Study reveals how CBD counters epileptic seizures – important for members of the autistic community

Microscope image


This microscope image of the brain region called the hippocampus shows the protein targeted by cannabis-derived CBD, GPR55 (red), and brain cells (blue) that send their extensions out to form the layers seen in the image. The interconnected nature of the hippocampus makes it a significant site for the initiation and spread of seizures.
Tsien et al, Courtesy of Cell Press

A study reveals a previously unknown way in which cannabidiol (CBD), a substance found in cannabis, reduces seizures in many treatment-resistant forms of pediatric epilepsy.  

Led by researchers at NYU Grossman School of Medicine, the new study found that CBD blocked signals carried by a molecule called lysophosphatidylinositol (LPI). Found in brain cells called neurons, LPI is thought to amplify nerve signals as part of normal function but can be hijacked by disease to promote seizures.

Published online February 13 in Neuron, the work confirmed a previous finding that CBD blocks the ability of LPI to amplify nerve signals in a brain region called the hippocampus. The current findings argue for the first time that LPI also weakens signals that counter seizures, further explaining the value of CBD treatment.   

“Our results deepen the field’s understanding of a central seizure-inducing mechanism, with many implications for the pursuit of new treatment approaches,” said corresponding author Richard W. Tsien, chair of the Department of Physiology and Neuroscience at NYU Langone Health.

“The study also clarified, not just how CBD counters seizures, but more broadly, how circuits are balanced in the brain,” added Tsien. “Related imbalances are present in autism and schizophrenia so that the paper may have a broader impact.”

Disease-Causing Loop

The study results build on how each neuron “fires” to send an electrical pulse down an extension of itself until it reaches a synapse, the gap that connects it to the next cell in a neuronal pathway. When it reaches the cell’s end before the synapse, the pulse triggers the release of compounds called neurotransmitters that float across the gap to affect the next cell in line. Upon crossing, such signals either encourage the cell to fire (excitation), or apply the brakes on firing (inhibition). Balance between the two are essential to brain function; too much excitation promotes seizures.   

The new study looked at several rodent models to explore mechanisms behind seizures, often by measuring information-carrying electrical current flows with fine-tipped electrodes. Other experiments looked at the effect of LPI by genetically removing its main signaling partner, or by measuring the release of LPI following seizures.

The tests confirmed past findings that LPI influences nerve signals by binding to a protein called G-coupled receptor 55 (GPR55), on neuron cell surfaces. This LPI-GPR55 presynaptic interaction was found to cause the release of calcium ions within the cell, which encouraged cells to release glutamate, the main excitatory neurotransmitter. Further, when LPI activated GPR55 on the other side of the synapse, it weakened inhibition, by decreasing the supply and proper arrangement of proteins necessary for inhibition. Collectively, this creates a “dangerous” two-pronged mechanism to increase excitability, say the authors.  

The research team found that either genetically engineering mice to lack GPR55, or treating mice with plant-derived CBD prior to seizure-inducing stimuli, blocked LPI-mediated effects on both excitatory and inhibitory synaptic transmission. While prior studies had implicated GPR55 as a seizure-reducing target of CBD, the current work provided a more detailed, proposed mechanism of action.

Zeroing in on a new treatment for autism and epilepsy

Scientists at Gladstone Institutes


Scientists at Gladstone Institutes reports new findings that could guide the development of better therapeutic strategies for Dravet syndrome and related conditions. Shown here are the study’s first authors, Eric Shao (left) and Che-Wei Chang (right). CREDIT Photo: Michael Short/Gladstone Institutes

Children with Dravet syndrome, a severe form of epilepsy that begins in infancy, experience seizures, usually for their entire life. They are at high risk of sudden unexpected death in epilepsy (SUDEP) and can also develop intellectual disability and autism. Available treatments typically fail to improve these symptoms.

Now, a group of scientists at Gladstone Institutes led by Lennart Mucke, MD, reports new findings in the journal Science Translational Medicine that could guide the development of better therapeutic strategies for Dravet syndrome and related conditions.

The researchers previously discovered, in a mouse model of Dravet syndrome, that genetically removing the protein tau from the entire body during embryonic development reduces epilepsy, SUDEP, and autism-like behaviors. In the new study, they pinpoint the key cell type in the brain in which tau levels must be reduced to avoid these problems. They also show that lowering tau is still effective in mice when the intervention is delayed until after their birth.

“Our findings provide new insights into the cellular mechanisms by which tau reduction prevents abnormal overexcitation in the brain,” says Mucke, director of the Gladstone Institute of Neurological Disease. “They are also encouraging from a therapeutic perspective, since in humans, initiating treatment after birth is still more feasible than treating embryos in the womb.”

Tau is a promising therapeutic target not only for Dravet syndrome, but also for a variety of other conditions, including different types of epilepsy and some forms of autism, as well as Alzheimer’s disease and related neurodegenerative disorders.

Pinpointing the Crucial Brain Cells

A well-functioning brain depends on the correct balance between the activity of excitatory and inhibitory neurons—the former stimulate the activity of other neurons, while the latter suppress it. Dravet syndrome causes an imbalance between these types of cells, resulting in abnormally high and synchronized activity in brain networks that can manifest as seizures and other symptoms.

Mucke and his colleagues recently showed that removing tau from the entire brain changes the activities of both excitatory and inhibitory neurons, although in different ways. The current study aimed to determine whether it is more important to reduce tau in excitatory or inhibitory neurons.

For this purpose, the scientists used genetic tools to eliminate tau selectively from one or the other cell type in the Dravet mouse model. They found that removing tau from excitatory neurons reduced disease manifestations, whereas removing tau from inhibitory neurons did not.

“This means that tau production in excitatory neurons sets the stage for all these abnormalities to occur, including autistic behaviors, epilepsy, and sudden unexpected death,” says Mucke, who is also the Joseph B. Martin Distinguished Professor of Neuroscience and a professor of neurology at UC San Francisco.

Initiating Treatment after Birth

While the genetic approaches the scientists used to remove tau from specific cell types are effective and precise, they are not yet easy to use as a therapeutic intervention in humans. So, the team turned to a more practical option: global tau reduction in the brain with DNA fragments known as antisense oligonucleotides, or ASOs. The scientists delivered an anti-tau ASO into the brain of mice 10 days after birth and found that most symptoms of Dravet syndrome were gone 4 months later.

“We observed a robust reduction of SUDEP, seizure activity, and repetitive behaviors,” says Eric Shao, PhD, a scientist in Mucke’s lab and first author of the study.

In addition, the ASO treatment had no obvious side effects.

“We are excited about these findings, especially since another anti-tau ASO has already undergone a Phase I clinical trial in people with Alzheimer’s disease,” says Mucke. “It could be useful to consider this strategy also for Dravet syndrome and related conditions. However, defining the optimal timing for treatment initiation will be key, as the window of opportunity might be quite narrow.”

Although Alzheimer’s disease, epilepsy, and autism have diverse causes, they all seem to be associated with abnormally high ratios between excitatory and inhibitory neuronal activities—and this abnormality could potentially be fixed by tau-lowering therapeutics.

Still, a treatment based on anti-tau ASOs would involve repeated spinal taps, a procedure most people would rather avoid. Therefore, Mucke is partnering with Takeda Pharmaceuticals to develop small molecules that could reduce brain tau levels when administered as a pill.

New dietary treatment for epilepsy well tolerated and reduced seizures – useful for the autism community

The first clinical trial of a new dietary treatment for children and adults with severe forms of epilepsy, co-developed by UCL researchers and based on the ketogenic diet, has been successfully completed.

For the study, published in Brain Communications, clinicians evaluated the use of K.Vita®, (also known as Betashot), an oral liquid dietary supplement developed by UCL in collaboration with Royal Holloway, University of London, and Vitaflo International Ltd.

The ketogenic diet (KD) consists of high-fat, low-carbohydrate and adequate protein consumption and mimics the fasting state, altering the metabolism to use body fat as the primary fuel source. This switch from carbohydrates to fat for body fuel is known as ketosis.

It is widely used to treat drug resistant epilepsies. However, the highly restrictive diet, which can cause constipation, low blood sugar, and stomach problems, can have poor compliance and is not suitable for everyone. Some KD supplements are also known to be unappetising.

K.Vita is based on novel findings by UCL researchers*, who discovered a different underlying mechanism to explain why the KD is effective against epilepsy; in developing a new treatment, researchers also sought to reduce the adverse side effects caused by KD.

Corresponding author Professor Matthew Walker (UCL Queen Square Institute of Neurology) said: “The ketogenic diet has been used for 100 years to treat epilepsy, helping reduce seizures in both children and adults.

“It has long been thought the diet was effective due to its production of ketones**, however we now believe the increase in levels of the fatty acid, decanoic acid, also produced by the diet, may provide the powerful antiseizure effects.

“In this study we evaluated a newly developed medium chain triglyceride (type of dietary fat) supplement, designed to increase levels of decanoic acid, while also reducing the adverse side effects, and to be more palatable.”

For the feasibility trial, researchers wanted to establish participants’ tolerance (side effects such as bloating or cramps) to the treatment, acceptability (flavour, texture, taste) and compliance (how easy it is to use K.Vita at the advised quantity, as part of their daily diet).

As secondary outcomes, they also monitored the frequency of epileptic seizures or paroxysmal events (fits, attacks, convulsions) and whether ketone production was decreased.

In total, 35 children (aged 3 to 18) with genetically caused epilepsy and known to be unresponsive to drugs, and 26 adults with drug-resistant epilepsy*** (DRE), were given K.Vita liquid supplements (a drink), to be taken with meals. They were also asked to limit high-refined sugary food and beverages from their diets.

The trial lasted 12 weeks with K.Vita treatments increasing incrementally over time, taking into account individuals’ tolerance to the treatment.

In total, 23/35 (66%) children and 18/26 (69%) adults completed the trial i.e they were continuing to take K.Vita at 12 weeks. Gastrointestinal disturbances were the primary reason for discontinuation, and their incidence decreased over time

Over three-quarters of participants/caregivers reported favourably on sensory attributes, such as taste, texture and appearance, and ease of use.

In regards to the secondary outcomes, there was a mean 50% reduction in seizures or paroxysmal events, and fewer than 10% of people on the diet produced significant ketones.

Commenting on the findings, Professor Walker, who is also a consultant neurologist at the National Hospital for Neurology and Neurosurgery, said: “Our study provides early evidence of the tolerability and effectiveness of a new dietary supplement in severe drug-resistant epilepsies in adults and children and provides a further treatment option in these devastating conditions.

“It also offers an alternative, more liberal, diet for those who cannot tolerate or do not have access to ketogenic diets.”

He added: “While this study was not designed to include enough patients to fully assess the supplement’s effects on seizures, it is exciting to report that there was a statistically significant reduction in the number of seizures in the group overall after three months of treatment.

“Furthermore, high ketone levels were not observed in over 90% of the participants. This indicates that the effect of the diet was independent from ketosis; this is important because high ketone levels in the ketogenic diets contribute to both short- and longer-term side effects.”

First author, Dr Natasha Schoeler, Research Dietitian at UCL Great Ormond Street Institute of Child Health, commented: “This novel dietary approach for epilepsy management involves following the principles of a healthy balanced diet alongside use of K.Vita, allowing greater dietary freedom compared to ketogenic diets. Our approach also requires much less input from a specialist dietician than is required by traditional ketogenic diets, and so may allow more widespread access to people with drug-resistant epilepsy.”

Researchers say larger, controlled studies of K.Vita are now needed to determine the precise epilepsies and conditions in which the supplement is most effective.

Purple Day 2019 – Helping Children With Epilepsy Live Better

Epilepsy is one of the most common neurological conditions worldwide; with around 600,000 people in the UK being diagnosed with epilepsy; 112,000 of these being children and young people.

Purple Day (26th March 2019) exists to promote international awareness, education and conversation about the condition. Epilepsy Action is calling for people to support Purple Day, and start talking about the effects that epilepsy has upon those living with the condition, and their family and friends.

One in every 240 children aged 16 and under in the UK will be diagnosed with epilepsy. Some of these children will be babies, some will be starting school and some will be teenagers. Every year, around 40-80 of these children will die because of their epilepsy.

Epilepsy is a condition that affects the brain. A seizure happens when there is a sudden burst of intense electrical activity in the brain. There are many different types of epileptic seizures, and these can affect people differently such as; having strange sensations, movements that can’t be controlled and falling to the floor and shaking.

Children with epilepsy also have a one in 4,500 risk of ‘Sudden Unexpected Death in Epilepsy’ (SUDEP), which is when a child with epilepsy dies suddenly and no reason can be found.

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Epilepsy Action chief executive Philip Lee said:“Finding out you have epilepsy is scary at any age. For young children, it can be terrifying. This Purple Day, Epilepsy Action wants to help children and their families to learn more about epilepsy, let them know they’re not alone and give them the confidence to deal with their diagnosis. We also know that it can be very hard for children to put into words their epilepsy and how it affects them.”

Picture: Ian Hodgkinson / Picture It Homefields Primary school in Parkway Chellaston has won the Edward award from Epilepsy Action in recognition for their work supporting seven year old Amrit Shergill. Pictured from left year 1+2 teacher Gail Heald, mum Gurvinder Shergill, Amrit Shergill, seven, with Will Butterworth from Epilepsy Action

Children with epilepsy are consistently found to be behind their peers academically, and to report a reduced quality of life compared to that of their peers. Supporting Purple Day can help explain epilepsy to children in a way that they understand, and also get more resources to teaching staff meaning children with epilepsy can be better supported to succeed in school.

Epilepsy Action has created a short video with groups of children, some living with epilepsy, talking through what the condition is and how it affects their lives.

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Rachael King, mum to Jenson, William and Darcie who took part in the filming said:“I think it’s really important for the children to talk about their epilepsy – not only to raise awareness of the condition and what to do if they have a seizure but also so they can share their experiences in a positive way and be proud of how strong they are. I don’t want their epilepsy to ever hold them back through childhood or anything they want to do in life. By sharing their journey from an early age it will hopefully make more people aware of the condition and get support from friends – putting an end to any misconceptions and prejudice about the condition.”

For more information visit https://www.epilepsy.org.uk/

Epilepsy – what are the signs and symptoms to look out for?




Epilepsy

Epilepsy




The main symptom of epilepsy is repeated seizures. These are sudden bursts of electrical activity in the brain that temporarily affect how it works.

Seizures can affect people in different ways, depending on which part of the brain is involved.

Some seizures cause the body to jerk and shake (a “fit”), while others cause problems like loss of awareness or unusual sensations. They typically pass in a few seconds or minutes.

Seizures can occur when you’re awake or asleep. Sometimes they can be triggered by something, such as feeling very tired.

 

Types of seizures

Simple partial (focal) seizures or ‘auras’

A simple partial seizure can cause:

a general strange feeling that’s hard to describe

a “rising” feeling in your tummy – like the sensation in your stomach when on a fairground ride

a feeling that events have happened before (déjà vu)

unusual smells or tastes

tingling in your arms and legs

an intense feeling of fear or joy

stiffness or twitching in part of your body, such as an arm or hand

You remain awake and aware while this happens.

These seizures are sometimes known as “warnings” or “auras” because they can be a sign that another type of seizure is about to happen.

Complex partial (focal) seizures

During a complex partial seizure, you lose your sense of awareness and make random body movements, such as:

smacking your lips

rubbing your hands

making random noises

moving your arms around

picking at clothes or fiddling with objects

chewing or swallowing

You won’t be able to respond to anyone else during the seizure and you won’t have any memory of it.

Tonic-clonic seizures

A tonic-clonic seizure, previously known as a “grand mal”, is what most people think of as a typical epileptic fit.




They happen in two stages – an initial “tonic” stage, shortly followed by a second “clonic” stage:

tonic stage – you lose consciousness, your body goes stiff, and you may fall to the floor

clonic stage – your limbs jerk about, you may lose control of your bladder or bowel, you may bite your tongue or the inside of your cheek, and you might have difficulty breathing

The seizure normally stops after a few minutes, but some last longer. Afterwards, you may have a headache or difficulty remembering what happened and feel tired or confused.

Absences

An absence seizure, which used to be called a “petit mal”, is where you lose awareness of your surroundings for a short time. They mainly affect children, but can happen at any age.

During an absence seizure, a person may:

stare blankly into space

look like they're "daydreaming"

flutter their eyes

make slight jerking movements of their body or limbs

The seizures usually only last up to 15 seconds and you won't be able to remember them. They can happen several times a day.

Myoclonic seizures

A myoclonic seizure is where some or all of your body suddenly twitches or jerks, like you've had an electric shock. They often happen soon after waking up.

Myoclonic seizures usually only last a fraction of a second, but several can sometimes occur in a short space of time. You normally remain awake during them.

Clonic seizures

Clonic seizures cause the body to shake and jerk like a tonic-clonic seizure, but you don't go stiff at the start.

They typically last a few minutes and you might lose consciousness.

Tonic seizures

Tonic seizures cause all your muscles to suddenly become stiff, like the first stage of a tonic-clonic seizure.

This might mean you lose balance and fall over.

Atonic seizures

Atonic seizures cause all your muscles to suddenly relax, so you may fall to the ground.

They tend to be very brief and you'll usually be able to get up again straight away.

Status epilepticus

Status epilepticus is the name for any seizure that lasts a long time, or a series of seizures where the person doesn't regain consciousness in between.

It's a medical emergency and needs to be treated as soon as possible.

You can be trained to treat it if you look after someone with epilepsy. If you haven't had any training, call 999 for an ambulance immediately if someone has a seizure that hasn't stopped after five minutes.

Seizure triggers

For many people with epilepsy, seizures seem to happen randomly.

But sometimes they can have a trigger, such as:

stress

a lack of sleep

waking up

drinking alcohol

some medications and illegal drugs

in women, monthly periods

flashing lights (this is an uncommon trigger)

Keeping a diary of when you have seizures and what happened before them can help you identify and avoid some possible triggers.