When someone says the word “seizure”, what do you think of?
Does the idea make you feel anxious or scared? Many people think that seizures only come in one form, those in which the person loses consciousness, falling to the floor with muscle contractions that cause them to jerk and shake. Previously called grand mal seizures, these are now termed tonic-clonic seizures. This is the form of the vast majority of my seizures. This type of seizure can be visually shocking and even scary for those nearby, and certainly memorable, which may be one reason people think this is the only type of seizure there is. This is also the classic seizure depicted on TV or in the movies. However, there are numerous types of seizures, as well as causes of these seizures.
But first, what is the relationship between seizures and epilepsy? Epilepsy is the manifestation of an underlying neurological disorder which is causing seizures. Epilepsy is an umbrella term to name a condition in which a person has more than one seizure. Just as there are many types of seizures, there are a range of epilepsies.
All seizures start as alterations in electrical activity in the brain. They can start in a small area of the brain – a focal seizure – or they can encompass most of the brain – generalized.
In 2017, the International League Against Epilepsy introduced a new method to group seizures so that they are more descriptive of the particular seizures that a person has. Seizures are divided into groups depending on:
- where they start in the brain (onset)
- whether or not a person’s awareness is affected
- whether or not seizures involve other symptoms, such as movement
Tonic-clonic seizures are also called generalized motor seizures. A person’s body will jerk and shake because their muscles are tightening and relaxing rhythmically. There are also partial, non-motor seizures that can go undiagnosed because they are not as easily recognized.
A recent study, headed by Jacqueline French, MD, director, Translational Research and Clinical Trials in Epilepsy, NYU Grossman School of Medicine, indicated the need to improve early identification of patients with focal epilepsy. People with focal epilepsy may go undiagnosed because they have non-motor seizures, leading to severe outcomes. To overcome this hurdle, more education on the variety of seizures must occur. In a recent interview with Neurology Live, French discusses the concept of the 5 S’s – Short, Sudden, Strange, Similar Spells – and how they may be indicative of a non-motor seizure.
The first thing that I think stands in the way is the public’s perception of what epilepsy is. I always talk about the “television seizure.” You never see anybody on TV having a seizure which is not falling to the ground, shaking their arms and legs, frothing at the mouth—and I think that if you asked a person on the street, “what is a seizure,” that’s what they would tell you.– Jaqueline French
The types of seizures that have a less obvious presentation and that go undiagnosed can have serious consequences. French says, “People would have these non-motor seizures, these subtle seizures, for a long time and often it only came to medical attention when they had the disruptive seizure, usually a convulsion.” She goes on to say “…we also found that there were a significant number of automobile accidents, and in some cases, interestingly enough, not only 1 automobile accident, but sometimes 2, or even 3. People would come in saying, “I don’t know what happened, the car came out of nowhere,” or whatever. But each time, in retrospect, they could describe that when that happened, they were having one of these episodes. That, to us, I think was quite a surprise, that there were so many preventable motor vehicle accidents.” Read her more of her interview here.
One person in 26 will develop epilepsy, but perhaps the number is even greater, considering that partial, non-motor seizures are often not recognized by the general population and by many in clinical practice.
Another type of seizures are absence seizures in which, as the name suggests, the person seems absent. The person will lose awareness of their surroundings but may be able to continue to walk. They may look blank, or even stare. I have had a few of these absence seizures soon after my head injury, when I was a teenager.
Chanda Gunn, who we will interview on our Voices For Epilepsy series, was a Olympic medal winning goalie for the US women’s ice hockey team. One time, she suffered an absence seizure while on the ice. When the coach questioned her actions because the opponent scored a goal, Chanda said “she couldn’t see the puck” but a replay showed that there was no obstruction between her and the attacker who scored. Chanda had a brief absence seizure that resulted in her letting in the goal!
Causes of Seizures and Epilepsy
There are a range of underlying causes for epilepsy and the resulting seizures, including genetic mutations, trauma, stroke, age, brain tumor, or infectious disease.
Some people develop epilepsy because changes in their genetic code leads to a mutation in a gene that will predispose the person to epilepsy. (expand the gray bar below to learn more about genetic mutations)
Genes, Mutations and Disorders: A Primer. . .
One often hears of disorders caused by genetic mutations. But what does this mean?
A cell contains instructions in its genome on how to make the living materials of that cell based on what is called the genetic code. In the above diagram, the cell is exploded to show the genome and zooms in on chromosomes, which contain the code of life, DNA. DNA is made up of codes for proteins (muscle, for example is largely made up of protein). These 3 letter codes each consist of the letters of A,T,C or G in numerous different sequences. Each letter series is a code for a protein building block called an amino acid.
For example, TAT codes for the amino acid tyrosine. CAT for histidine, TGT for cysteine. Importantly, there are also codes to stop making the protein, called stop codons. One example of a stop condon is TAG. So the sequence TAT-CAT-TGT-TAG would code for a string of amino acids, Tyrosine-Histidine-Cysteine, followed by the instruction TAG to stop making the protein. But imagine if the letters were slightly incorrect. Instead of TAT-CAT-TGT-TAG an error was present so that it now reads TAT-TAT-TGT-TAG, which would make the protein Tyrosine-Tyrosine-Cysteine. Another type of mutation might be TAG-CAT-TGT-TAG, which would provide the message to STOP making the protein at the beginning. These small errors, called mutations, lead to changes in the overall protein.
Imagine if one of the letters was missing (the first A for example) TAT-CAT-TGT-TAG becomes TTC-ATT-GTT-AG. This is called a frame shift and can end up with nonsense. A way of thinking of this is to compare the genetic code to a sentence. If we delete a letter in a sentence, and shift all of the letters forward by one what is the consequence for the words and meaning?
“I love to sail on the ocean and watch the stars and moon at night”
Let’s lose the S in sail and see the consequence for the sentence with the frame shift in letters in words.
“I love to ailo nt heo ceana ndw atcht hes tarsa ndm oona tn ight”
Small changes/mutations can have big effects for protein synthesis and the resulting function of the body.
One type of genetic epilepsy is Dravet syndrome, named after Charlotte Dravet, a French epileptologist, who first described the disorder. Dravet syndrome is caused by the SCNA1 gene. This gene codes for a voltage dependent sodium ion channel. This ion channel regulates the electrical excitability of neurons in the brain. A mutation of this gene can cause an increase in brain excitability, which then can lead to seizures.
Another genetic cause of epilepsy is the SLC6A1 gene. This gene codes for a protein that transports a chemical in the brain called GABA. There are two main types of chemical transmitters in the brain: GABA, which causes inhibition, and Glutamate, which causes excitation. This is akin to the gas (excitation) and brake (inhibition) pedals of a car. One needs the balanced use of both for effective operation of a car. In the SLC6A1 gene mutation, the inhibition/excitation, or brake/gas, gets out of balance, resulting in seizures.
Mutation of the SLC6A1 gene is the focus of our first Voices For Epilepsy interview with guest Amber Freed. Amber noticed that her son Maxwell wasn’t hitting the same developmental milestones as his twin sister. After genetic counseling they discovered that he had a recently identified mutation in the SLC6A1 gene, which impacts development and can lead to seizures. With no treatment available, Amber has developed a foundation called SLC6A1 Connect that is raising millions of dollars to find a cure. Her energy and and commitment to the cause is inspirational.
When the cause of epilepsy is unclear, sequencing of the person’s genome can be of assistance. Sequencing can identify a mutation in a gene that is the underlying cause of epilepsy, although frequently there is still no known medical treatment. However, in some cases, identification of the genetic cause can help determine the course of the medical treatment.
For example, when a mutation exists in the gene called SLC2A1, which codes for a glucose transporter, a diet called the ketogenic diet can often be useful. Yes, a diet! The core principle of the ketogenic diet is to reduce carbohydrate (such as glucose) consumption and replace that source of energy with fat.
Keto = ketones, which are produced when the source of energy in the body is from fat. Genic = producing. In fact, the ketogenic diet is the oldest known anti-convulsant treatment. Fasting or other dietary methods have been used to treat epilepsy since 500BC. A historical perspective of the ketogenic diet can be found here.
The first documented use of dietary change for treating epilepsy was in 1911 when a pair of Parisian physicians, Gulep and Marie, used a starvation diet for 20 children and adults with epilepsy and found less severe seizures as a result. In the 1920’s physicians started using a ketogenic diet, which is more sustainable than starvation, as a treatment, but then it fell out of favor. More recently, it has gained significant popularity in treating people with epilepsy (who do not respond to drugs) and has spawned great research interest in identifying how a diet reduces seizures. In fact, research in my neuroscience laboratory is focusing on how energy substrates (glucose versus fat) control the electrical activity of neurons in the brain. My personal hope is that we can identify alternative approaches to diet that can prevent seizures.
Anyone considering a dietary change to help control their epilepsy should first consult with their treatment team.
In addition to genetic causes, another significant cause of epilepsy is due to trauma. In people who otherwise did not suffer from epilepsy, seizures can be begin following a serious head injury, also termed a traumatic brain injury. Thus, these types of seizures are termed post-traumatic seizures. This is how I developed epilepsy when I was 15 years old.
Treating Seizures and Epilepsy
Given that there are so many different forms of epilepsy which arise from a variety of causes, it is not surprising that our current array of anticonvulsant medications do not successfully treat everyone with epilepsy. If 1 in 26 people worldwide will develop epilepsy in their lifetime, that means at any one time ~1% of the population have epilepsy. Of that 1%, 1/3rd are not medically controlled by anti-convulsant drugs. People who are not medically controlled can have numerous seizures per day and face limitations related to driving, working, maintaining relationships and living a normal life.
We should not give up hope for finding ways to treat seizures in the future. There is a very active research community that is working towards identifying underlying mechanisms of epilepsy. The goal of this knowledge will be to use it towards the development of new drugs for new treatments.
In the meantime, we will continue to educate the general public about different types of seizures, their causes, and how to support someone who is having a seizure. As more people gain a better understanding, hopefully the fear, anxiety, and stigma surrounding epilepsy will lessen and together we can help those with epilepsy live fuller lives.