Posts Tagged drug-resistant epilepsy

[Review] Ketogenic Diet and Epilepsy – Full Text PDF

Abstract

Currently available pharmacological treatment of epilepsy has limited effectiveness.
In epileptic patients, pharmacological treatment with available anticonvulsants leads to seizure control in <70% of cases. Surgical intervention can lead to control in a selected subset of patients, but still leaves a significant number of patients with uncontrolled seizures. Therefore, in drug-resistant epilepsy, the ketogenic diet proves to be useful. The purpose of this review was to provide a comprehensive overview of what was published about the benefits of ketogenic diet treatment in patients with epilepsy. Clinical data on the benefits of ketogenic diet treatment in terms of clinical symptoms and adverse reactions in patients with epilepsy have been reviewed. Variables that could have influenced the interpretation of the data were also discussed (e.g., gut microbiota). The data in this review contributes to a better understanding of the potential benefits of a ketogenic diet in the treatment of epilepsy and informs scientists, clinicians, and patients—as well as their families and caregivers—about the possibilities of such treatment. Since 1990, the number of publications on attempts to treat drug-resistant epilepsy with a ketogenic diet has grown so rapidly that it has become a challenge to see the overall trajectory and major milestones achieved in this field. In this review, we hope to provide the latest data from randomized clinical trials, practice guidelines, and new research areas over the past 2 years.

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[WEB SITE] A Look at Epilepsy – Electrical Outbursts in the Brain

Illustration of a man holding a child; a doctor and patient; and a brain.When you hear the word epilepsy, you might think of intense seizures with muscle spasms and loss of consciousness. But most epilepsy seizures are surprisingly subtle and may be hard to recognize. These little spells can be an early warning sign of epilepsy, a brain disorder that strikes an estimated 1 in 26 Americans at some point in their lives. The sooner epilepsy is recognized, the sooner it can be treated and seizures prevented.

Most people know surprisingly little about epilepsy, even though it’s the nation’s 4th most common neurological disorder, after migraine, stroke, and Alzheimer’s disease. Epilepsy is marked by repeated, unpredictable seizures that may last for seconds or minutes. Seizures arise from abnormal bursts of electrical activity in the brain that trigger jerky movements, strange emotions or sensations, falls, or passing out.

“Epilepsy can strike people of all ages, from the moment of birth—even in the delivery room—up to older ages,” says Dr. Jeffrey Noebels, an epilepsy expert at Baylor College of Medicine. The condition is most likely to first arise in children and in adults over age 60. “Most types of epilepsy last a lifetime, but some are self-limited, meaning they can go away on their own,” Noebels adds.

The causes of epilepsy are varied. “Defects in genes are probably responsible for the largest fraction of epilepsy cases,” Noebels says. Scientists so far have linked more than 150 genes to epilepsy. “Other types of epilepsy can be acquired through trauma (such as head injury or stroke), infections, brain tumors, or other factors.”

Anything that disrupts the normal pattern of brain activity—from illness to brain damage to faulty brain development—can lead to seizures. But for up to half of people with epilepsy, the underlying cause is simply not known.

Types of seizures can also vary widely, which is why epilepsy is sometimes called a “spectrum disorder.” In some people, seizures may appear only occasionally. At the other end of the spectrum, a person may have hundreds of seizures a day. The seizures can be severe, with convulsions, loss of consciousness, or even sudden death in rare cases. Or seizures may be barely noticeable.

Such subtle seizures—sometimes called partial or focal seizures—can cause feelings of déjà vu (feeling that something has happened before); hallucinations (seeing, smelling, or hearing things that aren’t there); or other seemingly mild symptoms. During some seizures, a person may stop what they’re doing and stare off into space for a few seconds without being aware of it.

“These little spells or seizures can sometimes occur for years before they’re recognized as a problem and diagnosed as epilepsy,” says Dr. Jacqueline French, who specializes in epilepsy treatment at the New York University Langone Medical Center. “They can be little spells of confusion, little spells of panic, or feeling like the world doesn’t look real to you.”

The symptoms of these small seizures generally depend on which brain regions are affected. Over time, these types of seizures can give rise to more severe seizures that affect the whole brain. That’s why it’s important to get diagnosed and begin epilepsy treatment as soon as possible. “If you notice a repeating pattern of unusual behaviors or strange sensations that last anywhere from a few seconds to a few minutes, be sure to mention it to your doctor or pediatrician,” French says.

Over the past few decades, NIH-funded scientists have been working to develop better approaches for diagnosing, treating, and understanding epilepsy. The condition can now be diagnosed through imaging tools like MRI or CT scans, by testing blood for defective genes, or by measuring the brain’s electrical activity. Seizures can often be controlled with medications, special diets, surgery, or implanted devices. But there’s still a need for improved care.

“Traditional medications for treating epilepsy are effective but problematic,” says Dr. Ivan Soltesz, who studies epilepsy at Stanford University. “About 1 in 3 patients has drug-resistant epilepsy, meaning that available drugs can’t control the seizures. In these cases, surgical removal of brain tissue may be the best option.” When the drugs do work, he explains, they can also cause numerous side effects, including fatigue, abnormal liver function, and thinking problems.

One issue with today’s medicines is they aren’t targeted to the malfunctioning brain cells. Rather, they tend to affect the whole brain. “The drugs are also not specific in terms of the timing of treatment,” Soltesz says. “The medications are always in the body, even when the seizures are not occurring.”

He and other researchers are working to create highly targeted epilepsy therapies that are delivered only to malfunctioning brain regions and only when needed to block a seizure. So far, they’ve developed an experimental approach that can stop epilepsy-like seizures as they begin to occur in a mouse. The scientists hope to eventually translate those findings for use in people who have epilepsy.

In another line of NIH-funded research, a team of scientists is studying a deadly and poorly understood condition called SUDEP (for sudden unexpected death in epilepsy). “Most people with epilepsy live long and happy lives. But SUDEP is the most common cause of the shorter lifespan that can occur with epilepsy,” says Noebels. “It’s been a real mystery. We haven’t known who’s at greatest risk for this premature death. It can happen to different people who have epilepsy, from all walks of life.”

Noebels and his colleagues have identified several mouse genes that seem related to both sudden-death seizures and heart rhythm problems. The researchers are now searching for similar human genes that may help predict who’s most at risk for SUDEP. “We believe that SUDEP doesn’t have to happen—that we can learn about it, predict it, and eventually find better ways to prevent it in every patient,” Noebels says.

You can take steps to reduce some risk factors for epilepsy. Prevent head injuries by wearing seatbelts and bicycle helmets, and make sure kids are properly secured in car seats. Get proper treatment for disorders that can affect the brain as you age, such as cardiovascular disease or high blood pressure. And during pregnancy, good prenatal care can help prevent brain problems in the developing fetus that could lead to epilepsy and other problems later in life.

“We’ve made exciting advances to date in our understanding of epilepsy, its prevention, and treatment,” says French. “But there’s still much we have to learn, and much we’re actively working to improve.”

References:
The evolution of epilepsy surgery between 1991 and 2011 in nine major epilepsy centers across the United States, Germany, and Australia. Jehi L, Friedman D, Carlson C, Cascino G, et al. Epilepsia. 2015 Oct;56(10):1526-33. doi: 10.1111/epi.13116. Epub 2015 Aug 7. PMID: 26250432.

On-demand optogenetic control of spontaneous seizures in temporal lobe epilepsy. Krook-Magnuson E, Armstrong C, Oijala M, Soltesz I. Nat Commun. 2013;4:1376. doi: 10.1038/ncomms2376. PMID: 23340416.

Sudden unexpected death in epilepsy: Identifying risk and preventing mortality. Lhatoo S, Noebels J, Whittemore V; NINDS Center for SUDEP Research. Epilepsia. 2015 Nov;56(11):1700-6. doi: 10.1111/epi.13134. Epub 2015 Oct 23. PMID: 26494436.

NIH News in Health, November 2015

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[WEB SITE] Brain Imaging: Advance Aims for Epilepsy’s Hidden Hot Spots

 

GluCEST signal

GluCEST imaging of the brain of a person with drug-resistant epilepsy, showing the hippocampi (highlighted) with signal for high glutamate (red). Credit: Reddy Lab, University of Pennsylvania

For many of the 65 million people around the world with epilepsy, modern medications are able to keep the seizures under control. When medications fail, as they do in about one-third of people with epilepsy, surgery to remove affected brain tissue without compromising function is a drastic step, but offers a potential cure. Unfortunately, not all drug-resistant patients are good candidates for such surgery for a simple reason: their brains appear normal on traditional MRI scans, making it impossible to locate precisely the source(s) of the seizures.

Now, in a small study published in Science Translational Medicine [1], NIH-funded researchers report progress towards helping such people. Using a new MRI method, called GluCEST, that detects concentrations of the nerve-signaling chemical glutamate in brain tissue [2], researchers successfully pinpointed seizure-causing areas of the brain in four of four volunteers with drug-resistant epilepsy and normal traditional MRI scans. While the findings are preliminary and must be confirmed by larger studies, researchers are hopeful that GluCEST, which takes about 30 minutes, may open the door to new ways of treating this type of epilepsy.

To understand why glutamate might be a useful marker for epilepsy, it’s useful to note that this molecule serves as the brain’s main excitatory nerve signal. In healthy people, when neurons fire off a stimulatory signal, they release short bursts of glutamate to relay the signal onward. Support cells then rapidly clear the glutamate. But in some people with epilepsy, glutamate seems to build up outside of brain cells, triggering continuous overstimulation and potential seizures.

The challenge has been finding these suspected glutamate hot spots, to see if they correlate with seizures. In the study, led by Ravinder Reddy and Kathryn Davis of the University of Pennsylvania, the researchers turned to GluCEST to image hot spots specifically in people with drug-resistant epilepsy localized to the brain’s temporal lobe. This includes the left and right hippocampi, which are parts of the brain that help to consolidate short-term thought into long-term memory, play a role in spatial navigation, and, importantly, are a frequent site of seizures.

While conventional MRI works by using strong magnets and radio waves to study water molecules directly in living tissue, GluCEST takes advantage of special chemical properties of glutamate that influence water to visualize and quantify it at high resolution. Reddy and Davis found in the study that their GluCEST images could detect an increase in glutamate in the hippocampi. In every case, glutamate levels were elevated on the side of the brain in which the participant’s seizures were found to originate, based on brain wave recordings during a seizure. In contrast to the people with epilepsy, GluCEST scans of 11 healthy volunteers didn’t show any consistent differences in glutamate levels on one side of the brain versus the other.

Although the new study represents a very small number of patients, it suggests that GluCEST might stand to improve patient care and quality of life in people with epilepsy who now have very limited treatment options. The researchers say they’ve reported their early findings in hopes that they can be validated in more people with epilepsy by researchers at other medical centers. The GluCEST technique requires powerful 7 Tesla MRI scanners, which are already in regular use for research purposes at some medical centers around the country, and special software, which the researchers intend to make freely available.

As for the UPenn team, they’re working to expand and improve upon the GluCEST method to produce images and data in three dimensions and over a wider swath of the brain. If they are successful, this new tool could yield important insights into epilepsy and a variety of other neurological disorders in which glutamate is thought to play an important role, including schizophrenia, Alzheimer’s disease, Parkinson’s disease, and maybe even autism.

References:

[1] Glutamate imaging (GluCEST) lateralizes epileptic foci in nonlesional temporal lobe epilepsy. Davis KA, Nanga RP, Das S, Chen SH, Hadar PN, Pollard JR, Lucas TH, Shinohara RT, Litt B, Hariharan H, Elliott MA, Detre JA, Reddy R. Sci Transl Med. 2015 Oct 14;7(309):309ra161.

[2] Magnetic resonance imaging of glutamate. Cai K, Haris M, Singh A, Kogan F, Greenberg JH, Hariharan H, Detre JA, Reddy R. Nat Med. 2012 Jan 22;18(2):302-306.

Links:

Epilepsy Information Page (National Institute of Neurological Disorders and Stroke/NIH)

Magnetic Resonance Imaging (National Institute of Biomedical Imaging and Bioengineering/NIH)

Center For Magnetic Resonance And Optical Imaging (Perelman School of Medicine, University of Pennsylvania, Philadelphia)

Kathryn Davis (Perelman School of Medicine)

Ravinder Reddy (Perelman School of Medicine)

NIH Support: National Institute of Biomedical Imaging and Bioengineering; National Institute of Neurological Disorders and Stroke

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[WEB SITE] Studies reveal how high-fat low-carb diets affect brain activity and highlight an approach for treating epilepsy with metabolic drugs.

One percent of the world’s population suffer from epilepsy, and a third of sufferers cannot be treated with antiepileptic drugs. Diet control has been used to treat patients suffering from drug-resistant epilepsy since the 1920s, but how metabolic processes affect epilepsy has not been fully understood. Now researchers at Okayama University and Kawasaki Medical School have identified the metabolic pathways altered by diet treatments, the enzymes that can control them and potential metabolic drugs that may be effective for treating types of epilepsy that are resistant to other drugs.

‘Ketogenic’ diets used to treat epilepsy are high in fat and low in carbohydrate. Due to the scarcity of glucose available as a result, the brain metabolises ketones, which uses a different metabolic pathway.

Tsuyoshi Inoue and his team examined neural cells in an artificial cerebrospinal fluid solution  switched from glucose to ketones. When glucose was switched to ketones the cells became hyperpolarized – a change in the cell’s membrane potential that makes neurons less prone to becoming excited and active.

The researchers further broke down the processes in the metabolism of glucose and identified a crucial enzyme – lactate dehydrogenase (LDH). Blocking LDH mimicked the switch from glucose to ketones in vitro. Further in vivo tests on mice confirmed the effect.

By testing the drugs already in use they identified LDH inhibitory action in stiripentol, a drug used for a rare form of the epilepsy. By modifying its chemical structure, they found an alternative LDH inhibitor with a similar structure that was more effective for in vivo tests on mice. They conclude, “Our study opens a realistic path to develop compounds for drug-resistant epilepsy by targeting LDH enzymes with stiripentol derivatives.”

Background

Epilepsy

Epilepsy describes the neurological disorder that results in seizures that have no other known cause. The seizures result from excessive excitation in the cortical nerve in the brain and the length and severity of the seizures may vary.

The transmission of signals by neurons relies on the rapid rise and fall of the membrane potential, and is affected by cell polarization. When the cell membrane becomes hyperpolarized, a greater stimulus is required to produce an action potential. As a result hyperpolarization can prevent the excessive cortical activity that causes epileptic seizures.

Continue —> Health News – Studies reveal how high-fat low-carb diets affect brain activity and highlight an approach for treating epilepsy with metabolic drugs..

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