Archive for category Epilepsy

[WEB SITE] Canceling Is Kindness: Keeping Safe From COVID-19 With Epilepsy

Those of us living with pre-existing health conditions like epilepsy have likely felt the impact of COVID-19. Medical appointments may have been rescheduled or switched to virtual, work and school may be closed, and we may worry about how the illness will impact ourselves and our loved ones.

Fortunately, social distancing is a powerful tool to slow or prevent the spread of infection. Social distancing only works when everyone stays home and limits their contact with others.

When Friends or Family Aren’t Worried

Some of us have family members or friends who think the threat of the virus is being blown out of proportion. They may pressure you to join in activities as usual or become upset when you cancel plans to help keep yourself and your community safe during this high-risk time.

Here are some tactics that may help you talk to them about why health — yours, theirs, and the community’s — should be everyone’s first priority right now.

Have a Heart-to-Heart

Ask them to walk in your shoes. Ask them to imagine what you must be going through. Maybe your loved one thinks they will be fine, but you may be more vulnerable to being severely impacted by it. Individuals with neurological conditions like epilepsy may be at increased risk for COVID-19 complications. Speak with your doctor to understand your particular risk.

If your doctors have canceled or modified your appointments, share how your medical care is being affected. If your health care provider has recommended any additional precautions you should take, share that as well.

Show Them the Numbers

According to research on COVID-19 in China, people who had one additional disease — from diabetes to cardiovascular disease to cancer — had a 79 percent higher risk of requiring intensive care, needing a respirator, or dying as a result of the coronavirus infection.

Six in 10 adults in America have at least one chronic illness.

Put It Into Perspective

The threat of COVID-19 was deemed serious enough to affect major institutions:

  • Walt Disney World and Disneyland are closed. These attractions have previously only closed for disasters such as the assassination of President John F. Kennedy or the terrorist attacks on September 11, 2001.
  • Las Vegas Strip casinos including Bellagio, MGM Grand, The Mirage, Wynn Las Vegas, and Wynn Encore are closing.
  • The NBA has suspended the professional basketball season.
  • MLB has ended its training season and pushed back the start of baseball season at least two weeks.
  • The 2020 Summer Olympics may be canceled or postponed.

These organizations are prioritizing public health over the hundreds of millions of dollars (or more) they will lose by closing. If we can stay home, we should stay home.

Use Peer Pressure

If you have any other friends or family who are taking the coronavirus threat seriously, ask them to talk to that loved one on your behalf. Social distancing only works if everyone is on board.

Distance Doesn’t Mean Isolation

As our families, communities, and countries make it through this pandemic together, it’s more important than ever to find ways to stay connected. Here are a few suggestions for ways to socialize from a safe distance.

  • Phone calls. Being stuck at home is a great time to call people and catch up.
  • Video gatherings. FaceTime and apps like Zoom or Skype can allow you to see and hear each other, no matter how distant, on mobile phone, tablet, or computer. You can even have a party with dozens of people on screen.
  • Gaming apps. Many mobile gaming apps allow you to connect and play with friends remotely.
  • Movie night. Cue up the same movie or show (whether on a streaming service or a DVD you both have) and stay on the phone or on video chat the whole time. You can even plan to eat the same snack while you watch and talk.
  • Listening party. Music apps, such as Spotify, allow people to share music playlists and even collaborate to create lists of songs.

MyEpilepsyTeam is another way our community of 81,000 members living with seizures stays strong together. Here are a few conversations about how members of MyEpilepsyTeam are getting through this difficult time:

Have you found ways to talk to your loved ones about COVID-19 safety measures? What are you doing to stay connected to others during this time of heightened concern and social distancing? Share in the comments below or post on MyEpilepsyTeam.

via Canceling Is Kindness: Keeping Safe From COVID-19 With Epilepsy | MyEpilepsyTeam

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[WEB SITE] You’ve Just Been Diagnosed With Epilepsy. Now What?

 

We all respond differently to information about our health. After learning you have epilepsy, you might be stunned, scared, or even relieved to have a diagnosis that explains your seizures. No matter what you’re feeling, you’re not alone. On MyEpilepsyTeam, there are thousands of others who have been in your shoes.

You can’t figure out everything about epilepsy at once, and you don’t need to. Taking small steps to adjust to your new reality can be empowering in a time of major change. According to the American Psychological Association, active coping strategies like getting organized and making a plan for managing your health can improve mental and emotional well-being.

Create Space for Epilepsy
It’s normal to feel out of control when you first learn you have epilepsy. You may have a pile of pamphlets crowding your kitchen table and a head full of questions that you forget the moment you set foot in a doctor’s office. You can begin to tame the chaos by implementing very simple organizational techniques that will help you create space for this new aspect of your life.

Put Everything in One Place
Storing all of your printed doctor’s visit summaries, pamphlets about epilepsy, and other resources in a designated spot can help create some order and help you find information when you need it. You don’t need a fancy filing system – a kitchen drawer, an old binder, or simply an orderly stack on your bedside table can make a big difference. In addition to helping you keep track of important papers, there is evidence that controlling clutter is associated with better moods.

Remember Your Questions
Keep a list of questions about epilepsy for your healthcare provider in a dedicated notebook or on your smartphone. Jot down your questions as you think of them and bring your list to your appointments so you can remember your questions and write down the answers.

Manage Your Appointments
If you already rely on a digital calendar or paper planner to manage work and family obligations, stick with that method for managing your new doctor’s visits. If keeping a calendar is new to you, consider using what you’ve already got at home, such as a grocery list notepad or a piece of paper and a magnet on the fridge. You can also ask your doctor’s office about phone call or text message reminders that can help you keep on top of appointments.

Track Your Medications
Using an old-fashioned pill organizer is a great way to keep track of oral medications. You can also use a paper medication tracker. If you’re comfortable using a smartphone, consider downloading a medication tracking app.

Reach Out for Support
It can feel overwhelming to reach out after receiving an epilepsy diagnosis, but you don’t have to face your diagnosis alone. Support from loved ones, your medical team, and other people with epilepsy is crucial as you embark on treatment and adjust to your new normal. There are a few basic steps you can take to start building your network of support.

Epilepsy Communities
You may not be ready to talk about your diagnosis with your loved ones right away. You may also not have time or be comfortable joining an in-person support group. That’s ok. Connecting with members on MyEpilepsyTeam can be a first step towards finding support. Your community on MyEpilepsyTeam can provide an ongoing emotional boost whenever you feel worried or overwhelmed about life with epilepsy or want to celebrate a victory.

Healthcare Providers
Many hospitals and medical practices offer resources that extend beyond your medical appointments. These may include chaplaincy services, health education classes, patient liaisons or nurse navigators, on-site support groups, and referrals to other services.

Friends and Family
Sharing your epilepsy diagnosis with friends and family can be hard. They may be afraid and struggle to react in a helpful way. Try to remember that everyone is doing their best with difficult news. If you’re able, let your loved ones know how they can be most helpful to you during this time, whether that’s helping with household chores or offering a listening ear.

Learn More About Epilepsy
You might not have known much about epilepsy before your diagnosis, but now you probably want to learn more. Your healthcare provider is a great resource for information, but you may also want to do your own research. Remember to be cautious of what you read online, especially if someone is offering a quick fix or selling a cure. You can always reach out to your healthcare provider or patient liaison if you have questions about something you’ve read.

Here are a few resources to get you started:

You never have to feel alone when you’re living with epilepsy. Members on MyEpilepsyTeam are always available to answer questions and offer encouragement when things get rough.

Here are some conversations from MyEpilepsyTeam members about facing a new diagnosis:

If you have a pressing question, you can go straight to the Q+A section.
You can also read more about how to get started on MyEpilepsyTeam.

For the newly diagnosed, what information are you seeking?
For the epilepsy veterans, what do you wish you knew when you were first diagnosed?
Share in the comments below or directly on MyEpilepsyTeam.

 

via You’ve Just Been Diagnosed With Epilepsy. Now What? | MyEpilepsyTeam

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[BLOG POST]What is epilepsy? A neurological disorder that causes seizures. – NARIC

According to the Mayo Clinicepilepsy is a “central nervous system (neurological) disorder in which brain activity becomes abnormal causing seizures or periods of unusual behavior, sensations, and sometimes loss of awareness.” Anyone can develop epilepsy and it affects all genders, races, ethnic backgrounds, and ages. Symptoms can vary widely, from staring blankly for a few seconds during a seizure to twitching of arms or legs, and may include temporary confusion, loss of consciousness or awareness, and psychiatric symptoms such as fear or anxiety. Epilepsy has no identifiable cause in about half the people with the condition. For the other half of the population with epilepsy, the condition may be traced to various factors, including genetic influence, head trauma, brain conditions, infectious diseases, prenatal injury, or developmental disorders. There are certain risk factors that may increase a person’s risk of epilepsy, which include age, family history, head injuries, dementia, and stroke and other vascular diseases.

To diagnose a person with epilepsy, a doctor will review their symptoms and medical history, along with ordering a neurological exam and blood tests. They may also suggest other tests to detect brain abnormalities, such as electroencephalograms (EEG), computerized tomography (CT) scans, a magnetic resonance imaging (MRI) scan, and/or a functional MRI. An accurate diagnosis of a person’s seizure type and where seizures begin gives the best chance for finding an effective treatment. Doctors may begin treatment of epilepsy with medications, which may help people become seizure-free. For some people, medications may not treat their epilepsy and their doctor may suggest surgery or different types of therapies, such as vagus nerve stimulation, a ketogenic diet, or deep brain stimulation.

Researchers continue to study epilepsy and are studying many potential new interventions for epilepsy, including responsive neurostimulation and minimally invasive surgery. During the last 28 years, NIDILRR has funded several projects to study the impact of epilepsy and develop and test interventions, including a currently funded project that is studying a home-based self-management and cognitive training program to improve the quality of life for people with refractory epilepsy.  NARIC’s information specialists searched REHABDATA and found over 1,500 research articles, book chapters, and factsheets related to epilepsy from the NIDILRR community and beyond. If you have any questions about epilepsy or would like assistance in conducting your own search in NARIC’s databases, contact NARIC’s information specialists for more information.

Please note: This article provides basic information and is not intended to diagnose or recommend interventions for epilepsy. If you believe you have experienced a seizure, seek medical advice from a qualified primary care provider or specialist.

via What is epilepsy? A neurological disorder that causes seizures. | Collection Spotlight from the National Rehabilitation Information Center

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[ARTICLE] Basic and clinical role of vitamins in epilepsy – Full Text PDF

Abstract

Background & Aims: Epilepsy is a brain disorder which affects about 50 million people worldwide. Good diet is an essential measure to controlling seizure attacks. Since some combination therapy can reduce epileptogenesis, therefore this review summarizes the available evidences about the application of vitamins in animal models and humans for understanding what specific combinations of antiepileptic drugs and vitamins are likely to be effective for epilepsy therapy.

Material and methods: In this review, electronic databases including PubMed and Google Scholar were searched for monotherapy and polytherapy by vitamins.

Results: Administration of vit A inhibits development of seizures and lethality in animal models. Also vitamins B1, B6 and B12 pretreatment might lead to a protective effect against degenerative cellular in mice. In addition use of low dose of sodium valproate with vitamins C or E increase the anticonvulsant activity of the drug in mice. Moreover, Vitamin D enhances antiepileptic effects of lamotrigine, phenytoin and valproate in animal’s models. Vitamin E has an anticonvulsant effect in ferrous chloride seizures, hyperbaric oxygen seizures as well as penicillin-induced seizures in contrast kindling, maximal electroshock and kainite models. Some researches demonstrated that vitamins D and B as adjunctive therapy in epileptic patient can relieve seizures. A clinical data have shown beneficial effects of vitamin E in raising total antioxidant capacity, catalase, and glutathione in patients with uncontrolled epilepsy. Only few clinical studies exist to support the efficacy of the vitamin A and K in epilepsy.

Conclusion: However vitamin therapy is not a substitute for antiepileptic drugs but add on therapy by them may relieve drugs-induced deficiencies as well as more researches are needed to evaluate the effectiveness of vitamins in epileptic humans.

[…]

Full Text PDF

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[WEB PAGE] Types of Epilepsy | MyEpilepsyTeam

 

Article written by Kelly Crumrin

Epilepsy is a spectrum of neurological disorders that involve recurring seizures caused by abnormal electrical activity in the brain. Diagnosing the specific type of epilepsy helps you and your doctor better know what to expect regarding seizure progression, any challenges in learning and physical development, and which treatments will be most effective.

Each type of epilepsy involves specific types of seizures and other symptoms.

Localized epilepsies and syndromes

Some types of epilepsy are referred to as localized, which means they are known by the location in the brain where seizures originate. A related term is focal epilepsy, which indicates seizures that have abnormal electrical activity focused in one area of the brain. Other types of epilepsy are known as syndromes, or collections of specific signs and symptoms that point to a certain medical condition. Each type of epilepsy has unique characteristics. Some syndromes are considered benign, meaning children will eventually become seizure-free with age, while other types of epilepsy are lifelong conditions.

Temporal lobe epilepsy (TLE)

Approximately 60 percent of people with epilepsy have temporal lobe epilepsy (TLE), or seizures that originate in the temporal lobe of the brain. The temporal lobe is located on the sides of the brain, near the ears, and is responsible for processing sound and language as well as memories relating to sound and vision. About one-third of TLE or other cases of focal epilepsy are resistant to anti-epileptic drugs (AEDs). Surgery may be recommended, and vagus nerve stimulation may also be therapeutic.

TLE usually develops between late adolescence and early adulthood, often after a head injury or febrile (fever-induced) seizure. For women with TLE, hormonal changes during the menstrual cycle can increase seizure activity. Focal onset seizures are most common for people with TLE, though some people may experience prolonged seizures or, in rare circumstances, status epilepticus. Read more about seizure types and symptoms.

Frontal lobe epilepsy (FLE)

Frontal lobe epilepsy is the second most common form of focal epilepsy after TLE. FLE may be inherited, or it may be caused by a structural problem such as a birth defect, an abnormal blood vessel, trauma, or scaring caused by infection. In about 50 percent of FLE cases, no cause is ever determined.

The frontal lobes of the brain are large, and some of its functions include reasoning, paying attention, regulating emotion, organizing, and solving problems. Researchers have not discovered the functions of many areas. It is possible for a seizure to begin in the frontal lobe and proceed without symptoms before spreading to other parts of the brain, leading to a tonic-clonic seizure. FLE seizure symptoms can vary widely, depending on the function of the affected part of the lobe. Learn more about seizure symptoms and types.

FLE is usually responsive to medications, but in cases where AEDs are ineffective, surgery or vagus nerve stimulation may help.

Occipital lobe epilepsy and parietal lobe epilepsy

Epilepsy that originates in the occipital and parietal lobes is much less common than TLE and FLE. Seizures that begin in these lobes are usually idiopathic – of unknown cause. The occipital lobe is in the back of the brain and is primarily responsible for vision. The parietal lobe is located on the top and upper sides of the head and is known as the “association cortex” because it is where perception becomes reality. Sounds are recognized as words, visual images are created, and touch becomes associated with an object.

In both types of epilepsy, AEDs are the first treatment option. If medication fails, surgery may be recommended.

Panayiotopoulos syndrome (PS)

Also known as early onset occipital epilepsy, PS commonly begins in early childhood. Typically, onset is between the ages of 3 and 10. PS affects boys and girls equally, and it is idiopathic (cause unknown). As many as 6 percent of children who have nonfebrile (not caused by fever) seizures have PS. PS frequently stops two to three years after the first seizure.

Children with PS will have focal seizures that can spread to a generalized seizure. Seizures in PS often last 20 to 60 minutes, and more than half occur during sleep. Pale skin, a sick feeling, and vomiting are typical symptoms during a PS seizure. Some children may also have tonic-clonic movements. Read more about types of seizures.

If seizures are infrequent, medication may not be needed. However, if they are needed, AEDs are usually effective at controlling PS seizures. Neurologists often teach parents how to initiate rescue therapy and create an emergency plan for children with PS.

Benign rolandic epilepsy (BRE)

Also known as benign epilepsy with centrotemporal spikes (BECTS), BRE usually begins around ages 6 to 8. Boys are slightly more likely to have BRE than girls. BRE accounts for approximately 15 percent of all epilepsies in children.

Benign rolandic epilepsy is characterized by numbness, twitching, or tingling of the face or tongue. Seizures may inhibit speech and cause drooling. The child remains conscious during the seizure. Seizures are not frequent and occur mostly at night. AEDs may be prescribed if the seizures happen during the day or disrupt sleep, but many children do not need medication. Seizures stop by early adolescence in almost all children with BRE.

Generalized epilepsies and syndromes

In contrast to localized types of epilepsy discussed above, generalized types of epilepsy feature seizures that do not originate, or do not remain confined, in one lobe or area of the brain. Generalized epileptic syndromes tend to be idiopathic – of unknown cause. Idiopathic generalized epilepsies account for one-third of epilepsy cases.

Juvenile myoclonic epilepsy (JME)

JME, also known as Janz syndrome, begins between the ages of 8 and 26, but most commonly between the ages of 12 and 16. Absence seizures may be the first type of seizure most people with JME experience, although this type happens less often. Mild myoclonic seizures, generalized tonic-clonic (GTC), or clonic-tonic-clonic seizures (GTC seizures that begin with a clonic phase) seizures are the most common types. Myoclonic seizures tend to occur immediately upon waking in the morning. Photosensitivity – seizures triggered by flashing or flickering light – affects 40 percent of people with JME. Photosensitive seizures usually show on an electroencephalography (EEG) test. Read more about seizure types.

Most cases of juvenile myoclonic epilepsy are treatable with AEDs. Most people with JME need to remain on medication for life.

Childhood absence epilepsy (CAE)

CAE accounts for 2 to 8 percent of childhood epilepsy. Childhood absence epilepsy typically begins between the ages of 3 and 11, most frequently between ages 5 and 8. One-third of children with CAE have a family history of seizures, suggesting that the cause may be genetic. Siblings of children with CAE have a 1-in-10 chance of developing epilepsy.

Children with CAE experience absence seizures (formerly known as petit mal seizures). The child is not aware or responsive during seizures, and may stare, blink, or roll their eyes up. You may notice a chewing motion or other repetitive movements. Seizures last about 10 seconds, after which the child immediately returns to normal. The child is usually not aware they have had a seizure. Seizures may be infrequent or happen as often as 100 times a day. One-third of children with CAE have concentration and memory problems before seizures start; these issues often improve after AEDs are started. Rarely, children who have very frequent seizures may develop learning difficulties.

If AEDs are not effective, the ketogenic diet may help children with CAE. At least two-thirds of children with CAE respond to treatment, and their seizures will cease by mid-adolescence. However, 10 to 15 percent of children with CAE will develop other seizure types during adolescence – typically myoclonic seizures, generalized tonic-clonic seizures, or both. Read more about seizure types.

Juvenile absence epilepsy (JAE)

JAE is similar to childhood absence epilepsy; however, it starts later in childhood (generally between ages 9 and 13) and is usually a lifelong condition. Two percent of people with epilepsy have juvenile absence epilepsy (JAE). Although it is rare to have a family history of seizures, the cause of JAE is thought to be genetic.

People with JAE experience absence seizures lasting from 10 to 45 seconds. Seizures may happen infrequently or 100 times a day. Seizures often happen during exercise. Seventy-five percent of those with JAE will also have tonic-clonic seizures. The risk of absence status epilepticus (also known as nonconvulsive status epilepticus), in which seizures can last minutes or even hours, is higher in people with JAE.

Children with JAE generally develop normally, though they may experience learning difficulties if they have frequent seizures. One-third of children with JAE have concentration and memory problems before seizures start; these issues often improve after AEDs are started. AEDs work well to treat JAE and must be taken for life.

Lennox-Gastaut syndrome (LGS)

LGS is an uncommon epilepsy syndrome; between 2 and 5 percent of children with epilepsy have LGS. Lennox-Gastaut syndrome often starts between the ages of 3 and 5. Atonic seizures, also known as drop attacks, are most common in children with Lennox-Gastaut syndrome (LGS). Seizures may happen multiple times a day and cause the child to suddenly drop to the ground. Drop attacks may be perceived as a trip or the result of poor balance. Injuries are common, making the seizures very upsetting for the child. Atypical absence seizures and tonic seizures are also common, especially at night, but children with LGS may experience other types of seizures as well.

LGS is very difficult to treat and is often referred to as intractable or refractory. Some AEDs can be effective, and the ketogenic diet may help. Surgery may be recommended if diet and medication do not work, though surgical treatment will not stop the seizures altogether.

Children with LGS have moderate to severe learning difficulties, with some children exhibiting developmental delays before their first seizure. Twenty percent of children who have West syndrome (infantile spasms) will develop LGS.

Progressive myoclonic epilepsies

The progressive myoclonic epilepsies are a group of rare syndromes characterized by a combination of tonic-clonic and myoclonic seizures. Disorders that fall under this category include Lafora disease, mitochondrial encephalopathies, severe myoclonic epilepsy of infancy (also referred to as Dravet syndrome), and Unverricht-Lundborg disease (also known as Baltic myoclonus). The cause is often hereditary but may be unknown. Progressive myoclonic epilepsies affect males and females equally and start at different ages, depending on the specific condition. Read more about seizure types.

In progressive myoclonic epilepsies, seizures are difficult to control. As the condition progresses, people with PME accumulate cognitive (relating to thinking and memory) and motor (relating to movement) disabilities.

Medications may be successful at first, but effectiveness declines over months or years as the disease progresses.

Other epilepsy syndromes

Epilepsy is a broad spectrum involving dozens of neurological disorders. While those described above are the most commonly diagnosed, there are many other syndromes that cause epilepsy. Examples include Angelman syndrome, Doose syndrome (myoclonic astatic epilepsy), Dravet syndrome, neurocutaneous syndromes (such as Sturge-Weber syndrome), Rasmussen’s syndrome, and Rett syndrome.

Resources

External resources

MyEpilepsyTeam resources

via Types of Epilepsy | MyEpilepsyTeam

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[WEB PAGE] The ABCs of CBD: Separating fact from fiction – NIH MedlinePlus Magazine

CBD. Cannabidiol. No matter what you call it, you may have heard health claims about this little-known part of the marijuana plant, which comes from the plant’s flowers. Some say it treats muscle aches, anxiety, sleeping troubles, chronic pain, and more.

But what does the science say?

We spoke to NIH expert Susan Weiss, Ph.D., to learn more and find out why consumers should be careful. Dr. Weiss is the director of the division of extramural research at the National Institute on Drug Abuse (NIDA).

What is CBD?

CBD (or cannabidiol) comes from the cannabis (or marijuana) plant.

The chemical compound THC [tetrahydrocannabinol] is the part of the cannabis plant that most people are familiar with because that is the part that makes people “high.” Most effects of marijuana that people think of are caused by THC.

Most recreational marijuana has very little CBD in it. CBD products are available through dispensaries, health food and convenience stores, and the internet. It’s a widely used product that’s not regulated—and is not legal to sell for its largely unproven health benefits.

How does CBD work?

Nobody really knows what is responsible for the mental and physical health benefits that have been attributed to it. CBD affects the body’s serotonin system, which controls our moods. It also affects several other signaling pathways, but we really don’t understand its mechanisms of action yet.

How much do we know about CBD as a potential treatment?

There are over 50 conditions that CBD is claimed to treat.

We do know that CBD can help control serious seizure disorders in some children (e.g., Dravet and Lennox-Gastaut syndromes) that don’t respond well to other treatments. Epidiolex is an FDA [Food and Drug Administration] approved medication containing CBD that can be used for this purpose.

There’s also data to suggest the potential of CBD as a treatment for schizophrenia and for substance use disorders. But these potential uses are in extremely early stages of development.

Are there side effects?

We don’t know of any severe side effects at this time. But there were mild side effects reported in the epilepsy studies, mostly gastrointestinal issues like diarrhea. There were also some reported drug-to-drug interactions. That’s why, for safety reasons, it’s important that CBD or any cannabis product go through the FDA review process.

Are there any specific CBD studies that you are focused on?

We are interested in CBD as a potential treatment of substance use disorders.

There is some research looking at it for opioid, tobacco, and alcohol use disorders. If CBD can help prevent relapse in those areas, that would be really interesting. We’re also interested in it for pain management. Trying to find less addictive medications for pain would help a lot of people.

What else would you like people to know?

Buyer beware.

We are concerned about the health claims being exaggerated or incorrect. The FDA issued warning letters to several companies because of untested health claims. And the CBD products themselves didn’t always contain the amount of CBD that they were reported to have—some actually had THC in them.

Another concern is that people are using CBD to treat ailments for which we have FDA-approved medications. Thus, they may be missing out on better treatments. And when they’re using CBD or other cannabis products for conditions we don’t know very much about, that’s worrisome.

via The ABCs of CBD: Separating fact from fiction | NIH MedlinePlus Magazine

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[WEB PAGE] Should epilepsy patients ever stop taking anti-seizure drugs?

Medication can control seizures in about two-thirds of people with epilepsy. The drugs are not a cure, but seizures don’t always last a lifetime; in as many as half of people with epilepsy, the seizures may stop on their own. This means there’s a subset of people taking anti-seizure medication who don’t need it.

After years without seizures, many people want to try stopping their medication. Some of them will stay seizure free, and some won’t.

Predicting who might safely come off medication and who should continue taking it is part science, part art and part personal preference. Some believe that anyone diagnosed with epilepsy should take medication for the rest of their lifetime; others say it’s clear that not all epilepsy is lifelong, and taking unnecessary medication for decades can be a physical, financial and psychological burden.

“There is certainly a group that benefits from medication withdrawal. Who are those patients and how do we identify them?” asked K.P. Vinayan, from the Amrita Institute of Medical Sciences in Kerala. Vinayan spoke during a debate at the ILAE International Congress in Bangkok focused specifically on tapering medication in people with adult-onset focal epilepsy with a known cause.

Alejandro De Marinis, University of Chile, represented the other side of the issue. “We have no idea when we should be taking someone off medication, or even if we should,” he said.

Roadblocks to research

Because of the variety of epilepsy types and patient characteristics, studies on stopping medication tend to combine heterogenous groups. One study might include adult-onset and pediatric onset epilepsy, generalized and focal epilepsy, and adults and children.

Randomized, double-blind studies-;while considered the gold standard of evidence-;are ethically compromising. Both physicians and people with epilepsy generally have strong opinions about whether to continue or stop medication, which could affect compliance. In addition, there’s general agreement that certain subgroups of people with epilepsy need to continue their medication for life.

Only two randomized studies about the effects of stopping medication have been completed; one also was double-blind. That study, known as the Akershus study, found that people whose medication was stopped (through gradual dose tapering) did not have a greater risk for seizures in the following year, compared with people who stayed on their medication. Of the group that stopped medication, 15% had seizures, compared with 7% of the group that continued. But because each group included only about 70 people, statistics showed that the difference in risk could have been due to chance (RR=2.46, 95% CI 0.85-7.08, p=0.095).

The other randomized trial-;a 1991 study of 1,013 adults and children authored by the Medical Research Council (MRC)-;found that stopping medication increased the risk for seizures in the first 2 years: 41% of the group that stopped medication had at least one seizure, compared with 22% of the group that stayed on medication. After that time point, the difference between the groups equalized.

A recent study from China focused specifically on people with adult-onset focal epilepsy. It categorized study participants by seizure-free period: 2 to 3 years, 3 to 4, 4 to 5, and more than 5. Unlike most studies, this one followed participants for up to 15 years after stopping medication.

The research found that people with at least 5 years of seizure freedom before stopping the medication could stop taking medication without an increased risk for seizures. Those with less than 5 years of seizure freedom under their belts were at double to triple the risk for seizures if they stopped their medication, compared with a similar group who stayed on their prescriptions.

In this study, most seizures happened during the first 4 years; in the group with 5 or more years of seizure freedom, most happened during the first 2 years.

As a real-world cohort study lasting more than 10 years, this study provides evidence for patients who would like to consider withdrawing from medications after a long period of seizure freedom.”

Xinshi Wang, First Affiliated Hospital of Wenzhou Medical University

She noted that seizure relapse rates were likely higher in this study than in most others, due to the study population. “Quite a proportion of adult-onset focal epilepsy is caused by focal lesions, whether detectable or undetectable,” said Wang. “This will result in recurrent seizures if the lesions are not removed through surgery.”

Risks and benefits

Study participants were not randomized; they chose whether to stop or continue medication. More than 80% decided to continue treatment. Other studies of patient preference have found similar skews; for example, a survey in Macedonia found that 55% of seizure-free adults preferred to stay on their anti-seizure medication.

“Patients who have been seizure free for a long time are usually tolerant of the drugs they are taking,” said Wang. “And some are afraid that a witnessed seizure would lead to job loss or put them in a dangerous situation.”

Wang said some people in the study may have been reluctant to stop medication because they had risk factors for seizure relapse, such as symptomatic epilepsy or abnormalities on EEG.

On the other hand, some patients may strongly prefer to try stopping their medication, due to side effects, cost, or other issues. This is another reason why clinicians must keep an open mind, said Vinayan, as they need to be involved in the process.

“If their physician is not willing to discuss this option with them, they may try to [stop taking medication] themselves,” she said. “This can be dangerous.”

Who stays seizure free?

Studies have found that between 34% and 88% of patients remained seizure free after stopping medication, which means that 12% to 66% had seizures. The wide range of estimates reflects diverse patient populations, study designs and follow-up times.

Only 15% of people had seizures in the Akershus study; however, that figure comes from the first year of follow-up. The study also had strict criteria that excluded people with certain risk factors for seizure relapse, such as juvenile myoclonic epilepsy or generalized epilepsy with abnormal EEG, as well as anyone taking more than one anti-seizure medication.

Over the years, studies have identified at least 25 factors associated with seizure risk after stopping medication. Eleven are included in an online risk estimator for health professionals. Based on a 2017 meta-analysis, the calculator estimates seizure risk two years and five years after medication is stopped.

Regaining seizure freedom

If seizures are going to recur, research suggests they will do so in the first five years after stopping medication, with about two-thirds of recurrences happening in the first year.

If seizures come back, how easy is it to regain control? Again results vary, due to diverse study populations and varying years of follow-up. A re-analysis of the 1991 MRC data found that 95% regained seizure control at 1 year and 90% at 2 years. A 2005 review of 14 studies found that between 76% and 85% of people could regain seizure freedom after stopping medication. In general, there are people who may need years to regain seizure control, or who may never regain it.

How and why this “acquired drug-resistant epilepsy” happens is still unknown, but certain subgroups appear to be at risk: People whose seizures were difficult to control after diagnosis, people who have been seizure free for a shorter period of time, and people who have focal seizures after stopping medication have all been shown to also have difficulty regaining seizure control.

A lack of seizure control can damage independence and affect driving privileges, employment prospects and overall quality of life.

Continuing medications is a solution that avoids any concerns about re-establishing seizure control, said De Marinis. “Complete seizure control is the best therapeutic measure to improve quality of life,” he said during the debate. “So we should keep people on the drugs.”

However, continued seizure freedom while taking medication is not a guarantee. The two randomized studies saw seizure recurrence rates in people who continued their medication of 7% after 1 year (Akershus) and 22% after 2 years (MRC). Participants in both studies had been seizure free for at least the previous 2 years.

An open question

De Marinis cautioned that any discussion of stopping medication must provide full information and interpretation. “They will need to know the chances of having seizures again, and that there is a chance that if they have seizures, they may no longer be controlled with medication,” he said.

Vinayan concluded that the data support stopping medication in some people; the key is carefully selecting the ones with the lowest risk profile.

“Many of the studies are in very diverse groups, with varying age at epilepsy onset,” he said. Yet they seem to consistently show that after a few years, about half of people who stop taking medication remain seizure free.

“We are not giving half of these people the benefit of coming off their medicine,” Vinayan said. “Because we don’t yet know who they are.”

Epilepsy surgery: A different animal?

Because epilepsy surgery is meant to “cure” seizures, it may seem like a natural next step for someone to stop taking anti-seizure medication after surgery. Though this is generally true for children, some adults remain on medication for years post-surgery, though many end up on tapered doses or fewer drugs.

Clinicians have no randomized trials to guide decisions; trials are done with selected patient cohorts, which “represent a biased sample in which both physicians and patients felt comfortable enough to attempt [medication] withdrawal,” said Lara Jehi in a 2013 commentary .

She suggested that medication withdrawal after surgery may be something like a cardiac stress test for coronary artery disease: A tool to screen for underlying pathology. However, she noted, until randomized controlled studies are done, this “stress test hypothesis” cannot be proven.

A 2015 meta-analysis calculated seizure-free rates of 71% after stopping medication after surgery. But a 2014 critical review estimated that only about 50% of “carefully selected” patients could successfully stop taking medication after temporal lobe surgery, and only about 25% could find success after extra-temporal surgery.

Even good candidates for stopping medication after surgery may prefer not to. A recent study in Denmark found that 3 seizure-free years after surgery, 62% of adults were still taking medication. About one-third were on the same doses and types of medications as before surgery; the rest were on reduced doses. Contacted again 4 years later (7 years after surgery), 18% were still taking medication.

Finding a balance

“For the most part, the decision to maintain the drugs was by the patient’s own wish, and not due to a doctor’s advice,” said study author Anna Stefansdottir, Copenhagen University Hospital.

“Perhaps the surgery allows them to decrease the medication doses and they reach a balance,” she said. “They are seizure free and their side effects have lessened. They’re happy with the results, even if they are still taking medication.”

Fear of relapse was the most commonly cited reason for continuing treatment. Because surgery can bring an end to years of seizures, it’s not surprising, said the authors, that people wouldn’t want to jeopardize that.

“When we discuss surgery, we tell patients that there will be an option to get off the medications,” said Anne Sabers, University of Copenhagen. “But maybe when a patient achieves seizure freedom after surgery, they don’t want to take that risk.”

 

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[WEB SITE] Causes of Seizures and Epilepsy

Epilepsy is a spectrum of neurological disorders involving recurring seizures. It is also possible to have nonepileptic seizures – seizures that are not caused by an epileptic disorder. Epilepsy and seizures have many different causes.

Epilepsy is not contagious. When the cause of a person’s epilepsy is known, it is called symptomatic or secondary epilepsy. Epilepsy with unknown causes is referred to as idiopathic or cryptogenic epilepsy. Some epilepsy is inherited or due to a genetic mutation. In other cases, epilepsy is structural in origin, resulting from brain damage or abnormal brain development.

Causes of epilepsy are often linked to the person’s age at diagnosis. In infants who have seizures, the cause is usually genetic or due to brain damage that happened during pregnancy or birth. In children, the cause of epilepsy could be genetic or due to fever, infection, or brain tumor. In people over 35, most epilepsy is caused by brain damage resulting from a stroke.

Genetic causes of epilepsy

Genes are known to play a role in approximately 30 to 40 percent of epilepsy cases. About 4 percent of Americans will develop epilepsy at some point in their lives. Having a first-degree relative (parent, child, or sibling) makes you two to four times more likely to develop epilepsy. It is common for family members who have epilepsy to have different types from one another.

Many cases of epilepsy are caused by a gene mutation, usually on a gene responsible for the activity of neurons in the brain. However, many people with a genetic mutation will never have seizures or develop epilepsy – an indication that genes are not the only factor that plays a role. When a genetic mutation occurs, seizures may be the first indication of a larger set of problems.

Hereditary types of epilepsy include juvenile myoclonic epilepsy (JME), childhood absence epilepsy (CAE), generalized epilepsy with febrile seizures plus (GEFS+), photosensitive epilepsy, and focal seizures.

Some of the known genetic causes of epilepsy are: Angelman syndrome, Doose syndrome (myoclonic astatic epilepsy), Down syndrome, Lennox-Gastaut syndrome, and Panayiotopoulos syndrome (PS). Read more about other genetic causes of epilepsy.

There is an association between autism spectrum disorder (ASD) and epilepsy. Approximately one-third of people on the autism spectrum also have epilepsy. Certain genetic syndromes, including Rett’s, fragile X, Prader-Willi, and Angelman, are associated with both seizures and autism. In children on the spectrum, intellectual disability increases the risk for developing epilepsy. An estimated 20 percent of autistic children with intellectual disability develop epilepsy, while 8 percent of those without intellectual problems begin having seizures. No specific type of epilepsy or severity of seizure is associated with ASD. The relationship between autism and epilepsy is poorly understood.

Some scientists believe there may be a genetic component to all forms of epilepsy. In other words, a person who starts having seizures always had a greater genetic likelihood to do so. If this is the case, when seizures begin after a brain injury or other structural change, it may be due to both the injury or change and the person’s genetic predisposition to seizures. This theory might explain why a brain injury might that leads to epilepsy in one person might not cause epilepsy in another person.

Structural causes of epilepsy

Abnormalities in the structure or metabolism (chemical processes) of the brain can cause seizures, some of which are considered nonepileptic seizures. Structural problems may be congenital (present at birth) or caused later by brain tumors, traumatic brain injuries (TBI) including automobile crashes and violence, strokes, brain infections, or alcohol or drug abuse. In situations like these, normal brain structure is distorted or disrupted, resulting in abnormal brainwaves that trigger seizures.

Metabolic causes of epilepsy include extreme dehydration, prescribed or illegal drugs, or extremely high or low blood glucose, as in uncontrolled diabetes. Metabolic problems can deprive brain cells of the glucose they need for fuel, or lower levels of electrolytes such as sodium or potassium needed in order to function properly. The result is abnormal brainwaves that cause seizures. Inflammation, which may occur as a result of TBI or a chronic inflammatory condition such as lupus, can flood the brain with proteins that may trigger seizures.

Congenital brain damage may be caused by malnutrition, infection, trauma, or drug use during pregnancy, or it may be due to a genetic defect. Children who are born prematurely or deprived of oxygen during birth can develop brain damage that causes seizures. Many newborns outgrow their seizures after the first month, but a small number will have difficult-to-treat seizures that can be lifelong. Typically, 50 to 75 percent of children who have epilepsy will eventually achieve seizure remission. The chances for remission are higher if seizure frequency is low, seizures are well treated by anti-epileptic drugs (AEDs), and there are no underlying neurological problems.

Epilepsy with unknown causes

“Idiopathic” comes from Greek words meaning “a disease of its own kind,” and it simply means that doctors do not know the cause. Similarly, “cryptogenic” comes from Greek words meaning “hidden cause.” As many as 60 percent of all epilepsies are the result of unknown causes. Certain types of seizures may stem from a scar or irritation on the brain, but the scar is undetectable by an MRI. If your doctor cannot identify the source of your epilepsy, you will be diagnosed with idiopathic or cryptogenic epilepsy. As brain imaging techniques improve, more causes of seizures will be identified.

Resources

External resources

MyEpilepsyTeam resources

FAQ

Is epilepsy inherited?

Yes and no. Certain genetic mutations that cause epilepsy are directly inherited, while some cases of epilepsy have no known genetic connection. However, some scientists believe that people who develop epilepsy always had a greater genetic predisposition for seizures. For instance, only 10 percent of people who suffer a traumatic brain injury (TBI) severe enough to require hospitalization develop epilepsy. Genes may be a risk factor that makes the difference between who develops seizures after a TBI and who does not.

If I have a seizure, do I have epilepsy?

Having one seizure does not mean that someone has epilepsy. In order to be diagnosed with epilepsy, a person must have had more than one seizure, and doctors must believe more seizures are likely. Some seizures are not related to epilepsy at all. Read more about how epilepsy is diagnosed.

via Causes of Seizures and Epilepsy | MyEpilepsyTeam

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[WEB SITE] Triggers and Epilepsy

Some common epileptic triggers are stress, eating certain foods, flashing lights, or even lack of sleep. Knowing what your triggers are may help when coping with epileptic seizures.

On MyEpilepsyTeam, the social network and online support group for those living with epilepsy, members talk about a range of personal experiences and struggles. Triggers are one of the top 10 topics most discussed.

Here are a few question-and-answer threads about triggers:

Has anyone noticed food triggers?

Who thinks that doing physical labor or exercise is a trigger?

Stress, lack of sleep, adrenaline rushes… what are other triggers you experience?

Here are some conversations about triggers:

I am stressing because I worry about my job and stress is a trigger for me.

•. Some of my triggers are overheating, eating MSG or citrus.

Christmas lights are a trigger for me.

Have another topic you’d like to discuss or explore? Go to MyEpilepsyTeam today and start the conversation.
You’ll be surprised just how many others may share similar stories.

via Triggers and Epilepsy | MyEpilepsyTeam

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[ARTICLE] 2020 Epilepsy Benchmarks Area III: Improved Treatment Options for Controlling Seizures and Epilepsy-Related Conditions Without Side Effects

Abstract

The goals of Epilepsy Benchmark Area III involve identifying areas that are ripe for progress in terms of controlling seizures and patient symptoms in light of the most recent advances in both basic and clinical research. These goals were developed with an emphasis on potential new therapeutic strategies that will reduce seizure burden and improve quality of life for patients with epilepsy. In particular, we continue to support the proposition that a better understanding of how seizures are initiated, propagated, and terminated in different forms of epilepsy is central to enabling new approaches to treatment, including pharmacological as well as surgical and device-oriented approaches. The stubbornly high rate of treatment-resistant epilepsy—one-third of patients—emphasizes the urgent need for new therapeutic strategies, including pharmacological, procedural, device linked, and genetic. The development of new approaches can be advanced by better animal models of seizure initiation that represent salient features of human epilepsy, as well as humanized models such as induced pluripotent stem cells and organoids. The rapid advances in genetic understanding of a subset of epilepsies provide a path to new and direct patient-relevant cellular and animal models, which could catalyze conceptualization of new treatments that may be broadly applicable across multiple forms of epilepsies beyond those arising from variation in a single gene. Remarkable advances in machine learning algorithms and miniaturization of devices and increases in computational power together provide an enhanced opportunity to detect and mitigate seizures in real time via devices that interrupt electrical activity directly or administer effective pharmaceuticals. Each of these potential areas for advance will be discussed in turn.

Introductory Vignette by Amanda Jaksha: Clinical Trials—A Parent’s Perspective

CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy that typically presents with refractory epilepsy, often epileptic spasms without hypsarrhythmia, in the first days or months of life. In 2012, at the age of 6.5 years, my daughter was diagnosed with CDD. By then, she had endured thousands of seizures and failed most available AEDs. She narrowly escaped liver failure from drug rash with eosinophilia and systemic symptoms syndrome upon the introduction of a second-generation AED adjunct therapy. Also seasoned in failed treatments for comorbidities of dysmotility, behavior, and sleep, we become cynical about introducing any compounds.

We recently convened serious discussions about seizure control due to a decrease in her quality of life, with puberty onset increasing daily seizure activity. My daughter was a candidate for 2 clinical trials, one a blinded, placebo-controlled study and the other an open-label investigation. It was a simple choice as there was no time for a placebo. Upon completion of the observation period, she received her first dose around 6 weeks later. There was an immediate increase in seizures, and a few days later, a gradual reduction from baseline activity emerged. Anxiety and vocal stimming behaviors decreased substantially, and her gross motor skills became more fluid and sustained. With these improvements, she enjoys more functional access to community and more independence with the ability to ambulate longer distances. She also appreciates expressing more of her voice as she uses her eyes to talk via an eye-gaze communication (AAC) device. She can tell me to go away or that she feels diabolical with higher efficiency and less frustration. While her epilepsy remains refractory, to our surprise and delight, her quality of life has increased beyond anything imagined with this assumed improvement in other neuronal functions.

—Amanda Jaksha, International Foundation for CDKL5 Research

Introduction to Area III

The goals of Epilepsy Benchmark Area III involve identifying areas that are ripe for progress in terms of controlling seizures and patient symptoms in light of the most recent advances in both basic and clinical research. These goals were developed with an emphasis on potential new therapeutic strategies that will reduce seizure burden and improve quality of life for patients with epilepsy. In particular, we continue to support the proposition1 that a better understanding of how seizures are initiated, propagated, and terminated in different forms of epilepsy is central to enabling new approaches to treatment, including pharmacological as well as surgical and device-oriented approaches. The stubbornly high rate of treatment-resistant epilepsy—one-third of patients2—emphasizes the urgent need for new therapeutic strategies, including pharmacological, procedural, device linked, and genetic. The development of new approaches can be advanced by better animal models of seizure initiation that represent salient features of human epilepsy,3 as well as humanized models such as induced pluripotent stem cells (iPSCs) and organoids.4 The rapid advances in genetic understanding of a subset of epilepsies5,6 provide a path to new and direct patient-relevant cellular and animal models, which could catalyze conceptualization of new treatments that may be broadly applicable across multiple forms of epilepsies beyond those arising from variation in a single gene. Remarkable advances in machine learning algorithms and miniaturization of devices and increases in computational power together provide an enhanced opportunity to detect and mitigate seizures in real time7,8 via devices that interrupt electrical activity directly or administer effective pharmaceuticals. Each of these potential areas for advance will be discussed in turn.

Seizure Mechanisms

There remains a pressing need to understand the initiation, propagation, and termination of seizures at the network level in different forms of epilepsy in order to devise better treatment strategies. Understanding how neuronal synchrony within a microcircuit reaches a critical threshold, subsequently allowing it to entrain larger populations of neurons, could suggest novel mechanisms that can be engaged to terminate a seizure. Although there are volumes of work on this topic over the decades,911 new advances in stratification of epilepsies through pharmacogenomics12 and genetic analysis13 could provide new understanding of mechanisms in models relevant for human disease. Advances in computational models have reached the point where both interictal and ictal activities can be reliably generated from the same network. The predictions of these models can now be practically verified.14,15 Additional insights may also follow from a determination of the relative contribution of shared cellular and network mechanisms to different models. Similarly, advances in modeling the process of epileptogenesis suggest interesting new mechanisms, yet highlight the complexity of the problem.16 These mechanisms could lead to the testing of more effective therapies.

Status epilepticus remains a clinical challenge, with a subset of patients proving refractory to multiple treatments17 despite the development and approval of new antiseizure medications (ASMs). The persistent seizures associated with this condition focus attention on how little we understand about the processes of seizure initiation, maintenance, and termination. Thus, insight into mechanisms that maintain hypersynchronous firing for prolonged durations in the face of adaptive changes, exhaustion of energy stores, and mounting inflammatory cascades may allow improved treatments that can stop ongoing seizures and status epilepticus. Although a variety of processes are considered relevant to status epilepticus,1820 we still lack a clear assessment of the relative contributions of each one. New mechanism-based targets would improve our ability to effectively terminate status epilepticus.

An impressive amount of electrophysiological analysis of mechanisms that can lead to hypersynchronous firing has been performed either in vivo in adult animals or ex vivo in brain slices from rodents that range in age from adolescence to young adulthood. There is a growing opportunity to complement animal tissue work with acute and organotypic human brain slices obtained following surgical resection21,22 as well as in vivo recordings from depth electrode–implanted patients.23 However, there is a stark lack of information in some areas, for example, related to features of the neonatal brain that contribute to hypersynchronous activity, apart from changes in chloride (Cl) gradients that render GABAergic transmission excitatory.24,25 Early-life seizures are an important therapeutic target because many epileptic encephalopathies become apparent early in life. In particular, understanding the mechanisms underlying hypersynchronous firing in neonatal brain could lead to the development of therapies that are more effective for neonatal seizures as opposed to simply modifying the dosing of drugs that showed a positive signal in clinical trials in adults with epilepsy. Strategies could involve use of repurposed drugs, specific combinations of therapies, or the development of new therapies, noting, however, the substantial hurdles for bringing to market drugs for a pediatric population. Although the first uncontrolled trial of the repurposed drug bumetanide did not show efficacy,26 this finding was controversial,27,28 and the results of a subsequent blinded controlled trial of bumetanide is reported to be more promising (clinicaltrials.govNCT00830531). To this end, new genetic models of ultrarare variants in genes capable of producing seizures and hyperexcitability may provide new models of mechanisms underlying development of an epileptic focus in neonatal animals. Indeed, multiple animal models of genetic epilepsies show seizure activity at an early age, providing an opportunity to study epilepsy in the developing brain.

The role of inflammation has been increasingly recognized in a wide range of neurological diseases, including epilepsy and status epilepticus.2931 Neuroinflammation can impact network excitability in several ways, including activating microglia, reshaping synaptic input, and altering ion channel function. Thus, there is the potential to explore anti-inflammatory therapies for use in conjunction with conventional ASMs in the chronic therapy of epilepsies that are thought to be inflammatory in nature, such as Rasmussen encephalitis.32 In addition, the utility of some treatments for seizure categories not conventionally believed to be related to inflammatory mechanisms should be explored. This has the potential to perhaps reduce the refractory rate, or increase seizure control, for some groups of patients.

There is an emerging appreciation of autoimmune encephalitis33 that involves antibodies against epitopes in proteins that control neuronal excitability, such as the NMDA receptor,34 GAD65,35 and GABAB receptor subunits.36,37 Patients with antibody-mediated encephalitis often exhibit nonconvulsive seizures, in addition to memory loss, psychiatric symptoms, and other features. For some epitopes, preclinical data validate the immunoglobulin G fraction as causative for seizures. Treatment with immunotherapy can be effective, but additional therapeutic strategies are needed.36,38 The full extent of this clinical condition is just now becoming appreciated, and it remains almost certainly underdiagnosed at this point. Thus, future work should focus on earlier recognition of these presentations and early and robust diagnosis in order to achieve potentially effective treatment before the development of irreversible sequelae of neuroinflammation.

Genetic Advances

An important consequence of the many genetic advances that are transforming clinical neurology39 is their ability to suggest new animal models to investigate the underlying disease mechanisms, including compensatory mechanisms that can contribute to a seizure focus.40 Such models are relevant to genetic human epilepsies and serve as an important complement to the acquired models of focal epilepsy (eg, pharmacologically induced seizure models) that have become the mainstay for development of in vivo models of chronic recurring seizures. Animal models of single-gene defects offer an opportunity to evaluate windows for therapeutic intervention in patients who have these specific variants, with the possibility that some therapies will be more broadly applicable to multiple epilepsies. In addition, such models offer a new opportunity to study common mechanisms that underlie maladaptive plasticity and can lead to generation of a seizure focus. Novel gene expression programs may be triggered by genetic deficiencies that engage similar mechanisms, and understanding these might allow better understanding of antiepileptic drug utility.40 In this respect, the intersection of gene expression data sets may inform key pathways that establish seizure foci regardless of the initial genetic defect driving seizures. In addition, genetic animal models can facilitate the evaluation and validation of strategies such as antisense oligonucleotides, gene replacement, and gene augmentation. The success of new genetic treatments of spinal muscular atrophy with intravenously delivered gene replacement via adeno-associated viral vector in very young infants41 has created hope for many patients that these therapies can correct other neurological conditions, stimulating work on this problem in academia and, importantly, in industry. Thus, there are actionable opportunities for genetic therapies for epilepsy on the horizon.

In addition to the value of new models suggested by genetic analysis, there are several opportunities to exploit advances in diagnostic and therapeutic genetic approaches. There are now multiple examples of strategies one could use to develop gene therapy employing viral vectors to treat focal and generalized epilepsies in animal models in which a missense variant or truncating mutation has modified the function of a target gene or reduced the gene dose.42 Other innovative uses of gene therapy include introduction of potassium channels that could reduce excitability, as well as engineering cells to release neuroactive molecules that can counteract excessive excitability.43,44 As more animal models are developed for different genes, there will be opportunities to test fundamental approaches that supplement underexpressed alleles or proteins with reduced function, as well as editing gene approaches to correct identified defects. These strategies will require demonstration of utility in animals with measurable defects, and the results will speak to the important question in epilepsy around whether symptoms are driven by the genetic defect, are a feature of maladaptive compensation, or reflect some combination of both. That is, there is a need for proof-of-concept data for oligonucleotide and antisense therapies for application in the treatment of genetically defined monogenic epilepsies, as well as data on effectiveness of the timing of treatment in the context of the development of a seizure focus. Advances are needed in genetic therapy using virus delivery vectors that are already approved for other payloads and access both brain and spinal cord following intrathecal administration. The rare genetic epilepsies might provide a test case for intervention, which can be evaluated in iPSC-based models in vitro, organoids derived from iPSC cells, and animal models now.

One opportunity that the accessibility of multiple new genetic models of human variants associated with epilepsy offers is evaluation of repurposed drugs. This requires a comprehensive functional evaluation of the effects of rare variants in vitro, which for ion channels is accessible. Functional evaluation of drug sensitivity of variant proteins will inform potential use of therapeutics, as will knowledge of the nature of the net functional effects as either gain of function or loss of function, or indeterminant.4549 Genetic models—from cellular models to zebrafish and mouse models—harboring variants can then be screened for actions of Food and Drug Administration (FDA)-approved medications for efficacy in reducing electroencephalogram abnormalities and seizures46,50,51 as a step toward using pharmacological treatments. If the models capture patient-relevant features of epileptogenesis, early treatment within a vulnerable window might have long-lasting consequences.

In addition to these pharmacological approaches, bioinformatics coupled with large-scale data sets have driven the development of computational resources52,53 that can suggest candidate drugs in the FDA library from patterns of changes in gene expression. Moreover, evaluation of multiple drugs in multiple models might identify candidate drugs as add-on therapies that could be used more broadly than for just for rare genetic conditions. Indeed, a large number of epilepsy models have been or are being made from various genes identified in patients with rare epilepsies (eg, sodium channels, potassium channels, postsynaptic ligand-gated ion channels, synaptic proteins), which will provide patient-relevant models in which to assess new pharmacological strategies. These same models can be used to understand developmental compensation, transformation of the foci with time, and pharmacological sensitivity. It seems likely that some compensatory mechanisms will be shared across these different models and may inform treatment of refractory epilepsy. In addition to rodent models, use of companion models and organisms (fly, zebrafish, mice, iPSC-derived neuronal cultures, and organoids) could provide faster and more efficient drug screening43 as well as evaluation of compensatory mechanisms.

The advances in genetic analysis could also expand our understanding of acquired epilepsies and yield insight into whether persons with genetic predispositions may be at greater risk and merit more aggressive treatment and management. This will require concerted effort to capture genetic information from patients with acute events that lead to seizures or increase seizure risk. With a sufficient sample size, some common polygenic factors might emerge, suggesting genes or genetic patterns that imply risk.6 In some cases, one might consider treating the predisposition if it can be identified as the first step to gain adequate seizure control before considering, for example, epilepsy surgery. This same form of analyses could be applied to traumatic brain injury, stroke, hypoxia, and other insults that enhance the likelihood of future seizures.

Refractory Epilepsy

About one-third of patients with epilepsy are in part or fully refractory to treatment, creating an enormous medical, social, and economic burden. Thus, an essential aspect of any future prioritization is the need to develop new or improve existing antiseizure therapies for patients with refractory epilepsy. Efforts should include analysis of sequencing data for patients who fail to show adequate improvement following surgical intervention to determine whether there are shared risk factors, as well as those who successfully respond. Approaches that deserve consideration in this regard include conventional drug development, selection of surgical patients, and genetic analysis of both responsive and refractory patients. Toward this end, several new drugs have entered clinical use following FDA approval, including cannabidiol for Dravet and Lennox-Gastaut syndromes,54,55 nasally administered midazolam for seizure clusters,56 stiripentol for Dravet syndrome,57 and everolimus for seizures in patients with tuberous sclerosis complex.58 In addition, new treatment approaches for specific epilepsies are under investigation with novel or disease-specific targets, including AMPA receptors containing the TARPγ8 subunit, expressed predominantly in the temporal lobe and of potential relevance to mesial temporal lobe epilepsy59; KCNQ (Kv7) potassium channels implicated in KCNQ2 developmental and epileptic encephalopathy60; and serotonin systems, representing a target of fenfluramine, which have been reported to cause seizure reduction in patients with Dravet syndrome.61 New routes of drug administration are also being explored.62 It will be important to carefully evaluate the utility of these new medications in refractory epilepsy beyond the initial indications for which they are tested or approved.

In addition to new medications, more effort is needed to understand the mechanisms of pharmacoresistance in order to overcome refractoriness to ASMs. To this end, new animal models together with humanized models in vitro based on genetic data may provide an opportunity to explore mechanisms of resistance for those specific models with clear seizure phenotypes for which the patient is known to be refractory to treatment with conventional anticonvulsants. Work in this area would benefit from integration of information about new targets into existing efforts to develop new medications that are effective against refractory seizures. In addition to traditional targets such as ion channels, neurotransmitter receptors, and neurotransmitter transporters, important targets include mTOR and related pathways, the extracellular matrix, oxidative stress, anti-inflammatory pathways, neurosteroid systems, microRNAs, and epigenetic targets include histone deacetylase.30,31,6367 Cell replacement strategies to introduce engineered cells that can support or release neuroactive substances and oligonucleotide approaches to regulate specific genes for therapeutic gain are also opportunities to identify new ways to treat refractory epilepsy. Moreover, clarification of the mechanisms underlying the ketogenic diet might identify metabolic and lipid targets that are relevant, the role of the gut microbiota,68 and allow a “ketogenic diet in a pill” treatment strategy for refractory epilepsy.

Real-Time Management of Seizures

Efforts have been made for decades to predict when seizures will occur and provide an immediate intervention to either prevent or terminate the seizure.69 These efforts rely on a range of recording devices, computational algorithms to identify at-risk periods, and active response in the form of electrical/optical stimulation or administration of a drug. Although there has been steady progress with these strategies over the decades, many approaches are maturing to the point where they seem poised to provide a workable and effective therapy for a larger number of patients.70 Indeed, the introduction in 2013 of an FDA-approved closed loop device that detects seizures and aborts them by deep brain stimulation has spawned many efforts to refine stimulation parameters for better seizure control.71 New seizure prediction algorithms8 as well as new devices may allow intravenous injection or even direct infusion of antiseizure agents into the brain at the onset of or immediately before a seizure is predicted.72 This approach has the capacity to harness the utility of proven pharmacological treatments without the side effects of chronic exposure to drug in blood and brain. Taken a step further, introduction of active drug locally into the epileptic focus could provide more selective treatment of certain epileptic conditions, including refractory epilepsies, localization-related epilepsies, and status epilepticus. Increasing power of computational algorithms7 should allow enhanced ability to predict seizures from multiple streams of data, including electrical recordings and peripheral readouts. In addition, miniaturization of devices can improve the ability to deliver electrical, light, or pharmacological stimuli to specific regions both inside and outside of the central nervous system. The emergence of new animal models of genetic epilepsies provides another opportunity to test detection and seizure interruption strategies in homogeneous models that share some basis with human epilepsy and thus might provide robust data that can be translated to patients harboring these variants. A range of models might stimulate improvements in the low signal to noise ratio in seizure prediction and in the abortion of seizures, such as evaluation of new biomarkers that change prior to seizure initiation73 and consideration of circadian rhythms.74 Ultimately, these systems need to be suitable for self-management in the home and other nonmedical settings in order to improve adherence and efficacy.

Taken to its logical albeit futuristic conclusion, one might envision a paradigm shift from ASMs in the form of multiple doses of a drug per day and steady-state blood levels (with attendant side effects) to delivery systems that provide anticonvulsants to the brain at the site they are needed and only when they are needed, improving the quality of life of the patient. Further, each patient’s treatment would be customized based on genetic and molecular profiles. This form of precision medicine would eliminate the need for chronic and systemic nonspecific and side effect-laden pharmacotherapy, improving efficacy and possibly reducing the development of pharmacoresistance.

Source: https://doi.org/10.1177/1535759719895279

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