A NEW THERAPEUTIC PARADIGM FOR EPILEPSY
March 26th, 2021
Epilepsy is a chronic neurological disease which affects around 50 million people of all ages worldwide . The disease is characterised by recurrent seizures caused as a result of excessive electrical discharges in a group of brain cells. Epilepsy is non-contagious, and although there are many known causes, from prenatal or perinatal brain damage and genetic conditions, to severe head trauma, stroke, tumours and brain infections like meningitis, the cause of the disease is still unknown in around 50% of cases globally .
Seizure symptoms vary widely, ranging from collapsing, jerking, and shaking, to stiffness, losing awareness, feeling strange sensations or unusual smells or tastes, and more . Seizure episodes also vary in frequency and severity . Seizures differ between people and between an individual’s seizure events in terms of; the brain region affected, physiological response, neurological response, physical response, and triggers . This variability means that seizures are notoriously difficult to detect or predict, and it can take years to find a successful treatment .
People living with epilepsy therefore report that the unpredictable nature of both their seizures, and the effectiveness of their medications, create daily challenges for them . If properly diagnosed and treated, however, it is estimated that up to 70% of people living with epilepsy could live seizure-free .
Establishing effective treatments for epilepsy is also hugely important because it can severely impact an individual’s social freedom and employability, for instance a single seizure will disbar someone from driving for six months, and those with recurrent seizures will need to be seizure-free for up to five years until they are able to drive.
ANTI-EPILEPTIC DRUGS (AEDs)
AEDs are the most commonly used treatment for epilepsy, helping to control seizures in around 60-70% of people . Around 20 different AEDs exist; most commonly used are sodium valproate, carbamazepine, lamotrigine, levetiracetam, and topiramate . They generally work to decrease membrane excitability by interacting with neurotransmitter receptors or ion channels, although their exact mechanism of action differs . They also produce a wide range of adverse side effects, the most common of which include drowsiness, lack of energy, agitation, headaches, tremors, hair loss or growth, swollen gums, and rashes . AEDs are neither preventive nor curative, but rather used solely to suppress symptoms of seizures.
It is estimated that 30-40% of people with epilepsy are unresponsive to AEDs , and therefore considered to be refractory.
If two or more types of AED have been tried but the person has not seen a cessation or reduction in seizures, brain surgery may be considered. Patients will undergo brain scans, an electroencephalogram (EEG), and memory, learning abilities and mental health tests to determine if surgery is an option, i.e. if seizures are caused by a problem in a small part of the brain that can be removed without causing serious effects . Brain surgeries for epilepsy can involve disconnecting one part of the brain from another, or removing part of the brain in its entirety .
Success rates differ depending on the type of surgery, but around 70% of people who undergo temporal lobe surgery report a total cessation of seizures, with a further 20% finding that their seizures are reduced . Around half of people who have this surgery will also still be seizure-free 10 years after their surgery .
It’s important to note, however, that not all refractory epilepsy patients will be eligible for brain surgery. In the UK, for instance, only 1.5% of people with epilepsy have surgery , but for those who do not qualify, limited alternative treatment options exist.
For children, a ketogenic diet may be explored for many different seizure types and epilepsy syndromes. Supported by an experienced epilepsy specialist and dietitian, carbohydrates are cut out of the child’s diet so that the body uses ketones (produced when the body uses fat for energy) instead of glucose for its energy source. As a result, fat intake increases and it is therefore not widely used in adults due to risk of diabetes and cardiovascular disease associated with high-fat diets .
A 2008 Great Ormond Street Hospital study found a 38% decrease in the number of seizures in children receiving the ketogenic diet after 3 months compared to a 37% increase in seizures for the control group who received medications as usual .
Once a child comes off the diet, however, they usually still have to take seizure medications to manage their condition.
Two types of neuromodulation are regularly used in the treatment of epilepsy.
Vagus nerve stimulation (VNS) has long been approved for the treatment of epilepsy, and involves the implantation of a pulse generator (IPG) in the chest which is connected by a wire to the vagus nerve in the neck. The IPG sends regular, mild electrical stimulations to the nerve via the wire in order to help control seizures by modulating electrical brain activity that leads to seizures. A special magnet, often worn on a bracelet, or a belt, or attached to a wheelchair, can be passed over the stimulator when the patient feels a seizure coming on to provide stronger stimulation. If the patient does not experience warning signs prior to seizures, someone else can use the magnet for them when a seizure happens.
VNS does not usually cause a cessation in seizures completely, but rather can make them less severe and less frequent. One study found that in a cohort of 62 patients, 53% reported ≥50% reduction in seizure burden after their VNS device was inserted .
Recent developments in VNS treatment include a transcutaneous vagus nerve stimulation (tVNS) technique, in which the stimulation device sits non-invasively in the patient’s ear. One study of tVNS showed an average reduced seizure rate of 64.4% in those 16 patients who did experience a decrease in seizure frequency .
First steps have also been taken towards a VNS device that can detect seizures and apply automatic stimulation, in the form of LivaNova’s AspireSR® device. This device senses the individual’s heart rate via electrocardiography (ECG), meaning in individuals whose seizures are initiated by a substantial increase in heart rate, automatic stimulation can be triggered to stop or shorten a seizure . One study of 44 patients found that 71% reported ≥50% reduction in seizure burden after the AspireSR® device was inserted . Notably, however, only 57% of seizures cause an increased heart rate .
Deep brain stimulation (DBS) is similar to VNS for epilepsy, also involving the surgical implantation of an IPG. Connected leads called electrodes may be implanted in the anterior nucleus of thalamus (ANT) of the brain or the seizure focal point to deliver more precise electrical stimulation that optimises symptom suppression. The 2010 SANTE trial found a median decrease in seizure frequency of 56%, with 6 out of 81 patients experiencing complete seizure freedom14. Median seizure frequency reduction continued to improve over three years of the trial, from 41% in year 1, to 56% in year 2, to 68% in year 3 .
More recent developments in DBS have seen two devices, the Percept™ PC  and RNS® System , record internal brain waves (local field potentials) and surface brain waves (via electrocorticography or ECoG) to inform stimulation protocols, respectively. This once again represents a growing trend of more proactive seizure treatment enabled by new real-time insights into their pathophysiology.
There are, however, serious risks associated with DBS, including brain hemorrhage, infection, depression and memory problems, to name a few [4,14].
A MOVE TOWARDS PERSONALISED TREATMENT
Upon analysis, it becomes clear that for people with refractory epilepsy, and especially those that are not eligible for brain surgery, alternative treatment options are limited. Considering that around 20 million people worldwide are affected by refractory epilepsy, it’s safe to say that it is an underserved condition and research into safer and more effective treatments must continue. So, where should we focus our efforts?
There is a paradigm shift occurring within healthcare in general as therapeutic interventions move away from generalised care, which often involves broad categories of patients treated with the same medicines resulting in varying efficacies, to the personalisation of care. Innovations in digital health technologies are facilitating the capture and analysis of new sources of health data that are helping us learn more about how medical conditions manifest themselves on both a molecular level and in the day-to-day experiences of patients.
Epilepsy is perfectly positioned to benefit sooner rather than later from this paradigm shift. The heterogeneous nature of seizures has exposed the shortcomings of generalised medicine, proving it a very difficult condition to treat. However, the first steps have already been taken towards informing treatment in real-time based on changes in the physiological environment of the individual; the use of heart rate as a parameter to inform automatic VNS in the aforementioned AspireSR® device.
In a sense, this represents a move towards establishing a personalised treatment ecosystem for each individual patient. Future research should focus on harnessing state-of-the-art signal processing and machine learning algorithms to develop digital medicines that sense multiple physiological parameters to automatically inform increasingly personalised (read: effective) therapeutic intervention.
The opportunities here range from enabling the prediction of seizures , in turn improving quality of life for millions living with epilepsy across the globe, to advancing our scientific understanding of the condition in hope of one day establishing a cure.
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 WHO Epilepsy Fact Sheet, 2019; CDC Epilepsy Data and Statistics, 2020: https://who.int/news-room/fact-sheets/detail/epilepsy
 ILAE 2017 Classification of Seizure Types: https://www.epilepsy.com/sites/core/files/atoms/files/Presentation%20Illustrating%20the%202017%20Classification%20of%20Seizure%20Types.pdf
 Epilepsy Foundation Survey, 2016 https://www.epilepsy.com/sites/core/files/atoms/files/community-survey-report-2016%20V2.pdf
 Macdonald RL, Kelly KM. Antiepileptic drug mechanisms of action. Epilepsia. 1995;36 Suppl 2:S2-S12. doi:10.1111/j.1528-1157.1995.tb05996.x
 Sander, J.W. The epidemiology of epilepsy revisited. Curr Opin Neurol. 2003;16:165–170.
 Rugg-Gunn F, Miserocchi A, McEvoy A. Epilepsy surgery. Practical Neurology. 2020;20:4-14.
 Neal EG, Chaffe H, Schwartz RH, Lawson MS, Edwards N, Fitzsimmons G, Whitney A, Cross JH. The ketogenic diet for the treatment of epilepsy: a randomised, controlled trial. Lancet Neurol. 2008;7:500-506.
 Hamilton P, Soryal I, Dhahri P, et al. Clinical outcomes of VNS therapy with AspireSR® (including cardiac-based seizure detection) at a large complex epilepsy and surgery centre. Seizure. 2018;58:120-126. doi:10.1016/j.seizure.2018.03.022
 Liu A, Rong P, Gong L, et al. Efficacy and Safety of Treatment with Transcutaneous Vagus Nerve Stimulation in 17 Patients with Refractory Epilepsy Evaluated by Electroencephalogram, Seizure Frequency, and Quality of Life. Med Sci Monit. 2018;24:8439-8448. Published 2018 Nov 23. doi:10.12659/MSM.910689
 Fisher R, Salanova V, Witt T, Worth R, Henry T, Gross R, et al. . Electrical stimulation of the anterior nucleus of thalamus for treatment of refractory epilepsy. Epilepsia. 2010;51:899–908. doi:10.1111/j.1528-1167.2010.02536.x
 King-Stephens D, Leguia M, Proix T, Rao V, Tcheng T, Truccolo W, et al. Forecasting seizure risk in adults with focal epilepsy: a development and validation study. The Lancet Neurology. 2020;20;127-135. https://doi.org/10.1016/S1474-4422(20)30396-3