely, and significantly, disordered the neuropeptides become when daily glucocorticoid levels are out of synch with light and dark cues. However, the authors suggest the neuropeptides identified in this study may be promising targets for pharmacological treatments for eating disorders and obesity.
Research Fellow Dr Becky Conway-Campbell, the study’s senior author, said: “For people working throughout the night, a reversed body clock can play havoc with their health.
“For those who are working night shifts long-term, we recommend they try to maintain daylight exposure, cardiovascular exercise and mealtimes at regulated hours. However, internal brain messages to drive increased appetite are difficult to override with ‘discipline’ or ‘routine’ so we are currently designing studies to assess rescue strategies and pharmacological intervention drugs. We hope our findings also provide new insight into how chronic stress and sleep disruption leads to caloric overconsumption.”
Professor Stafford Lightman, co-senior author on the study, added: “The adrenal hormone corticosterone, which is normally secreted in a circadian manner, is a major factor in the daily control of brain peptides that regulate appetite. Furthermore when we disturb the normal relationship of corticosterone with the day to night light cycle it results in abnormal gene regulation and appetite during the period of time that the animals normally sleep.
“Our study shows that when we disturb our normal bodily rhythms this in turn disrupts normal appetite regulation in a way that is at least in part a result of desynchrony between adrenal steroid hormone production and the timing of the light and dark cycle.”
Dr Benjamin Flynn, one of the study’s co-authors who conducted the study while at Bristol but is now based at the University of Bath, added: “This is further evidence of how phase shift ‘jet-lag’ affects feeding behaviours and neuronal gene expression – data important for shift work co-morbidity research.”
A new paper in the journal Function finds that a widely prescribed drug for treating hypertension, amlodipine, is not dangerous for patients, despite recent concerns from researchers and clinicians that there may be risks associated with taking amlodipine.
Approximately one in five adults worldwide have the disease, which is responsible for 7.6 million deaths per year. If untreated, hypertension significantly increases the risk of premature death through heart attack, stroke, or kidney disease.
One widely prescribed drug for treating hypertension is amlodipine, now taken regularly in pill form by over 70 million Americans. Amlodipine inhibits an L-type calcium channel that is found on blood vessels. When the calcium channel opens, calcium enters the muscle and causes it to constrict, increasing blood pressure. Amlodipine prevents calcium from coming in, leading to vessel relaxation and a decrease in blood pressure.
Recently some researchers have questioned the benefit of amlodipine for treating hypertension. Studies suggested that amlodipine may activate a different type of calcium channel, resulting in changes to blood vessels and an increase in heart failure in patients. Removing amlodipine as a prescribed anti-hypertensive medication carries significant health implications, since hypertension is such a common health condition.
A new study by research teams from National Institutes of Health and Glasgow University finds that taking amlodipine is unlikely to result in an increase in heart failure in patients. The researchers found that amlodipine appears to have unique chemical properties that caused the drug to mimic the calcium channel activation, without in fact opening the channels as clinicians worried. When the study’s authors controlled for these chemical properties, they found that amlodipine did not activate calcium channels. A meta-analysis combining clinical trials and a prospective real-world analysis both showed that amlodipine was not associated with increased heart failure or other cardiovascular problems.
“Removal of amlodipine as a front-line therapy would most likely increase deaths from hypertension dramatically,” said Anant Parekh, one of the study’s authors. “The study recommends that amlodipine remain a first-line treatment for high blood pressure.”
A study in Frontiers in Immunology has demonstrated that, in animal models, a protein antigen from a childhood vaccine can be delivered into the cells of a malignant tumour to refocus the body’s immune system against the cancer, effectively halting it and preventing its recurrence.
Instead of using vaccines tailored with tumour-specific antigens to prime the immune system to attack a particular cancer, this method makes use of the immune system’s encounter with common vaccines. The bacteria-based intracellular delivering (ID) system uses a non-toxic form of Salmonella that releases a drug, in this case a vaccine antigen, after it’s inside a solid-tumour cancer cell.
“As an off-the-shelf immunotherapy, this bacterial system has the potential to be effective in a broad range of cancer patients,” writes senior author Neil Forbes, professor of chemical engineering, in the recently published article.
The research, carried out in Forbes’s lab, offers promise toward tackling difficult-to-treat cancers, including liver, metastatic breast and pancreatic tumours.
“The idea is that everybody is vaccinated with a whole bunch of things, and if you could take that immunisation and target it towards a cancer, you could use it to eliminate the cancer,” Forbes explains. “But cancers obviously aren’t going to display viral molecules on their surface. So the question was, could we take a molecule inside the cancer cell using Salmonella and then have the immune system attack that cancer cell as if it was an invading virus?”
To test their theory that this immune treatment could work, Forbes and team genetically engineered ID Salmonella to deliver ovalbumin (chicken egg protein) into the pancreatic tumour cells of mice that had been immunised with the ovalbumin ‘vaccine’. The researchers showed that the ovalbumin disperses throughout the cytoplasm of cells in both culture and tumours.
The ovalbumin then triggered an antigen-specific T-cell response in the cytoplasm that attacked the cancer cells. The therapy cleared 43% of established pancreatic tumours, increased survival and prevented tumour re-implantation, the paper states.
“We had complete cure in three out of seven of the pancreatic mice models,” Forbes says. “We’re really excited about that; it dramatically extended survival.”
The team then attempted to re-introduce pancreatic tumours in the immunised mice. The results were exceedingly positive. “None of the tumours grew, meaning that the mice had developed an immunity, not just to the ovalbumin but to the cancer itself,” Forbes says. “The immune system has learned that the tumour is an immunogenic. I’m doing further work to figure out how that’s actually happening.”
In preliminary research, the team previously showed that injecting the modified Salmonella into the bloodstream effectively treated liver tumours in mice. They advanced their findings with the current research on pancreatic tumours.
Before clinical trials can begin, the researchers will repeat the experiments on other animals and refine the ID Salmonella strain to ensure its safety for use in humans. Liver cancer would be the first target, followed by pancreatic cancer.
In photoacoustic imaging, laser light is pulsed through the skin into tissues, which release ultrasound signals with which the internal structure can be imaged. This works well for people with light skin but has trouble getting clear pictures from patients with darker skin. A Johns Hopkins University-led team found a way to deliver clear pictures of internal anatomy, regardless of skin tone. Their technique is described in the journal Photoacoustics.
In experiments the new imaging technique produced significantly sharper images for all people – and excelled with darker skin tones. It produced much clearer images of arteries running through the forearms of all participants, compared to standard imaging methods where it was nearly impossible to distinguish the arteries in darker-skinned individuals.
“When you’re imaging through skin with light, it’s kind of like the elephant in the room that there are important biases and challenges for people with darker skin compared to those with lighter skin tones,” said co-senior author Muyinatu “Bisi” Bell, Associate Professor at Johns Hopkins. “Our work demonstrates that equitable imaging technology is possible.”
“We show not only there is a problem with current methods but, more importantly, what we can do to reduce this bias,” Bell said.
The findings advance a 2020 report that showed pulse oximeters, which measure oxygen rates in the blood, have higher error rates in Black patients.
“There were patients with darker skin tones who were basically being sent home to die because the sensor wasn’t calibrated toward their skin tone,” Bell said.
Bell’s team created a new algorithm to process information from photoacoustic imaging, a method that combines ultrasound and light waves to render medical images. Body tissue absorbing this light expands, producing subtle sound waves that ultrasound devices turn into images of blood vessels, tumours, and other internal structures. But in people with darker skin tones, melanin absorbs more of this light, which yields cluttered or noisy signals for ultrasound machines.
The team was able to filter the unwanted signals from images of darker skin, in the way a camera filter sharpens a blurry picture, to provide more accurate details about the location and presence of internal biological structures.
The researchers are now working to apply the new findings to breast cancer imaging, since blood vessels can accumulate in and around tumours. Bell believes the work will improve surgical navigation as well as medical diagnostics.
“We’re aiming to mitigate, and ideally eliminate, bias in imaging technologies by considering a wider diversity of people, whether it’s skin tones, breast densities, body mass indexes – these are currently outliers for standard imaging techniques,” Bell said. “Our goal is to maximise the capabilities of our imaging systems for a wider range of our patient population.”
For National Health Insurance to succeed in South Africa, a meaningful collaboration needs to take place between private and public health care so as to speed up the implementation of the initiative and overcome major obstacles.
This was the opinion of the five panellists who on the first day of the Hospital Association of South Africa conference in Cape Town spoke of how best the NHI could be rolled out by calling on private health care for assistance.
“’It’s fundamental to the economic growth that we so desperately need in South Africa, and a productive nation needs access to health care. So we do need to address the inequalities, we need to address the gap and do not need to preserve the status quo,” said Professor Roseanne Harris, of Discovery Health.
But a concern she raised is the risk of the introduction of a single funding model reliant on taxes, and the introduction of a monopoly market.
“And one of the implications of the bill is centralisation (of health care). There is a need for planning to ensure that it won’t have an unintended consequence of impacting service delivery and impacting on the rights of the healthcare personnel,” she added.
Harris said that both the private sector and public sector needed to go through a consultative process and that sustainable critical milestones needed to be put in place to hold the process to account.
Another panellist at the event Dr Simon Strachan of the South African Private Practitioners Forum (SAPPF), pointed out that the COVID pandemic showed how public and private health care could collaborate successfully. Here service agreements between the two entities were met and were focused solely on fighting the pandemic.
“So to create the way forward, what we need to be able to do is to have a very clear understanding of what it is we’re trying to achieve, that there is robust trust, and that there is a groundwork for sustainable collaboration,” he explained.
An urgent need for this collaboration he said was the recent introduction of Section 33 of the NHI bill, which in its present form would have health care professionals working for the state at a fee the state sets, with benefits not included.
A second issue he said was the need for a successful funding model that will be acceptable to all South Africans.
Economist Nicola Theron of FTI consulting told the audience that structures already in place and used in the private sector could make for a smoother transition for the NHI. In particular when it comes to issues like the pricing of medicines.
“We are now at a point with the current NHI that there are talks about the lowest possible price at a reasonable return for healthcare providers. There is no indication of what return means,” she said.
“But what we have is an existing system of pricing which has been developed over time, and which should form the basis of pricing going forward,” said Theron.
By not getting the pricing right could lead to investment leaving South Africa, she warned. She suggested in turn that it would be a better model to have multiple buyers that will stimulate competition.
Dr Ali Hamdulay, CEO, Metropolitan Health, said that a way forward would be to implement the suggestions that came out of the Health Marketing Inquiry that took a hard look at both the public and private health care systems, outlining the problems with both.
“So effectively by addressing the recommendations of the Health Market Inquiry you’re actually foster an environment of culture and direction to work towards universal health care,” said Hamdulay.
Barry Childs, of Insight Actuaries, said that while fundraising mechanisms in the public sector needed to be improved, the introduction of the NHI offers a great opportunity to reform the healthcare system.
“As much as we talk about the need for reform of the private sector side, there’s been no meaningful reform of the public sector for many decades. And the NHI is a wonderful opportunity for them to introduce some better, more responsive financing mechanisms.” he said.
But for NHI to ultimately provide the services it promises, Childs said South Africa’s economy needed to improve, and more jobs to be created.
Fathers who have been on parental leave have a significantly reduced risk of being hospitalised due to alcohol consumption. This is shown by a study published in Addiction from researchers at the Department of Public Health Sciences, Stockholm University.
The aim of the study was to assess whether fathers’ parental leave influences alcohol-related morbidity and mortality. In order to try to find out if that is the case, the researchers have investigated the effects of parental leave policy that was implemented in Sweden in 1995. The policy encouraged fathers to use parental leave by reserving 30 days of leave for their use alone and resulted in the proportion of fathers using parental leave increasing from 43% to 75%.
“Our findings were pretty remarkable considering the severity of the studied outcome. Although alcohol-related hospitalizations were rather uncommon, we found that after the policy was implemented there was a 34% decrease in these hospitalizations among fathers in the two years after birth, as well as smaller decreases up to 8 and 18 years after birth,” says Helena Honkaniemi, researcher at the Department of Public Health Sciences, Stockholm University.
“Most changes were found among hospitalisations for alcohol intoxication and alcohol-related mental and behavioural disorders. Additional analyses evaluating actual changes in parental leave use from before to after the policy suggest that these health consequences could be explained by the increase in fathers’ parental leave use, rather than other underlying trends,” says Helena Honkaniemi.
However, no changes were found for alcohol-related mortality.
Co-author Associate Professor Sol Juárez believes that the results of the study could be useful for policymakers.
“Policymakers should consider that fathers’ parental leave not only promotes more gender-equal participation in childcare, but can also reduce alcohol-related harms,” Juárez says.
The study “Alcohol-related morbidity and mortality by fathers’ parental leave: A quasi-experimental study in Sweden” draws on Swedish register data of all fathers of singleton children born from January 1992 to December 1997, three years before and after the policy was implemented.
In soccer, goalkeepers have a unique role: they must be ready to make split-second decisions based on incomplete information to stop their opponents from scoring a goal. Now researchers reporting in Current Biology on have some of the first solid scientific evidence that goalkeepers show fundamental differences in the way they perceive the world and process multi-sensory information.
“Unlike other football players, goalkeepers are required to make thousands of very fast decisions based on limited or incomplete sensory information,” says Michael Quinn, the study’s first author at Dublin City University who is also a retired professional goalkeeper and son of former Irish international Niall Quinn. “This led us to predict that goalkeepers would possess an enhanced capacity to combine information from the different senses, and this hypothesis was confirmed by our results.”
“While many football players and fans worldwide will be familiar with the idea that goalkeepers are just ‘different’ from the rest of us, this study may actually be the first time that we have proven scientific evidence to back up this claim,” says David McGovern, the study’s lead investigator also from Dublin City University.
Based on his own history as a professional goalkeeper, Quinn already had a feeling that goalkeepers experience the world in a distinctive way. In his final year working on a psychology degree, he wanted to put this notion to the test.
To do it, the researchers enlisted 60 volunteers, including professional goalkeepers, professional outfield players, and age-matched controls who don’t play soccer. They decided to look for differences among the three groups in what’s known as temporal binding windows – that is, the time window within which signals from the different senses are likely to be perceptually fused or integrated.
In each trial, participants were presented with one or two images (visual stimuli) on a screen. Those images could be presented along with one, two, or no beeps (auditory stimuli). Those stimuli were presented with different amounts of time in between.
In these tests, trials with one flash and two beeps generally led to the mistaken perception of two flashes, providing evidence that the auditory and visual stimuli have been integrated. This mistaken perception declines as the amount of time between stimuli increases, allowing researchers to measure the width of a person’s temporal binding window, with a narrower temporal binding window indicating more efficient multisensory processing.
their tests showed that goalkeepers had marked differences in their multisensory processing ability. More specifically, goalkeepers had a narrower temporal binding window relative to outfielders and non-soccer players, indicating a more precise and speedy estimation of the timing of audiovisual cues.
The test results revealed another difference too. Goalkeepers didn’t show as much interaction between the visual and auditory information. The finding suggests that the goalies had a greater tendency to separate sensory signals. In other words, they integrated the flashes and beeps to a lesser degree.
“We propose that these differences stem from the idiosyncratic nature of the goalkeeping position that puts a premium on the ability of goalkeepers to make quick decisions, often based on partial or incomplete sensory information,” the researchers write.
They speculate that the tendency to segregate sensory information stems from goalies need to make quick decisions based on visual and auditory information coming in at different times. For example, goalkeepers watch how a ball is moving in the air and also make use of the sound of the ball being kicked. But the relationship between those cues in time will depend on where the outfielder making the shot is on the field. After repeated exposure to those scenarios, goalkeepers may start to process sensory cues separately rather than combining them.
The researchers say they hope to explore other questions in future studies, including whether players with other highly specialised positions, such as strikers and centre-backs, may also show perceptual differences. They’re also curious to know which comes first. “Could the narrower temporal binding window observed in goalkeepers stem from the rigorous training regimens that goalkeepers engage in from an early age?” McGovern asks. “Or could it be that these differences in multisensory processing reflect an inherent, natural ability that draws young players to the goalkeeping position? Further research that tracks the developmental trajectory of aspiring goalkeepers will be required to tease between these possibilities.”
In cases where standard therapies fail, an in-development drug called XEN1101 reduces seizure frequency by more than 50% in some patients and in some cases eliminates them, according to a new study published in JAMA Neurology. Unlike several treatments that must be started at low doses and slowly ramped up, the new drug can safety be taken at its most effective dose from the start, the authors say.
Focal seizures, the most common type seen in epilepsy, occur when nerve cells in a particular brain region send out a sudden, excessive burst of electrical signals. Along with seizures, this uncontrolled activity can lead to abnormal behaviour, periods of lost awareness, and mood changes. While many available therapies control or reduce seizures, they fail to stop seizures in about one-third of patients and may cause harsh side effects, experts say.
Led by researchers at NYU Grossman School of Medicine, a new clinical trial found that patients who added XEN1101 to their current antiseizure treatments saw a 33% to 53% drop in monthly seizures, depending on their dose. By contrast, those given a placebo had on average 18% fewer seizures during the treatment phase of the trial, which lasted eight weeks. Most patients then volunteered to extend the trial, with about 18% of those treated with the new drug remaining entirely seizure free after six months, and about 11% having no seizures after a year or longer.
“Our findings show that XEN1101 may offer a swift, safe, and effective way to treat focal epilepsy,” said study lead author, neurologist Jacqueline French, MD. “These promising results offer hope for those who have struggled for decades to get their symptoms under control.”
French, a professor in the Department of Neurology at NYU Langone Health, notes that XEN1101 was well tolerated by the study participants, who reported side effects similar to other antiseizure treatments, including dizziness, nausea, and fatigue, and the majority felt well enough to continue the regimen. Another benefit of the drug, she adds, is that it takes more than a week to break down, so levels in the brain remain consistent over time. This steadiness allows the treatment to be started at full strength and helps to avoid dramatic spikes that worsen side effects, and dips that allow seizures to return. This lengthy breakdown time also allows for a “grace period” if a dose is accidently skipped or taken late.
XEN1101 is part of a class of chemicals called potassium-channel openers, which avert seizures by boosting the flow of potassium out of nerves, stopping them from firing. French notes that while other drugs of this kind have been explored for epilepsy patients in the past, such treatments were taken out of use because the compounds were later found to gradually build up in the skin and eyes, prompting safety concerns, the researchers say.
Meanwhile, XEN1101 combines the effectiveness of potassium-channel openers with the safety of more traditional drugs, says French, who is also a member of NYU Langone’s Comprehensive Epilepsy Center.
For the study, which included 285 men and women with epilepsy and ran from January 2019 to September 2021, the research team recruited adults with epilepsy who had already tried and stopped taking an average of six drugs that failed to treat their focal seizures. Patients in the trial had to have experienced at least four episodes a month despite ongoing treatment to qualify. The patients were randomly provided either a daily oral capsule of XEN1101 (in 10mg, 20mg, or 25mg doses) or placebo.
Among the results, the trial revealed no signs of dangerous side effects such as heart problems, allergic reactions, or concerning skin discolourations. However, French says that the research team plans to expand the number of patients exposed to the drug and monitor for potential issues that could arise in the long term, or include specific groups of people, such as pregnant women. In addition, the team also intends to explore XEN1101 for other types of seizures, including those that broadly affect the brain at the same time (generalised seizures).
“Our study highlights the importance of finding as many therapeutic options as possible for those who suffer from seizures,” says French. “Since everyone responds differently, treating epilepsy cannot be a one-size-fits-all approach.”
