Epilepsy is known as the condition of recurrent unprovoked seizures in which abnormal electrical activity in the brain causes the loss of consciousness, partial or whole-body convulsion (Ahammad, 2014). There are multiple types of non-epileptic seizures, such as a psychogenic epileptic seizure. However, the distinguishing factor between non-epileptic seizures and epileptic seizures is the electrical discharges that are associated with epileptic seizures. Therefore, a seizure caused by something like hypoglycemia, does not fall under the disorder of epilepsy as it is due to a secondary condition and is not recurrent (Stafstrom, 2015).
Unfortunately, seizures are the only visible symptom of epilepsy so those who have it will not have any way of knowing so until after experiencing a seizure. These seizures can range from just a few seconds to a few minutes in duration. Different levels of seizures can be seen affecting consciousness, whole body spasms or stiffening, a small twitch, or even just staring off into space for a couple seconds (Stafstrom, 2015).
Once an epileptic seizure has occurred, depending on the severity of it and if someone is already being taken to the hospital or they feel the need to get themselves examined, the history is very important. History in this sense can be defined in its normal sense as if something like this has occurred before. However, when examining the history of the epileptic seizure, doctors are often concerned with the historical features associated with the episode. These features include things like clinical context in which the seizure occurred and details of the seizure itself such as: responsiveness, focal features, and phenomenology (Stafstrom, 2015).
An important tool used for diagnosing and analyzing the significance of an epileptic episode is an Electroencephalogram, also known as an EEG. An EEG works by placing multiple electrodes in different locations on a patient’s head where the electrodes record and produce a visual representation of action potentials (the electrical activity), produced by the firing of neurons within the brain (Ahammad, 2014). According to (Kim, 2010), the use of MRI’s and CT scans can be utilized when testing brain activity during epileptic episodes (also known as epileptiform activity) and can be directly correlated with the findings of an EEG. A specific type of an MRI, known as a functional MRI (fMRI) utilizes blood oxygen level dependence to produce an image of neuronal activation and map epileptiform activity (Moeller, 2013). Combining the use of an EEG with the use of an fMRI has been known to be useful in determining the area within the brain where the abnormal neural activity is occurring (Liu, 2014). This combination of EEG/fMRI was first utilized to measure epileptic spikes in the 1990s (Kay, 2014).
There are 2 main groups that epilepsy disorders are arranged into. These groups are arranged dependent upon what happens genetically and causes the seizures. The first is caused by genomic deletions and duplications in the form of copy number variation and is categorized as genetic generalized epilepsies (Thomas, 2015). The second group, focal epilepsies, is due to Mendelian mutations in a single gene such as the DEPDC5 gene or the LGI1 (Thomas, 2015).
Copy number variation (CNVs) are also known as structural genomic variants as they are deletions or duplications of genetic material (Helbig, 2015). These CNVs are relatively small as they are only 1 kB in size, where there are an estimated 3.2 billion bases in the human genome. Through the use of microarray comparative genetic hybridization and single nucleotide polymorphism arrays, the determination of certain microdeletions from individuals suffering from generalized genetic epilepsies have been found to commonly occur. The goal of the experiment done by (de Kovel et al, 2010), was to determine if recurrent microdeletions particular genomic hotspot regions predisposed individuals to idiopathic (which has since been regrouped under the generalized genetic epilepsies) genetic epilepsies or not. A genomic hotpsot region is a spot on the chromosome where recombinations and mutations are more likely to occur. In this study, there was five specific hotspot regions tested, located at: 1q21.1, 15q11.2, 16p11.2, 16p13.11, and 22q11.2. The study was conducted from 1234 patients with the disorder from North-western Europe and a control group of 3022 of the German population. A high-density single nucleotide polymorphism array, which requires a deletion size of larger than 400 kb to be detected, was utilized while conducting the study (de Kovel et al, 2010).
One theory as to why the microdeletions or microduplications occur is because the CNVs create a pathogenic effect as they rearrange the genome thus producing non-allelic homologous recombinants (de Kovel et al, 2010). The five microdeletions listed above were considered to be present in the patients involved in the study if the deletions seen from the SNP overlapped at least 85% of the genomic region of the candidate microdeletion (de Kovel et al, 2010). Out of the 1234 patients, deletions were detected in 22 of them. When comparing this to the 9 found out of the 3022 controls, a 6:1 ratio of detected deletions was seen in those diagnosed with the disorder to those not. Some of these microdeletions have also been found in other disorders.
One example of this, is the most prevalent of the microdeletions occurring at 15q13.3, which occurs in approximately 1% off patients who have general genetic epilepsies. This microdeletion syndrome has been seen in individuals suffering from mental retardation and epilepsy, schizophrenia, autism, as well as other neuropsychiatric features (Helbig, 2009). However, other studies found that intellectual disability is only co-found in a small number of individuals carrying the microdeletion, although a larger number of individuals with the microdeletion were found to have schizophrenia and the related psychoses.
The microdeletion of BP4-BP5 on 15q13.3 contains at least seven genes they may contribute to producing seizures. CHRNA7 is one of these genes and is believed to be the main cause in this particular microdeletion. In a study conducted by (Adams et al, 2012), the deletion at 15q13.3 containing CHRNA7 was tested in mice. CHRNA7 (humans) / Chrna7 (mice), encodes the α7 subunit of the nicotinic acetylcholine receptor which is responsible for both excitatory and inhibitory functions. In this case, the excitatory neurotransmitter regulated is glutamate and the inhibitory neurotransmitter is GABA. The α7 subunit is a rapidly desensitizing, ligand-gated ion channel that allows for the movement of calcium. Upon activation of the Hippocampal α7 subunit receptor, both inhibitory GABA and excitatory glutamate are released (Albuquerque, 2009).
Adams and her team wanted to determine how decreased Chrna7 expression altered hippocampal inhibitory circuit function (Adams et al, 2012). In the experiments, there was two different types of mice used. The first type being the wild type mice, which contained the normal expression of Chrna7. The second type being the heterozygous mice expressing a significant decrease in hippocampal α7 subunit receptors. Through different testing of the mice post-mortem, a select number of GABAergic markers could be detected. The only one showing significant supporting data in both the male and female mice was GAD-65, which is primarily located in inhibitory nerve terminals (Martin and Tobin, 2000). Stimulation of the α7 subunit receptor activates PKC, CaMKII, and MAPK which ultimately increases GAD-65 activity. Thus meaning, a decrease in hippocampal α7 subunit receptors leads to a reduction in kinase activation, resulting in lower levels of GAD-65 found in the heterozygous mice (Adams et al, 2012). This can be an explanation as to one of the factors that may cause things such as epilepsy and or schizophrenia as the reduction in kinase activity would shift the hippocampus into an excitatory state.
The second main group of epilepsy disorders are caused by Mendelian mutations within a single gene. One example of this is a mutation in the DEPDC5 gene. This mutation is known to cause familial focal epilepsy with variable loci which is unfortunately autosomal dominant. A focal epileptic seizure is known to originate within only one hemisphere of the brain and a locus is a specific spot on a chromosome. Familial focal epilepsy with variable loci (FFEVF) is characterized by seizures occurring in distinct cortical regions (Ishida, 2013). Even though this is an autosomal dominant trait and runs in families, these distinct cortical regions can differ from family member to family member.
Ishida and his team previously conducted a study using two large French families who have been diagnosed with FFEVF to determine what kind of Mendelian mutation causes this disorder. In this study, a high-density genome-wide scan was used surveying 10,000 SNP’s. They found that a frameshift mutation occurred on 22q12 on exon 16, due to a single base deletion, ultimately inducing a stop codon 29 amino acids later (Ishida, 2013). Ishida and his team then wanted to see if there were any further mutations on this specific locus. Therefore, they conducted a study of five other families known to have FFEVF using parallel pyrosequencing screening of all 43 coding exons and splice regions found on DEPDC5. Their findings included four families having nonsense mutations while the fifth family had a missense mutation (Ishida, 2013). Within all of the specific families, each mutation had its own specific location and was consistent throughout all of the family members. Interestingly enough, two of the nonsense mutations also occurred on exon 16 which may indicate that this is a hotspot for mutations. Five out of the six mutations introduced a premature stop codon most likely indicating a loss-of-function of DEPDC5, which presumably causes epilepsy (Ishida, 2013).
Another example of an epileptic disorder cause by a mutation on a single gene is Autosomal dominant lateral temporal epilepsy (ADLTE). ADLTE is characterized by lateral temporal seizures with prominent auditory or aphasic auras occurring in adolescence (Bonaventura, 2011). ADLTE follows an autosomal dominant inheritance pattern in families and a contributing factor to this disorder is a mutation to the LGI1 gene. LGI1 stands for leucine rich, glioma inactivated 1 gene. The protein produced by the gene is made up of an N-terminal domain composed of four leucine rich repeats and a C-terminal 7-repeat domain (Bonaventura, 2011).
Bonaventura and team decided to test four Italian families who are known to have members diagnosed with ADLTE. These mutations appear to occur sporadically within a lineage, but once they have occurred, they tend to be passed on. In the first and second families of interest, the specific missense mutation calls for a cytosine where a tyrosine is normally present. Whereas, in the fourth family, a tyrosine replaces the normal cytosine. The third family is a little different from the others as the missense mutation seen is the replacement of adenine with guanosine. Ultimately these mutations prevent secretion of the LGI1 gene protein supporting their pathogenicity (Bonaventura, 2011).
Although ADLTE follows an autosomal dominant inheritance pattern, it does not always show penetrance. Penetrance can be defined as the proportion of individuals carrying a particular allele of a gene that also expresses the expected phenotype. In this particular scenario, the allele would be the mutation on the LGI1 mutation and the expected phenotype would be someone having epilepsy. The fourth family in the study conducted by Bonaventura and team, displays how ADLTE does not express complete penetrance as three out of the nine mutation carriers display the phenotype of epilepsy (Bonaventura, 2011). A mere 33% penetrance rate is not what would normally be expected by a mutation that follows an autosomal dominant inheritance pattern. The specific mutation to the LGI1 gene in the fourth family is an example of one of the mutations that cause a lower number of recurring disorders within a lineage as the penetrance is not high. So far, there has been a total of 36 different mutations found to occur to the LGI1 gene, with each one displaying a different penetrance rate ranging from 2% to 50% (Baulac, 2012). These levels of penetrance can possible be attributed to the sensitivity to auditory or aphasic auras causing the seizures. In Baulac and colleagues’ study in mice, they also hypothesize that mutations within the LGI1 gene may cause a depletion of the protein in neurons and not just an inhibition of secretion. This was confirmed by the use of a Western Blot test of isolated neurons from the cortical culture of mutated LGI1 mouse where the signal was much weaker (not as dark of a stain) than the mouse containing the non-mutated gene (Baulac, 2012).
Although we do not know everything about epilepsy and it can be sometimes difficult to determine what type of epilepsy a person has or whether or not what they are suffering from can even be categorized as epilepsy, there are multiple types of treatments available. Some of these treatments are specific for a specific category of epilepsy and utilize invasive operations, while for others pharmacological medications are able to help minimize the amount of epileptic effects felt. Some of the pharmacological medication treatments are medically recognized and considered ethical by most of society while there are also studies supporting other types of treatments that are starting to become recognized in the medical field but are often not seen as ethical by most of society.
The type of treatment being referenced above refers to the use of medical marijuana in epilepsy. There has been numerous cases and studies done on how the effect of medical marijuana can be combined with the pharmacological medications (antiepileptic drugs) to drastically reduce the number of seizures felt in patients who have a numerous on a daily basis. In some of these cases, after months of combining the use of medical marijuana with the use of antiepileptic drugs, patients have been able to be weaned off of the antiepileptic drugs which can cause detrimental side effects to not only the patient but there family as well. Some of these side-effects felt by the patient include: memory-problems, fatigue, tremors, osteoporosis, depression, gastrointestinal problems, and weight change among many others (Kinderan, 2013). On the other hand, the side-effects felt by the family can be just as harmful. Other than the fact of having to see their loved one suffer through the disease and some of the side-effects listed above, the use of antiepileptic drugs and the side-effects that may cause other specialist doctors to be involved carries an astronomical financial burden (Kinderan, 2013).
One particular study conducted supporting medical marijuana involves a girl suffering from Dravet syndrome, a very severe form of epilepsy. In the article by Maa and Figi, they talk about how the use of CBD:THC is a strain of cannabis that does not produce the normal psychotropic properties associated with other strains of cannabis. This could be contributed to CBD, or a phytocannabinoid which has been tested on animals to show that it may be very effective against seizures. Charlotte, the little girl, mother did her research and discovered a man who specifically grew a strain of cannabis high a high CBD concentration in comparison to THC. As the family lived in Colorado where is legal, she consulted with a team of epileptologists, pediatricians and the state to begin administering low amounts of the CBD:THC extract (Maa and Figi, 2014). Charlotte’s treatment began by giving her the low does of the extract and in the first week following the initiation of treatment, she did not experience a single epileptic seizure compared to the previous amount of on average of 300 seizures a week. As time went on, the amount of CBD extract increased while keeping the level of THC relatively low to avoid the psychotropic effects and by month three, Charlotte had a reduction in seizures of over 90% and was weaned off of her antiepileptic medications (Maa and Figi, 2014).
This combination of CBD:THC extract was later named “Charlotte’s Web” and after 20 months of this treatment, Charlotte was only experiencing one nocturnal seizure per night. Charlotte was now able to drink and eat on her own, sleep soundly through the night and her autistic behavior which is associated with Dravet Syndrome, has significantly improved.
Two of the major drawbacks to the use of pharmacological medications in treating epilepsy is that patients often experience side effects to these medications and sometimes patients will still have their seizures associated with epilepsy. According to Schulze-Bonhage, a third of all epilepsy patients will have their persistent seizures even though they are receiving the most optimal medical treatment available. When a patient fails to respond to the first or second antiepileptic medication, their chance of responding to any further medication is diminished to approximately 5-10% (Schulze-Bonhage, 2014).
Schulze-Bondage and team conducted two random trials testing the effectiveness of epileptic surgery with treating focal temporal lobe epilepsy who did not respond to antiepileptic drugs. Before conducting the surgical operation on these patients, they are evaluated for the risks of surgery, especially cognitive function compared to the risks of continuing pharmacological medical treatments. The patient is made aware of the risks of the procedure, the probability of controlling their seizures, and their overall quality of life (Schulze-Bondage, 2014). Patients who are eligible for such an operation must have an EEG and fMRI confirmation that they are indeed suffering from this specific form of epilepsy.
An example of one of the multiple surgeries that can be done to help patients suffering from a form of epilepsy is a topectomy. A topectomy is known as a resective, which is an operation in which the specific epileptogenic area of the brain is surgically removed. If the use of the EEG/fMRI system cannot specifically detect where the epileptogenic activity is coming form there is a series of surgeries that can be done. During the first surgery involves implanting several subdural or intracerebral electrodes that will detect and record epileptogenic activity allowing for the distinct detection of the area of interest. After this has been done and the area has been detected, a second surgery is conducted to remove the specific area where the epileptogenic activity is occurring (Schulze-Bondage, 2014).
Due to the ever-growing knowledge and technology used today, the success rates of a procedure like this are very high especially compared to what they may have been even 20 or 30 years ago. In the temporal procedures looked at by Schulze-Bondage and team, 70% to 80% of patients became completely free of seizures while 10% to 20% experienced a significant decrease in the frequency of their seizures. Despite these astonishing success numbers, there are still risks that need to be considered for patients considering such a surgical procedure. A resective surgery, such as a topectomy, is associated with a temporary surgical morbidity of 5.1% of patients and a permanent surgical morbidity of 1.5% with the morbidity typically being defects in things such as visual field defects, hemiparesis, aphasia, and cranial nerve palsies. Meanwhile the ultimate fear of any surgery, mortality, occurs in less than 0.1% of patients (Schulze-Bondage, 2014).
Luckily the advances in imaging and molecular chemistry has made it possible to identify the etiology for some types of epilepsies (Shorvon, 2011). However, the matter of the fact is epilepsy is a disorder that can be very difficult to determine even in well-developed and high-income countries, let alone the countries who are struggle on a daily basis found essentials of existence like food and water. These factors make it hard to establish an estimate for a worldwide prevalence of epilepsy. A meta-analysis of 65 studies determined that the median prevalence of epilepsy in developed and high-income countries was 5.8 per 1,000 population (Bell, 2014). In the United States, this number was found to be 10.4 per 1,000 population (Bell, 20114). If this is the case, that means that out of the current 323.1 million people living in the US, 3.36 million will experience a form of an epileptic episode at some point in their life. Hopefully as our knowledge and understanding of the genetic causes of epilepsy increase and our treatment regimens continue to become significantly better, the prevalence of epilepsy in humankind will drastically decrease.