A Broad View of Epilepsy - from a Neuroscientist
Favourite food: Anything sweet
Favourite book(s): When the Air Hits Your Brain (Frank Vertosick), Trouble with Testosterone (Robert Sapolsky)
Our Cognitive Abilities
Our cognitive abilities emerge from the coordinated activity of the cells (neurons) in our brains. Neurons are interconnected through synapses, which are the contact points for communication. The patterns of which neurons connect themselves are called neural circuits, which mediate data processing in the brain. Neural circuits can be deconstructed into their basic motifs which involve either feedforward and feedback (occasionally both) connections between different varieties of neurons. At any level of this circuitry, the opposing forces of excitation and inhibition are held in balance through numerous homeostatic mechanisms.
Epilepsy is a neurological disorder characterized by spontaneous recurrent seizures, affecting up to 65-75 million people worldwide. While genetic epilepsies usually involve an identifiable mutation or mutations within crucial neuronal genes, acquired epilepsies including temporal lobe epilepsy (TLE) usually involve numerous hallmark pathologies which are then thought to give rise to the development of recurrent spontaneous seizures.
Seizures are sustained by progressive microcircuit recruitment and end once synchrony is sufficiently pervasive, that there are no neurons left to excite. It can appear at any age, but incidence rates show a bimodal distribution with higher prevalence occurring in early childhood and in the elderly. Most people associate epilepsy with tonic-clonic seizures, but epilepsy has a multifaceted presentation with a range of severities, types, and etiologies. Focal seizures are the predominant type and occur more frequently than generalized seizures. The most common causes of epilepsy in younger patients include congenital, developmental, and genetic disorders; while cerebrovascular disease is the common cause in elderly patients. Sudden death in epilepsy (SUDEP) is the most common cause of epilepsy-related death (Grabowski et al., 2018). Other disorders associated include strokes, migraines, dementia, and autistic spectrum disorder (Kanner et al., 2017). Not only are those with epilepsy at greater risk of developing these comorbidities, but also patients with these primary psychiatric and neurologic disorders are at greater risk of developing epilepsy.
A Common Comorbidity
One of the most common comorbidities is depression, affecting 24% of those diagnosed. Those with epilepsy have close to three times the odds of having active depression compared with those without epilepsy. Decreased serotonergic and noradrenergic activity is the pivotal pathogenic mechanisms of mood disorders and has been found to be present in several animal models of epilepsy as well as in neuroimaging studies of humans (Kanner et al., 2017).
Although one antiepileptic drug (AED) may be effective in treating some seizure types, the same AED may aggravate others, which is especially relevant for patients with mixed seizure disorders and existing comorbidities. Over 30% of patients with epilepsy have seizures that cannot be fully controlled with medications, and even patients who are well-controlled suffer side effects from their medications (Reily et al., 2017). For some drug-resistant patients, surgical resection of seizure-producing neural tissue can be an effective treatment, but success in this approach relies on accurate analysis of EEG signals to localize the seizure onset.
Patients with epilepsy also face social challenges in independent living, in school, driving limitations, and employment uncertainties. The disorder remains highly stigmatized, which consequently negatively affects the quality of life, leading to compounding anxiety and depression, and often can result in poor treatment adherence.
Understanding the biology of this disorder is crucial for acceptance societal integration. Brains are not things we have, but rather brains are what we are: the physical and chemical processes in our brain determine how we react and who we are (Levay).
Seizures begin in an onset 'zone', which can be conceptualized as a core of intense, hypersynchronous neuronal firing surrounded by an inhibitory 'penumbra' of desynchronized neuronal firing that restrains seizure propagation. An emerging model of seizure initiation portrays seizures as developing from a merging of multifocal, initially asynchronous epileptic microdomains. This particular model explains the otherwise counterintuitive observation that the preictal (before the seizure) period and early stages of seizures are actually characterized by desynchronization, accompanied by increasing macroscale synchronization as the seizure progresses. The mechanisms underlying the failure to inhibit are the main subject of investigation. Despite the multiple ways inhibition can fail, an obvious but profound observation is that most seizures end spontaneously. The sudden and seemingly random nature of seizures is one of the most disabling and puzzling features of epilepsy.
So, how do normal levels of brain activity transform into the self-reinforcing, expanding patterns of excessive activity that characterize seizures? There are many different theories to explain this, coinciding with many different types of epilepsy activity.
First, it seems necessary to explain why some regions suffer more than others. Some regions of the brain present themselves as more vulnerable than others, for evolutionarily conserved reasons. Different cortical areas have varying levels of plasticity, areas that need to consistently rewire themselves and incorporate new information carry a vulnerability to the disruption in disease. High plasticity necessitates high metabolic activity and cellular stress while endowing these areas with the flexibility necessary for learning and memory. The stress of plasticity comes from different planes, one being changes in the strength of existing excitatory synapses. The modification of postsynaptic receptors results in long-term potentiation (which is necessary for learning and memory), causing a long-lasting increase in EPSP (excitatory postsynaptic potential). Meaning, there is a long-term intrinsic excitability in these neuronal populations. Another factor is that there's a high rate of disassembly and reassembly of new synapses with cooperation from other parts of the cell followed by circuit stabilization (Cabezas et al., 2018). You can imagine these regions similar to a building that’s always under construction, building up a new edition then tearing it down with something better. It won’t have much structural integrity as it’s always accommodating to new needs.
For example, one of the common types of epilepsy is temporal lobe epilepsy (TLE). The temporal lobe includes limbic structures that are associated with neural coding and memory associations (hippocampal formation). It crucial for learning and memory, therefore requiring a high degree of flexibility. Other areas of the cortex that are responsible for the processing of stable information, such as vision or audition, are relatively stable and resistant to stress. They are not equipped with plasticity simply because colors and depth in our environment don’t change, same with other aspects of our perception.
Knowing that certain brain regions are more vulnerable than others, the next question would be what pushes them to become pathological? There are a few ways epilepsy comes about: It’s acquired genetically or developed later in life (epigenetically or through brain injury, viruses, etc).
Regarding genes, there are hundreds and hundreds of genes have been implicated in human epilepsy. Abnormal gene products can disrupt neural circuit function at various cell biological levels, giving faces to the many different classes of epilepsy. I will name a few of the most common places for errors to occur:
-NTRK2 gene, this encodes a neurotrophic tyrosine kinase receptor family known as TrkB, this gene is known to regulate synaptic strength and plasticity. Polymorphisms of NTRK2 have been associated with neuropsychiatric disorders specifically with epilepsy. NTRK2 variants were first studied in psychiatric diseases including mood disorders, anorexia nervosa, eating disorders, and attention-deficit/hyperactivity (Adams et al., 2005, Ribases et al., 2005, Ribases et al., 2008, Dong et al., 2009).
- Ion channels (stabilize a resting cellular potential, shaping action potentials and other electrical signals through the flow of ions) are critical for neuronal excitability and network stability, and heritable mutations in these molecules were among the first genes identified in association with epilepsy.
- Mutations in GABA (a neurotransmitter) receptor subunit genes have been associated with a variety of epilepsy syndromes. The bulk of inhibitory neurotransmission in the brain is mediated by GABA receptors, but, during periods of prolonged activation, GABA receptors can become excitatory due to shifts in transmembrane Gradients (Gulledge et al., 2003). Mutations in inhibitory GABA receptor subunit genes have been associated with a variety of epilepsy syndromes.
- Mutations in genes affecting the mTOR intracellular signal transduction pathway, which is critical for metabolic sensing and neurite outgrowth, have been implicated in a variety of epilepsy syndromes.
Determining the specific onset site of epileptogenesis would identify the cause and allow for specificity in treatment. I will list just a few of the potential biomarkers for epilepsy activity:
- Chronic neuroinflammation (Brennan et al., 2016), neuronal death/apoptosis (Brennan et al., 2016) epigenomics (gene modification), altered neurogenesis (neuron growth) and others. Progressive loss of neurons within vulnerable zones of the hippocampus is another pathological hallmark of epileptogenesis. It is thought to contribute to hyperexcitable network generation by unbalancing excitation-inhibition and effects on synaptic reorganization among remaining neurons. Some other biomarkers are:
- MICRO-RNA: miRNAs maintain dendritic integrity in epilepsy as well as dendritogenesis (dendrite growth). Dendrites are the extensions of neurons that receive messages. Dendritic spine abnormalities and changes in spine volume are typically seen in hippocampal neurons in TLE patients. Loss of or reduction in spine volume likely disrupts the delicate excitatory-inhibitory balance in the brain. (McKinney et al., 2005).
- The thalamus plays a critical role in integrating and modulating the flow of information in different cortical areas (Yoong et al., 2016) and has long been recognized to be involved in many different types of epilepsy. It plays an important role in primary and secondary generalized seizures through the driving of recruitment in cortico-thalamic circuits and serves as a main oscillatory regulator. The left thalamic volume may be a useful biomarker to help predict cognitive impairment in children with early onset epilepsy. The degree of volume reduction has been correlated with the severity of cognitive impairment (Yang et al., 2017).
Those who experience brain trauma are much more likely to have a seizure and develop epilepsy. Since the thalamus is intimately connected with the cortex, it’s proved to be a promising target in epilepsy treatment. By selecting neurons in the thalamo-cortical loop with a transgenic virus to enable precise hyperpolarization (causing a reduction in neuronal firing) can immediately dampen excitability, so far this method has only been used on lab animals.
There are many difficulties when it comes to studying epilepsy, primarily stemming from the inability to have live human participants in tissue studies. Maturation stages of cultured neurons may differ from pathogenic mature neurons in patients. An essential component for epileptogenesis, seizure generation, and propagation are missing in cultured neurons: the architectural organization of neural networks and cerebral structures. Without knowing the cortex’s architectural organization many clues are still missing. Intact living organisms are required to explore pathophysiological mechanisms underlying genetic focal epilepsies at fully integrated levels.
Advancement in gene-editing technologies, such as TALENs (transcription activator-like effector nucleases) and CRISPR (clustered regularly interspaced short palindromic repeats) which can add, disrupt or change targeted sequences of DNA demonstrate high levels of potential for the future of epilepsy treatment. A handful of companies are in the beginning stages of clinical gene therapy for specific pathologies, with more people than ever living with epilepsy.
Epilepsy is not something people have a say in.
For its extreme commonality, awareness is lacking significantly. People with epilepsy are still discriminated against in the workforce, denied medical benefits (in the US) and poorly understood by the general population. Those afflicted overcome a remarkable amount of distress and have to permanently alter their lives to accommodate the affliction. People with epilepsy can live normal active lives and are strong, resilient people. It is unique to the individual, and a majority of people don’t know the cause of their epilepsy. It has many triggers and many symptoms unique to the individual. It’s important to take the time to consider those you know and consider their challenges, and to remember that regardless of the severity of the individual's condition, everyone deserves basic ethical consideration, respect for autonomy, and freedom from discrimination.
Very interesting and informative article. I had a car wreck and was in a coma for a few months. This happened in 1997. I have had epilepsy ever since and I’ve been able to go long periods of time without a seizure and got my license back. Before the accident I owned and two separate businesses in two different cities close to each other. My doctors advised me to sell them immediately which I didn’t do. I went through TBI rehab immediately after the recovery. In my opinion it was too soon because I denied my conditions. I eventually sold them and have gone through two additional TBI rehabs many years apart. I lost everything. I have been able to work at different jobs, sometimes over a year, but my seizures eventually came back every time. With a TBI, epilepsy, no short term memory it’s hard to not just maintain work, but many friends are no longer around, family barely, etc... My sisters get mad when I say this but I actually believed I died and am now (currently) in hell even though I have been saved and believe. I attended three cognitive brain programs, sometimes months, one time almost a year and at one there was at least one suicide. I don’t believe in it and never understood how one could until living with this. Death will be a blessing and relief compared to ‘living’ with a TBI. It’s been 21 years of pure hell. There are some good things but few and extremely far between.