Medication to help children with life threatening seizures

Research has shown that an investigational medication can help treat children with potentially life threatening seizures.

In its first clinical application in pediatric patients, an investigational medication developed and manufactured at UC Davis has been found to effectively treat children with life-threatening and difficult-to-control epileptic seizures without side effects, according to a research report by scientists at UC Davis and Northwestern University.

The investigational formulation of allopregnanolone was manufactured by UC Davis Health System's Good Manufacturing Practice Laboratory. Two children were treated with the allopregnanolone formulation, one at UC Davis Children's Hospital, the other at the Ann & Robert Lurie Children's Hospital in Chicago. Both children were weaned from general anesthetics and other seizure treatments and their seizures resolved. In both instances the children are recovering.

The research is published online in Annals of Neurology, an official journal of the American Neurological Association and the Child Neurology Society.

Super-refractory status epilepticus is a condition diagnosed in patients with refractory status epilepticus being treated with infusions of general anesthetics when seizures continue for longer than 24 hours, despite anesthesia, or when seizures recur on reduction or withdrawal of the anesthesia. Super-refractory status epilepticus has high morbidity and mortality. There are no Food and Drug Administration (FDA)-approved treatments for the condition.

Allopregnanolone is a positive allosteric modulator of GABAA receptors in the brain. Research in animals has shown that allopregnanolone protects against seizures and can stop status epilepticus. Although the allopregnanolone used to manufacture the investigational treatment was produced by chemical synthesis according to procedures regulated by the FDA, it is synthesized normally in small quantities in the body from progesterone.

"Our laboratory studies have shown that allopregnanolone is effective in stopping status epilepticus that is refractory to treatment," said Michael Rogawski, professor in the UC Davis Department of Neurology and a co-author of the report.

In both of the clinical cases, the patients continued to have seizures despite weeks of intensive treatment with medications, including infusion of anesthetics. Emergency treatment with the investigational medication was approved by the FDA; the two patients received the medication over a five-day period, during which time both were weaned from anesthetics and other seizure medications. Status epilepticus did not recur after treatment. There were no adverse drug effects, the researchers said.

Mortality rates in super-refractory status epilepticus can be as high as 50 percent, and those who survive experience high rates of subsequent neurological impairment. The authors note that progesterone and ganaxolone, a chemical analog of allopregnanolone, have been studied in clinical trials for epilepsy and have shown benefit. Researchers at UC Davis, led by Rogawski, currently are investigating the use of allopregnanolone as a treatment for traumatic brain injury.

"Neurosteroids, including allopregnanolone, are a promising treatment for epilepsy and refractory status epilepticus that may overcome resistance to benzodiazepines and barbiturates and facilitate the withdrawal of these agents by preventing rebound seizures, a key problem in treatment of super-refractory status epilepticus," Rogawski said.

Read more here

Diet changes to help tough-to-treat epilepsy

This article explains low-carb high-fat diets and how they help tough-to-treat epilepsy.

Diets high in fat and low in carbohydrates, such as the ketogenic or modified Atkins diet, may reduce seizures in adults with tough-to-treat epilepsy, according to a review of the research published in the October 29, 2014, online issue of Neurology®, the medical journal of the American Academy of Neurology.

Epilepsy is a nervous system disorder in which the nerve cells in the brain work abnormally, causing seizures. About 50 million people have epilepsy worldwide, according to the World Health Organization.

"We need new treatments for the 35 percent of people with epilepsy whose seizures are not stopped by medications," said study author Pavel Klein, M.B.,B. Chir., of the Mid-Atlantic Epilepsy and Sleep Center in Bethesda, Md., and a member of the American Academy of Neurology. "The ketogenic diet is often used in children, but little research has been done on how effective it is in adults."

The ketogenic and modified Atkins diets include items such as bacon, eggs, heavy cream, butter, leafy green vegetables and fish. The ketogenic diet consists of a ratio of fat to protein/carbohydrates of three or four to one by weight. The modified Atkins diet has a one-to-one fat to carbohydrate/protein ratio by weight.

Scientists reviewed five studies on the ketogenic diet with a total of 47 people included in the analysis and five studies on the modified Atkins diet with 85 people included.

Researchers found that across all studies, 32 percent of people treated with the ketogenic diet and 29 percent of those treated with the modified Atkins diet experienced a 50 percent or better reduction in their seizures. Nine percent in the ketogenic treatment group and 5 percent in the modified Atkins group had a greater than 90 percent reduction in seizures.

The positive results occurred quickly with both diets, within days to weeks. The effect persisted long-term, but, unlike in children, the results did not continue after participants stopped following the diet. Side effects of both diets were similar and not serious, with weight loss the most common side effect.

Fifty-one percent of the ketogenic diet group and 42 percent of the modified Atkins group stopped the diet before the study was completed.

"Unfortunately, long-term use of these diets is low because they are so limited and complicated. Most people eventually stop the diet because of the culinary and social restrictions," said Klein. "However, these studies show the diets are moderately to very effective as another option for people with epilepsy."

Read more here

Difficulties of treating epilepsy while pregnant

This article explains the difficulties of pregnant mothers with epilepsy treating the condition while pregnant.

A new study published in The Cochrane Library, highlights the difficult decisions women with epilepsy have to face when they become pregnant. Taking certain drugs used to control epilepsy during pregnancy may be linked to developmental problems in children. The authors of the study say evidence on the safety of anti-epileptic drugs is limited and that more research is needed to ensure women and their doctors make the most informed choices.

Studies on children born to women with epilepsy increasingly suggest that some anti-epileptic medications affect development in the womb. However, most women with epilepsy rely on these medications to control seizures during pregnancy.

To assess the safety of taking anti-epileptics during pregnancy, the researchers drew together evidence from 28 studies. They measured children's global cognitive ability using either intelligence quotient (IQ), for school aged children, or developmental quotient (DQ), for younger children, to provide a summary of development across a range of cognitive skills. The researchers looked at DQ and IQ scores in the children of three groups of women: those with epilepsy who took anti-epilepsy medication, those with epilepsy who did not take epilepsy medication and those without epilepsy.

The children of women who took one drug, sodium valproate, had lower DQs and IQs than the children of women in the other groups. Higher doses of this drug were linked to larger effects on IQ or DQ. However another drug, carbamazepine, did not appear to have any significant effects on DQ or IQ. Younger children born to women who took carbamazepine did have lower DQs but the researchers concluded that this effect was due to random variation between the results of studies.

"This review highlights the need for preconception counselling in women with epilepsy," said Rebecca Bromley, lead researcher of the study based at the Institute of Human Development at the University of Manchester in Manchester, UK. "Counselling should take account of the fact that many pregnancies are unplanned and cover the risks of anti-epileptic drugs, whilst considering how well they control epileptic seizures."

"The review also highlights the need to counsel patients about risks and benefits of treatment alternatives at the time of epilepsy diagnosis and treatment initiation, so that informed decisions can be made. This is particularly important for women with idiopathic generalised epilepsy for whom valproate is the most effective treatment. Some women may choose to initiate valproate as they have no plans to conceive, while others may choose to avoid valproate and try a less effective drug accepting the associated risk of further seizures." Tony Marson, Coordinating Editor Cochrane Epilepsy Group, University of Liverpool.

Some studies made comparisons between different drugs. The children of women who took valproate had lower IQs than children exposed to carbamazepine or lamotrigine in the womb. They also had lower DQs and IQs than children born to women who took phenytoin. There were no differences between the IQs of children exposed to either carbamazepine, phenytoin or lamotrigine.

Only a few studies analysed the effects of newer anti-epileptic drugs like lamotrigine, levetiracetam and topiramate. "Data was not available for all anti-epileptic drugs that are in use today and data on newer anti-epileptic drugs was especially scarce," said Bromley. "This makes it difficult for women and their doctors to know which medications are safe to use during childbearing years. Future research needs to be carried out in a timelier manner to ensure that when prescribing decisions are being made the risks are already established. Women should however not stop or make alterations to their medication without first seeking medical advice."

Read more here

Fish Oil Might Ease Tough-to-Treat Epilepsy

Interesting potential adjunct with few risks. JR

Fish Oil Might Ease Tough-to-Treat Epilepsy: Study

People taking the low-dose omega-3 supplements had fewer monthly seizures, but more research is needed

By Robert Preidt

HealthDay Reporter

MONDAY, Sept. 8, 2014 (HealthDay News) -- Low doses of fish oil may help reduce the number of seizures experienced by people with a form of tough-to-treat epilepsy that no longer responds to drugs, a small new study suggests.

The research was led by Dr. Christopher DeGiorgio, of the University of California, Los Angeles, and included 24 people with epilepsy that could no longer be controlled using medications.

One expert not connected to the study said many people with epilepsy remain without adequate treatment.

"Although medications remain the primary treatment for newly diagnosed epilepsy, more than 35 percent of patients continue to haveseizures despite taking antiepileptic drugs," said Dr. David Friedman, director of the Comprehensive Epilepsy Center at Winthrop University Hospital in Mineola, N.Y.

Friedman said that in these cases, patients often resort to alternative treatments such as epilepsy surgeries, special diets or brain-stimulating devices. So the new study using a common nutrient is intriguing, he said.

In the study, the UCLA team gave the patients three separate treatments, each lasting 10 weeks and separated by a period of six weeks.

The treatments were: the "low-dose" intervention of three capsules offish oil (about 1,080 milligrams) a day plus three "dummy" capsules containing corn oil only; the "high-dose" involving six capsules of fish oil a day, and a placebo treatment of three capsules of corn oil taken twice a day.

The average number of seizures while taking the low dose of fish oil was about 12 a month, compared with just over 17 when taking a high dose of fish oil, and just over 18 when taking the corn oil only.

Two people were completely free of seizures while taking a low dose of fish oil. This did not occur while patients were taking a high dose of fish oil or corn oil....

Article here

Normal life for a person with epilepsy

This article provides much information on epilepsy and describes what an average day is like for a person who has epilepsy.

The roots of epilepsy have been traced as far as 3000 years ago. Because of its disturbing and dramatic features, back then epilepsy was feared and was thought to be a result of some sort of supernatural force or evil influence.

Today we are in the 21st century, yet people with epilepsy are not free from the social stigma, discrimination and isolation. In many rural parts of the country, it is still believed that people with epilepsy are mentally challenged and cannot be treated or lead a normal life. Women with epilepsy face problems in getting married because of the belief that they cannot have children or if they do their children will also be affected. (Read: World Epilepsy Day 2012: Top myths about epilepsy busted)

This clearly shows a lack of understanding of the disorder. Epilepsy doesn’t mean being mentally challenged or having an abnormal life. A person with epilepsy can lead a normal life, get married and have children as well. All you need is a better understanding of the disorder and ways to treat and prevent it.

What is epilepsy?

Epilepsy is a chronic brain condition having unique characteristics. One of the characteristics of people with epilepsy is the recurrence of seizures. That is why epilepsy is commonly known as seizure disorder.

The brain functions with the help of millions of neurons that transmits and receives signals. Epilepsy is caused when the normal pattern of transmission of signals to and from the brain is disturbed. This results in seizures that affect consciousness, body movements and sensations in the affected person for a short period of time until the electric impulses settle. Physical changes that occur during an epileptic seizure may arise either from disturbance in one part of the brain (partial seizure) or in nerve cells from different parts of the brain (generalized seizures). (Read: Epilepsy patients’ brain activity to be monitored)

What is the difference between seizures and epilepsy?

Seizure is just a sign of epilepsy. All patients with epilepsy have seizures but all people having seizures may not have epilepsy. An episode of a single seizure doesn’t indicate that the person is suffering from epilepsy. Seizures can also be triggered by synchronised activity of neurons in the brain occurring in different conditions like high fever, lack of oxygen supply to the brain and hypoglycaemia. Epilepsy is a condition that makes a person susceptible to seizures.

What happens during an epileptic seizure?

Several physical changes take place during an epileptic seizure. Although nothing can describe what the person going through an epileptic attack feels, but the following signs may be seen during an epileptic seizure:

• Sudden jerking movements or twitches in the arm, legs and facial muscles (clonic movements) 
• Rapid movement of the eye balls and head
• Altered consciousness or complete loss of consciousness
• Abdominal discomfort
• Tendency of tongue biting and incontinence.
• Later the patient may feel confused, drowsy and weak

What causes epilepsy?

The exact cause of epilepsy is not found in most cases. Since epilepsy involves the brain function at the neuronal level, several events or conditions that affect the brain may cause epilepsy.

• Trauma to the brain or head injury
• Lack of oxygen supply to the brain during birth
• Brain tumors
• Infections such as meningitis and encephalitis which affect the brain.
• Stroke caused by damage to a blood vessel in the brain
• Neurological diseases such as Alzheimer disease
• Genetic conditions
• Lead poisoning or carbon monoxide poisoning can cause epilepsy
• Drug addiction and overuse of certain antidepressants

Does epilepsy affect a particular age group? Who is at risk?

Dr Arjun Srivatsa, renowned neurosurgeon and founding trustee of Spine Trust India says, ‘Epilepsy is statistically more prevalent in older population. In children, nearly 30 percent of cases are reported in the first 5 years of age. ‘ ‘There is no particular group of people who have greater chances of getting epilepsy,’ he adds further. 

How is epilepsy diagnosed?

According to the Indian Guidelines of Epilepsy, diagnosis of epilepsy requires a detailed medical history of the patient. Dr Srivatsa mentions that epilepsy is usually well described by an eye witness. Therefore, family members and friends of the patient may be required to describe the event and the physical changes observed. The guidelines suggest video recording of the epileptic event can be useful for correct diagnosis.

The doctor will then examine pulse rate and blood pressure of the patient. Presence of subcutaneous nodules and other neurological signs are also examined.

Confirmation of epilepsy is done through various brain imaging procedures. An electroencephalogram (EEG) is a common diagnostic tool used to detect signals from the neurons in the brain and classify the type of epilepsy. The waves resulting from these signals may show a specific pattern which helps the doctor to confirm epilepsy as the cause of seizures. A CT scan or MRI scan may be taken to detect other conditions that may be causing seizures. A positron emission tomography (PET)  scan may be performed to analyze which centers in the brain are involved in seizures. (Read: World Epilepsy Day: Epilepsy more disabling than acknowledged)

How is epilepsy treated? Are there any advances in treatment?

The aim of treatment in epilepsy is to control seizures through anti-epileptic drug (AED) therapy and surgery.

Anti-epileptic drug (AED) therapy: AED is the most common form of treatment given to patients with epilepsy. A single AED (monotherapy) is first given to the patient. Drugs like phenytoin, oxcarbazepine, valproate, phenobarbitone and carbamazepine are conventional drugs used for monotherapy. A combination of these drugs may be given if monotherapy shows no effect on reduction in seizure events. Complete withdrawal of drugs is considered only when the patient is seizure-free. Usually the dosage of drug is reduced gradually and over a period of 3–6 months (or longer) the patient may be free from seizures. Dr Srivatsa says ‘A small group of patients having seizures may need life long medications because of chances of relapse’ (Read: Scientists cure epilepsy in mice) 

Surgery:

‘There is a small population of patients, who do not respond to drug treatments at all. Such patients are termed as refractive to treatment,’ Dr Srivatsa says. ‘However, in such patients, if appropriate diagnosis is done and the areas of the brain which are prone to seizures are mapped using advanced EEG, surgery can be considered,’ he mentions.  

• Removal of seizure focus:It is the most common type of surgery where a small part of the brain where disturbance in signals is observed is removed.
• Multiple Subpial Transection: Sometimes, when the affected part cannot be removed, the surgeon may introduce series of incisions to prevent the signals from the affected part to reach other parts of the brain. 
• Lesionectomy: Epilepsy caused by the presence of a lesion can be treated by surgical removal of the legion.

‘There are newer methods like Vagus nerve stimulation (VNS) which are considered in patients who are not fit for surgeries,’ says  Dr Srivatsa. In this method, a device called vagus nerve stimulator is implanted under the skin of the patient in the chest. The device remains attached to the vagus nerve that delivers electrical signals to the brain thereby reducing seizures by 20-40 percent. 

Diet:

Researchers believe that diet rich in fats and low in carbohydrates (ketogenic diet) may help to reduce the frequency of seizures.

Can epilepsy be prevented? How?

Because the cause of epilepsy is not known, it cannot be prevented. However, childhood epilepsy can be prevented with good care during pregnancy. Genetic screening may help the mother to identify the chances of epilepsy in her child. Preventing head injuries can be taken as a preventive measures since they can lead to epilepsy.

People with epilepsy can control the frequency of their seizures by:

• Adhering to recommended prescribed medication
• Following a regular sleep cycle
• Avoiding stress
• Modifying diet
• Undergoing regular medical checkups and adhering to their follow-up schedule.

Read more here

FDA approved marijuana-based CLINICAL TRIAL to treat Epilepsy

PLEASE NOTE: The FDA has recently approved a clinical trial  or an experiment with a marijuana-base to treat epileptic disorders. The agent has not been approved for clinical use. If interested call the study sponsors below.  JR

The US Federal Drug Association approved clinical studies that aim to determine whether purified cannabidiol (CBD) is a viable anti-seizure treatment. Physician investigators will be provided with Epidiolex, a new 98% CBD product made by GW Pharmaceuticals, and conduct Investigational New Drug studies involving epileptic children.

According to O’Shaughnessy, the clinical studies will be sponsored by Orrin Devinsky, MD, at the NYU School of Medicine, and Roberta Cilio, MD, PhD, at University of California, San Francisco. Both are expected to monitor the progress of 25 patients, but they may enroll more with approval from the FDA. Additionally, Cilio will conduct two individual studies as well.

GW Pharmaceuticals, the British company responsible for the cannabis-based spray Sativex, will provide researchers with their latest “pure CBD” product – Epidiolex. The drug will come in the form of a viscous liquid to be dispensed in syringe droppers. Additionally, there will be two strengths available: 25 milligrams per milliliter and 100 mg/ml.

According to GW, Epidiolex contains no tetrahydrocannabinol (THC), the psychotropic component in cannabis. It is said to contain more than 98% cannabidiol (CBD) and trace amounts of other cannabinoids. GW chairman Geoffrey Guy, MD, told O’Shaughnessy, “Our definition of pure is no THC.”

Guy believes the studies will help provide “better understanding and experience in what cannabidiol does in these different children groups, what benefit we can see, and how the results can best be measured.”

Considering anecdotal evidence that cannabis can help treat epileptic seizures, and nearly 5 years of pre-clinical trial data from GW Pharmaceuticals, Guy expects more studies to come in the future.

“In the coming months, if the FDA is comfortable about how things are going, there will be a number of senior epileptologists in major university centers throughout the U.S., each treating a couple of dozen patients with various epilepsies,” he explained.

Read more here

Causes, symptoms and treatments for epilepsy

This article gives a great general overview of the causes, symptoms and treatment options for epilepsy.

Epilepsy is usually identified only after the occurrence of more than one seizure in a person and the chances of Epileptic seizures increases with age and leads to abnormal, excessive or hypersynchronous neuronal activity in the brain. Moreover, the condition is also very common among the infants. Presently over 50 million people are victim of Epilepsy globally of which about 80 percent cases are observed in the developing countries. So, in order to avoid Epileptic condition it is very important to know about thecauses, symptoms, treatment and prevention of Epilepsy. Moreover you should also know about the types of seizure as well as diagnosis of Epilepsy.

Types of Seizure

Depending upon the source of seizure, they are primarily classified into two types of which first is called partial or focal onset seizures in which the seizure within the brain is localized. However, in the second type of seizure called generalized seizures, the seizure within the brain is distributed.

Partial seizures depending upon the extent to which alertness is affected is further divided into two types called the simple partial seizure in which the awareness is unaffected, while the second type is called complex partial (psychomotor) seizure.

Generalized seizures are further divided as per the effect on the body but over all involve loss of consciousness and alertness. The types of generalized seizures include absence (petit mal), myoclonic, clonic, tonic, tonic-clonic (grand mal), and atonic seizures.

Causes of Epilepsy

Though, in most of the cases the reason behind Epileptic seizures are not known but the major cause of Epilepsy is injury to the brain due to some reasons. The major causes of Epilepsy can be characterized by:

• Inadequate oxygen during birth.
• Any head injury at the time of birth or as a result of some accident during the adulthood.
• Recovering patients as a consequence of brain surgery.
• Due to brain tumors.
• Central nervous system (CNS) infections and trauma.
• Some of the genetic factors can also result in epileptic condition such as tuberous sclerosis.
• People suffering from meningitis or encephalitis have increased chances of Epilepsy.
• Sudden stroke or brain injury.
• Abnormal levels of substances such as sodium or blood sugar.

However, the major causes for Epileptic condition are mentioned above but these are not restricted to these only. There are some factors, which may also provoke Epileptic seizures. These are:

• Not taking medicines properly.
• Excessive consumption of alcohol.
• Consumption of drugs like cocaine and others.
• Emotional stress, sleep deprivation
• Taking drugs that interfere with seizure medications.

Symptoms of Epilepsy

Symptoms of Epilepsy are seizure and may vary from person to person. While, some people show simple seizure attacks, some are diagnosed by violent seizures leading to loss of alertness. The symptoms of epilepsy depend upon the part of brain affected causing epilepsy. Some of the common symptoms of Epilepsy are:

• Feeling strange and restless.
• Sudden jerk in the arms.
• Twitching and trembling.
• Sudden unconsciousness. You may fall to the ground due to black out.
• Sometimes you may feel stiffness in your muscles or limp.
• You also may get a warning sign, like strange smell before the seizure provokes. These are called auras.
• Lack of sleep is also a common symptom.

Diagnosis of Epilepsy

Diagnosis of Epilepsy is a tedious task as it requires access to various facts and figures about the patients and the cause of seizures due to lack of an absolute diagnostic tool or test. However, it you have suffered two or more seizures, you may be diagnosed with epilepsy. The diagnosis of Epilepsy is based on many factors.

In order to diagnose Epilepsy, it is very essential to know patient's medical history, which also includes if there is any case of family history of seizures, associated medical conditions, and current medications if any.

Some of the common questions asked to the patient in order to diagnose Epilepsy are:

• At what age did you get the first seizures?
• For how long did you felt the seizure and what was the feeling?
• What do you think should be the reason for the seizure?
• What do you feel before, during, and after the seizures?
• Have you undergone for any treatment for epilepsy before?
• What are the medications prescribed to you and in what dosages?
• Was the treatment effective?
• Are you suffering from any illnesses, diseases, injuries or other medical condition?
• Do you have any family history of Epilepsy?

After analyzing and evaluating all your answers to the questions asked by the doctor, the doctor might provide the answer whether you are getting the seizure due to epilepsy or not.

Treatment of Epilepsy

Though, there is not any absolute treatment for Epilepsy yet, but there are certain methods usually used to reduce the severity of Epilepsy from being increasing.

• Ketogenic diet is one of the common practices deployed for the treatment of Epilepsy and has also shown some success in reducing the rate of seizure to certain extent especially among the children.
• Nerve stimulation through Vagus nerve stimulation method is another option. This treatment is mostly for people who cannot have surgery.
• In some cases where medication does not show proper result, surgery proves to be quite effective.

Prevention of Epilepsy

As such the exact reason of Epilepsy is still unknown. There is no stiff treatment for the disease but by keeping certain common things in mind, you can certainly prevent Epilepsy from being occurring. Some of the preventive measures of Epilepsy are:

• Try to prevent any type of head injuries by wearing seat belts and helmets while driving.
• Immediately rush to a doctor after suffering from the first seizure for medical help.
• Start taking proper medication on doctor's advice after the first or second seizure.
• Avoid the consumption of alcohol.
• Avoid the intake of tobacco products and harmful drugs
• If you are suffering from high blood pressure or any other infection, take proper treatment for that.
• Proper diet enriched with vitamins and minerals is recommended.

Read more here

'Epilepsy in a dish' may result in better drug treatment

The 'epilepsy in a dish' technique using skin cells from an epileptic person reveals much about epilepsy's origins and potentially how to better treat epilepsy.

A new stem cell-based approach to studying epilepsy has yielded a surprising discovery about what causes one form of the disease, and may help in the search for better medicines to treat all kinds of seizure disorders.

The findings, reported by a team of scientists from the University of Michigan Medical School and colleagues, use a technique that could be called "epilepsy in a dish."

By turning skin cells of epilepsy patients into stem cells, and then turning those stem cells into neurons, or brain nerve cells, the team created a miniature testing ground for epilepsy. They could even measure the signals that the cells were sending to one another, through tiny portals called sodium channels.

In neurons derived from the cells of children who have a severe, rare genetic form of epilepsy called Dravet syndrome, the researchers report abnormally high levels of sodium current activity. They saw spontaneous bursts of communication and "hyperexcitability" that could potentially set off seizures. Neurons made from the skin cells of people without epilepsy showed none of this abnormal activity.

They report their results online in the Annals of Neurology, and have further work in progress to create induced pluripotent stem cell lines from the cells of patients with other genetic forms of epilepsy. The work is funded by the National Institutes of Health, the American Epilepsy Society, the Epilepsy Foundation and U-M.

The new findings differs from what other scientists have seen in mice -- demonstrating the importance of studying cells made from human epilepsy patients. Because the cells came from patients, they contained the hallmark seen in most patients with Dravet syndrome: a new mutation in SCN1A, the gene that encodes the crucial sodium channel protein called Nav1.1. That mutation reduces the number of channels to half the normal number in patients' brains.

"With this technique, we can study cells that closely resemble the patient's own brain cells, without doing a brain biopsy," says senior author and team leader Jack M. Parent, M.D., professor of neurology at U-M and a researcher at the VA Ann Arbor Healthcare System. "It appears that the cells are overcompensating for the loss of channels due to the mutation. These patient-specific induced neurons hold great promise for modeling seizure disorders, and potentially screening medications."

With the new paper, Parent, postdoctoral fellow Yu Liu, M.D., Ph.D. and their collaborators Lori Isom, Ph.D., professor of Pharmacology and of Molecular and Integrative Physiology at U-M, and Miriam Meisler, Ph.D., Distinguished University Professor of Human Genetics at U-M, report striking discoveries about what is happening at the cell level in the neurons of Dravet syndrome patients with a mutated SCN1A gene.

They also demonstrated that the effect is rooted in something that happens after function of the gene is reduced due to the mutation, though they don't yet know how or why the nerve cells overcompensate for partial loss of this channel.

And, they found that the neurons didn't show the telltale signs of hyperexcitability in the first few weeks after they were made -- consistent with the fact that children with Dravet syndrome often don't suffer their first seizures until they are several months old.

"In addition, reproduction of the hyperactivity of epileptic neurons in these cell cultures demonstrates that there is an intrinsic change in the neurons that does not depend on input from circuits in the brain," says co-author Meisler.

A platform for testing medications

Many Dravet patients don't respond to current epilepsy medications, making the search for new options urgent. Their lives are constantly under threat by the risk of SUDEP, sudden unexplained death in epilepsy -- and they never outgrow their condition, which delays their development and often requires round-the-clock care.

"Working with patient families, and translating our sodium channel research to a pediatric disease, has made our basic science work much more immediate and critical," says Isom, who serves on the scientific advisory board of the Dravet Syndrome Foundation along with Meisler. Parent, who co-directs U-M's Comprehensive Epilepsy Program, was recently honored by the foundation.

The team is now working toward screening specific compounds for seizure-calming potential in Dravet syndrome, by testing their impact on the cells in the "epilepsy in a dish" model. The National Institutes of Health has made a library of drugs that have been approved by the U.S. Food and Drug Administration available for researchers to use -- potentially allowing older drugs to have a second life treating an entirely different disease from what they were initially intended.

Parent and his colleagues hope to identify drugs that affect certain aspects of sodium channels, to see if they can dampen the sodium currents and calm hyperexcitability. The team is exploring new techniques that can make this process faster, using microelectrodes and calcium-sensitive dyes. They also hope to use the model to study potential drugs for non-genetic forms of epilepsy.

Having a U-M team that includes experts in induced pluripotent stem cell biology, sodium channel physiology and epilepsy genetics expertise helps the research progress, Parent notes. "Epilepsy is a complicated brain network disease," he says. "It takes team-based science to address it."

Patients as part of the research team

The U-M team's research wouldn't be possible without the participation of patients with Dravet syndrome and other genetic forms of epilepsy, and their parents.

More than 100 of them have joined the International Ion Channel Epilepsy Patient Registry, which is based at U-M and Miami Children's Hospital and co-funded by the Dravet Syndrome Foundation and the ICE Epilepsy Alliance. The researchers hope to be able to conduct clinical trials of potential drugs with participation by these patients and others.

Meanwhile, patients with other genetically based neurological diseases can also help U-M scientists discover more about their conditions, by taking part in other efforts to create induced neurons from skin cells. Parent and his team have worked with several other U-M faculty to create stem cell lines from skin cells provided by patients with other diseases including forms of ataxia and lysosmal storage disease.

Read more here

Link found between autism and ADHD

Research shows that adults who have epilepsy are likely to have symptoms of autism as well.

Adults with epilepsy are more likely to have a greater number of characteristics of autism and Asperger syndrome, according to new research by the University of Bath, England.

The finding was discovered by Dr. SallyAnn Wakeford, a PhD student from the University's Department of Psychology, and revealed a previously unknown link between epileptic seizures and the signs of autism in adults.

Traits of autism, such as impaired communication and social interaction and restricted and repetitive interests, can be serious and go undetected for several years - creating a lasting impact on the lives of those who endure them.

The investigators found that epileptic seizures interfere with the neurological function that affects social functioning in the brain - causing the same characteristics that depict autism.

Dr Wakeford said:

"The social difficulties in epilepsy have been so far under-diagnosed and research has not uncovered any underlying theory to explain them. This new research links social difficulties to a deficit in somatic markers in the brain, explaining these characteristics in adults with epilepsy."

The researchers revealed that having elevated autistic traits was standard to all types of epilepsy, however, it was more evident for adults with Temporal Lobe Epilepsy (TLE).

The authors believe one reason may be because anti-epileptic medications are many times less effective for TLE. These drugs may cause an impact because they are significantly related to the severity of autistic characteristics. 

Dr. Wakeford and her colleagues conducted a comprehensive range of studies with participants who have epilepsy and found that all adults with epilepsy exhibited autism traits.

She explained:

"Epilepsy has a history of cultural stigma, however the more we understand about the psychological consequences of epilepsy the more we can remove the stigma and mystique of this condition. "These findings could mean that adults with epilepsy get access to better services, as there is a wider range of treatments available for those with autism condition."

The findings may lead to better treatment for people with epilepsy and autism. Dr. Wakeford suggested that although epilepsy has a cultural stigma, the more understood the physical outcomes of this condition are, the better chance there is to eliminate this stigma.

She concluded, "These findings could mean that adults with epilepsy get access to better services, as there is a wider range of treatments available for those with autism condition."

Margaret Rawnsley, research administration officer at Epilepsy Action, was pleased with the results of the study, saying: "We welcome any research that could further our understanding of epilepsy and ultimately improve the lives of those with the condition. This research has the potential to tell us more about the links between epilepsy and other conditions, such as autism spectrum disorders."

A study released earlier this year suggested a link between mothers who took the antiepileptic drug sodium valproate during pregnancy and an increased risk for autism in their children. Researchers found that neurodevelopmental issues were more prevalent in children whose mothers had epilepsy.

Read more here

Children of pregnant women who use anti-epileptic drug may have increased risk of autism

Pregnant mothers who use valproate, an anti-epilepsy drug, may have children with an increased risk of autism. Dont jump to assume causation.  With the finding that autism is noted in families with other neuro-psychiatric illness, there may be some confounding variables in this observation. - JR

Maternal use of valproate (a drug used for the treatment of epilepsy and other neuropsychological disorders) during pregnancy was associated with a significantly increased risk of autism in offspring, according to a study in the April 24 issue of JAMA. The authors caution that these findings must be balanced against the treatment benefits for women who require valproate for epilepsy control.

"Anti-epileptic drug exposure during pregnancy has been associated with an increased risk for congenital malformations and delayed cognitive development in the offspring, but little is known about the risk of other serious neuropsychiatric disorders," according to background information in the article.

Jakob Christensen, Ph.D., of Aarhus University Hospital, Aarhus, Denmark, and colleagues evaluated the association between maternal use of valproate during pregnancy and the risk of autism spectrum disorder and childhood autism in offspring. The population-based study included all children born alive in Denmark from 1996 to 2006. National registers were used to identify children exposed to valproate during pregnancy and diagnosed with autism spectrum disorders (childhood autism [autistic disorder], Asperger syndrome, atypical autism, and other or unspecified pervasive developmental disorders). Data were analyzed and adjusted for potential confounders (factors that can influence outcomes) such as maternal age at conception, paternal age at conception, parental psychiatric history, gestational age, birth weight, sex, congenital malformations, and parity. Children were followed up from birth until the day of autism spectrum disorder diagnosis, death, emigration, or December 31, 2010, whichever came first.

The analysis included 655,615 children born from 1996 through 2006. The average age of the children at end of follow-up was 8.8 years. During the study period, 5,437 children were diagnosed with autism spectrum disorder, including 2,067 with childhood autism. The researchers identified 2,644 children exposed to antiepileptic drugs during pregnancy, including 508 exposed to valproate. The authors found that use of valproate during pregnancy was associated with an absolute risk of 4.42 percent for autism spectrum disorder and an absolute risk of 2.50 percent for childhood autism.

"In this population-based cohort study, children of women who used valproate during pregnancy had a higher risk of autism spectrum disorder and childhood autism compared with children of women who did not use valproate. Their risks were also higher than those for children of women who were previous users of valproate but who stopped before their pregnancy," the researchers write.

"Because autism spectrum disorders are serious conditions with lifelong implications for affected children and their families, even a moderate increase in risk may have major health importance. Still, the absolute risk of autism spectrum disorder was less than 5 percent, which is important to take into account when counseling women about the use of valproate in pregnancy."

Read more here

Genetic discovery for common form of epilepsy

Research from Australia has found a gene indicating one of the most common forms of epilepsy. This could have major implications for future treatment options.

An Australian-led international research team has discovered a gene associated with the most common form of epilepsy, a discovery that will help with diagnosis and new treatments.

Through genetic counselling, it will help people plan a family, lead researcher Professor Ingrid Scheffer of the University of Melbourne said.

Two per cent of people have epilepsy and most do not know the cause of their condition. The research will help some of those with the most common form, focal epilepsy, discover the underlying cause.

Professor Scheffer said a gene test would help in cases where everything else in the brain looked normal. ''It will give you a cause. That has important implications in terms of genetic counseling and managing the risk to your own offspring.''

Advertisement

She said a small proportion of people with the gene also had psychiatric or autism-spectrum disorders.

''Therefore genetic counselling is even more important. Knowing the gene means people can go forward and get pregnant and have proper medical assistance to ensure their baby does not have the disorder.''

Professor Scheffer said 90 families took part in the study, which was conducted in partnership with Associate Professor Leanne Dibbens of the University of South Australia.

Scientists in Europe and Canada also worked on the research, which is published in the journal Nature Genetics.

Read more here

Zebrafish research promises new epilepsy treatment

Research on zebrafish shows compounds that help suppress seizures showing promise for future epilepsy treatment.

The prospect of developing new treatments for epilepsy sufferers has been given a boost by a pioneering discovery at a leading international centre of research into human disease in the University of Sheffield.

Researchers at the University’s Medical Research Council Centre for Developmental and Biomedical Genetics (CDBG), in the Department of Biomedical Science, screened a collection of 2,000 biologically active compounds to identify molecules that suppressed epileptic seizures in two day old epileptic zebrafish.

Within this collection, 46 compounds – including some which are used to treat infectious, psychiatric and inflammatory disorders – were found to exhibit anticonvulsant activity and could represent starting points for the development of new drugs for treating epilepsy.

Approximately one out of every 140 people in the UK has epilepsy – more than 400,000 people – of which about 30 per cent do not respond favourably to the available anti-epileptic drugs.

Consequently, many patients live with the disruptive and often devastating effects of untreatable seizures in their daily lives, whilst other patients who receive medication for their seizures experience side-effects that can result from taking some of these drugs.

The University of Sheffield team’s innovative approach to identifying small molecules with potential as anti-epileptic therapies offers new prospects of reducing the burden of suffering from this devastating illness.

Dr Vincent Cunliffe of the University of Sheffield’s Department of Biomedical Science, who led the project, said: “We took advantage of a unique set of features of the zebrafish to look for new anticonvulsant agents within a library of many different types of compounds with a wide range of known biological activities.

“We found that a small number of them had previously-unknown anti-convulsant effects. Some of the identified compounds already have a variety of different medical uses in treating conditions such as fungal infections, as well as psychiatric and inflammatory disorders.”

The research, published in the journal Disease Models & Mechanisms, suggests that some of these existing drugs could be re-purposed for treatment of epilepsy.

Nerve cells communicate with one another by passing electrical impulses along their lengths, leading to the release of a variety of chemical signals known as neurotransmitters at nerve endings, which may then stimulate or inhibit neighboring cells.

Epileptic seizures occur as a result of imbalances in the types of neurotransmitters produced within the brain, causing the simultaneous activation of abnormally large numbers of nerve cells, some of which may then stimulate body muscles to contract vigorously, resulting in convulsions.

Observing these processes at the level of individual nerve cells and molecules is especially difficult because the brains of mammals such as humans and mice, are so large, complex and relatively inaccessible.

However, the three milimetre-long, microscopic zebrafish larva develops rapidly, independently of its parents, and it is structurally simple, transparent and accessible, which allows the behaviours of nerve cells within the brain to be easily viewed in a remarkable level of detail. To study the effects of drugs on the zebrafish brain, they are simply diluted into the water in which the zebrafish develop, which then allows them to be readily absorbed by the body.

Dr Cunliffe added: “The zebrafish is proving to be a remarkably powerful in vivo system for gene function analysis and drug discovery. Over the last ten years our zebrafish research has helped us to understand how the nervous system is built and how faults in this construction process may cause neurological and psychiatric diseases.

“Three years ago we began to explore the usefulness of the zebrafish for drug discovery and we have been surprised by the success we have had in a relatively short period of time.”

More traditional approaches to identifying and developing new pharmaceuticals are slower and more costly, so adopting the zebrafish – a small tropical fish of the minnow family – for this type of research, could help to shorten the timescales and reduce the overall costs of drug development.

Read more here

New technologies utilized for epilepsy treatment

This article claims that developing new technologies is the best way to treat epilepsy. It also goes over a few of the technologies currently utilized for epilepsy treatment.

Speaking in the lead up to Purple Day for Epilepsy Awareness (Tuesday 26 March), geneticist Professor Jozef Gecz says advances in DNA sequencing have been a huge leap forward in understanding epilepsy. 

This, combined with the use of stem cells in laboratory research, will lead to further advances in epilepsy treatment, he says. 

However, he cautions that the same technology has also helped to reveal that epilepsy is a far more complex condition than previously thought. 

"Scientists used to believe that epilepsy was just one condition, possibly with one main cause. But now we know it is a very complex series of neurological disorders – it is many epilepsies, instead of just one epilepsy, with multiple causes and various symptoms," says Professor Gecz, from the University of Adelaide's School of Paediatrics and Reproductive Health. 

Epilepsy is common, with up to 3% of the Australian population experiencing epilepsy at some stage in their lives. Genetic and environmental factors, and trauma, can all play a role in the development of epilepsy. Most (but not all) forms cause sufferers to experience seizures, which vary in severity. 

Research in Adelaide has played an important role in the understanding of epilepsy in recent years. 

"It's really thanks to the pioneering work of Dr John Mulley (Women's and Children's Hospital and University of Adelaide), who discovered the first gene for idiopathic epilepsy almost 20 years ago. Since then, almost 40 idiopathic epilepsy genes have been discovered, many of them by researchers here in Adelaide," Professor Gecz says. 

"There are more than 300 genes known today in which DNA mutations can give rise to some form of epilepsy, in addition to other problems like intellectual disability, autism or psychiatric problems. 

"Thanks to genetic sequencing technology, in most cases we are now able to solve the mystery about what kind of epilepsy a patient has, and we can do this very quickly, very accurately, and cost effectively. 

"Molecular diagnosis is making a huge impact on treatment – it's really taken off in the last few years, and it has the potential to be even more effectively used in the future. Clinicians can now be guided by genetic information when considering treatment of patients with specific epilepsies." 

Professor Gecz and colleagues are currently involved in a major national study of epilepsy, with his lab focusing on the "genetic architecture" of the condition.

Read more here