Noncoding RNAs: diagnosis/cure for epilepsy?

Epilepsy Topics, , ,

Assessment 13

Introduction

Several reviews present data to support the hypothesis that noncoding RNAs have the potential to serve as a diagnostic marker for epilepsy. Additionally, because noncoding RNAs play an integral function in the disease process, they may also serve as a therapeutic target to cure epilepsy.  In these two respects, noncoding RNAs are worth discussing.

In the US, there are approximately 3 million Americans living with epilepsy and each year approximately 150,000 more are diagnosed with this disease (https://www.epilepsyallianceamerica.org).  Of these, roughly 30-50%, depending on the type of epilepsy, are not helped with medications and many on medications are dissatisfied due to drug-related side effects.  Therefore, it is postulated that this embarrassing gap in effective therapy is largely due to a lack of noninvasive biomarkers coupled with a modest understanding of the molecular instigators of epilepsy.  Here is where research may help.

Noncoding RNAs

High school biology taught that one gene produces one protein and that genes via this principle dictate our heredity e.g. who we are.  Furthermore, genes (actually DNA molecules) transcribe their information to another smaller molecule, RNA, which then translates DNA’s instructions precisely into a specific protein.  Scientists now know that this pathway is tightly regulated by many factors, one of which is noncoding RNA, the subject of this blog. 

Thus noncoding RNA is a RNA molecule but as its name implies, it does not code for a protein.  Instead, noncoding RNAs control which proteins are made and how much is made. Interestingly, certain classes of noncoding RNAs regulate other noncoding RNAs.  The bottom line is that noncoding RNAs are essential for the normal health of all cells.  However, when they exist in excess or in lesser amounts compared to normal, gene regulation falls apart, essential proteins are not made and pathology ensues.

Role in epilepsy

The role of noncoding RNAs in epilepsy has been extensively studied in animal models of epilepsy and largely confirmed with tissues surgically removed in patients with intractable, drug-resistant epilepsy. In animal models and human tissues, the majority of disease-associated regulating RNAs are present in abnormally high amounts. Therefore, they are instrumental in supporting a pro-inflammatory milieu, damaging neuronal structure and encouraging neuronal cell death.  These are changes essential for initiation and continuance of epilepsy (see Blog 12).

Noncoding RNAs as a noninvasive biomarker for epilepsy

There is a desperate need for noninvasive biomarkers of epilepsy.  Briefly, a biomarker is a measurement of a pathological process and/or a biomarker indicates the response to a therapeutic/surgical intervention.   To date, the seizure, observed clinically or by EEG, is the only validated biomarker (see Blog 7 for issues) for epilepsy.   Because noncoding RNAs are small molecules, they exit the cell and appear in body fluids e.g. blood.  Present day instrumentation is capable of detecting very low levels of circulating noncoding RNAs.  Studies confirm that variations in blood levels of disease-associated noncoding RNAs mimic changes in the brain, making them a potentially valuable noninvasive biomarker for detection/diagnosis of epilepsy.

There have been a number of studies in man with the objective of assessing the role of noncoding RNAs as a diagnostic noninvasive biomarker.  Many show that certain regulating RNAs measured in serum, plasma or cerebrospinal fluid are indicative of specific epilepsies compared to normal controls.  Some studies measured noncoding RNAs as a biomarker for drug-resistant epilepsy.  In all studies, the select or disease-associated noncoding RNAs were statistically significantly changed from controls and hence have potential to accurately characterize the epilepsy.

Noncoding RNAs as a target to cure epilepsy

Data show that certain disease-associated noncoding RNAs create instability severe enough to ferment inflammation and cause neuronal death. This ignites the beginning stages of epilepsy. Thus, noncoding RNAs represent potential targets for future therapy.  Several anti-noncoding RNA therapies e.g. antisense oligonucleotides, anti-microRNA, microRNA mimics, microRNA sponges (Manna et al., 2022), are currently in development in animal models and could prove valuable to patients with epilepsy.

Issues to overcome

There is little doubt that noncoding RNAs will become useful diagnostic biomarkers and therapeutic targets in the future.  However, several hurdles remain.  One is standardization.  There is the need to develop valid universal methods to allow critical comparison of results between separate studies and different laboratories.  Studies also need to improve on sensitivity and specificity.  “Sensitivity measures the proportion of correctly identified subjects having the specific condition or disease. Specificity measures the proportion of correctly identified subjects not having the disease (Pitkanen et al., 2019).  From well-designed studies, scientists can use these measurement to determine acceptable values. Also, larger studies in man are clearly essential.

Conclusions

Understanding the  role of noncoding RNAs in health and disease is an important endeavor.  Noncoding RNAs are key regulators of gene expression and aberrant regulation leads to dysfunction and disease.  Results from animal models of epilepsy and various studies in patients with epilepsy strongly indicate epilepsy-associated noncoding RNAs could become reliable diagnostic biomarkers for the disease as well as future therapeutic targets.

Biological principle of noncoding RNAs
noncoding RNAs regulate gene function

Select References (Pubmed)

Manna I et al., Non-Coding RNAs: New Biomarkers and Therapeutic Targets for Temporal Lobe Epilepsy. Int. J. Mol. Sci. 23, 3063, 2022.

Papadelis C, Perry MS. Localizing the Epileptogenic Zone with Novel  Biomarkers. Semin Pediatr Neurol 39:100919,  2021.

Pitkanen A. et al., Epilepsy biomarkers – Toward etiology and pathology specificity. Neurobiol Dis. 123: 42–58, 2019.

Some studies in man

Wang X et al., Serum microRNA-4521 is a potential biomarker for focal cortical dysplasia with refractory epilepsy. Neurochem Res 41  :905-12, 2016.

Yan S et al., Altered microRNA profiles in plasma exosomes from mesial temporal lobe epilepsy with hippocampal sclerosis. Oncotarget 8:  4136–4146, 2017.

An N et al,. Elevated serum miR-106b and miR- 146a in patients with focal and generalized epilepsy. Epilepsy Res 127:  311–316, 2016.

Sun J. et al.,  Identification of serum miRNAs differentially expressed in human epilepsy at seizure onset and post-seizure. Mol. Med. Rep 14:  5318–5324, 2016.

Oxidative Stress and Epilepsy

Pathophysiology of epilepsy, , , ,

Blog 12 – Oxidative Stress and Epilepsy

Oxidative stress is thought to be the underlying cause of major brain diseases including epilepsy.  In association with neuroinflammation (Blog 11 Sleep Disturbances and Epilepsy – Adversaries), oxidative stress is considered an important facilitator in epilepsy that eventually leads to brain damage.  On this point, there exist numerous reviews and animal studies supporting a causative role of oxidative stress in epilepsy.  Sadly, there are only a handful of clinical trials that have tested this role.

Scientists know very little about the development and progression of epilepsy.  It is clear that abnormal repetitive neuronal activity called seizures, are the major symptom of the disease.  A small percentage of  epilepsies are due to known genetic mutations.  The remainder, termed acquired epilepsies, have possible origins in known neurological insults e.g. trauma, illness. However, the cause of acquired epilepsy for most, remains unknown.  Therefore, studies that might identify a common biological pathway such as oxidative stress, for the majority of epilepsies, may lead to better therapies and a possible cure.

Recall that approximately 30-40 percent of patients with epilepsy do not respond to anti-seizure medication.   Those that do, however, must endure side effects, some of which cause patients to stop their medication.  Furthermore, anti-seizure medication treats the symptoms and not the underlying pathological processes.  Thus, it is vital that research into the basic mechanism(s) of epilepsy is front and center.  Evaluation of the role of oxidative stress in epilepsy is a reasonable place to start.

What is Oxidative Stress?

Metabolic processes in our cells, whether dependent on enzymes or not, constantly produce substances (small molecules, particles) that are highly reactive with nearby essential compounds.  These reactive species (RS) contain oxygen, nitrogen or carbon that promote oxidative changes.  Importantly, there is an abundance of RS in our cells and at high concentrations, all RS may directly harm neighboring indispensable compounds, such as proteins, DNA and fats.  Specifically, if the damaged compound is not repaired, these random oxidative changes hinder and subsequently prohibit normal cellular functions.  The outcome is that cells die prematurely and create a state of inflammation.

Fortunately, humans possess a wealth of anti-oxidative defense mechanisms to prevent random oxidative destruction.  These mechanisms include the well-known anti-oxidative compounds e.g. vitamin C and E, selenium, polyphenols, lycopene and flavonoids, all found in fruits and vegetables.  Lesser known mechanisms but of higher overall benefits are the anti-oxidative enzymes e.g. superoxide dismutase (SOD), catalase and glutathione peroxidase.  Additionally, sophisticated repair mechanisms exist that exclusively identify and repair oxidized DNA and proteins.

Oxidative stress occurs when the amount of RS overwhelms the antioxidative systems.  Therefore, key components are not repaired and become dysfunctional.  Fortunately, our anti-oxidative mechanisms are so effective that oxidative stress is minimal.  However, with age, illness, injury, extreme stress, and initial stages of chronic disease, oxidative stress is evident and harmful.

Role of Oxidative Stress in Epilepsy

Several recent reviews summarize the experimental data supportive of a role of oxidative stress in seizures and progression of epilepsy (Lin et al., 2020; Parsons et al., 2022).  Mainly, oxidative stress as defined above is considered “one of the early cellular events and a critical factor to determine the fate of neurons in epilepsy.” (Lin et al., 2020). 

Supportive Data that Oxidative Stress is a Key Mechanism in Epilepsy

1.  Epilepsies due to genetic mutations and genetic animal models of epilepsy show production of reactive species, deficiency of anti-oxidative mechanisms and subsequent neuronal damage (Pearson-Smith et al., 2017). 

2.  The amount of oxidative metabolites and antioxidative potential in children and adults with severe epilepsy correlate with seizure frequency (Morimoto et al., 2016).  Additionally, altered anti-oxidative systems have been identified in patients with temporal lobe epilepsy (Keskin et al., 2016).   Analysis of resected human brain tissue (those undergoing surgery) show evidence of oxidative damage and neuronal cell damage and death (Pecorelli et al., 2015).

3.  Results of numerous experiments in experimental models of epilepsy report that anti-oxidants e.g. N-acetyl-cysteine, melatonin, vitamin C and vitamin E inhibit seizure-induced oxidative damage.  Also, artificial activation of the genetic network that promotes anti-oxidative mechanisms prevents oxidative stress, preserves neurons and reduces seizures in animal models of epilepsy.

Clinical Trials

Armed with aforementioned findings, clinicians began to assess the efficacy of anti-oxidant therapy in patients with epilepsy.  Nineteen antioxidant compounds have been successfully evaluated in animal models of epilepsy (Lin et al.,2020).   Of these, 7 compounds (N-acetyl cysteine; ubiquinone; vitamin C, selenium/sildenafil; vitamin E and melatonin) have undergone clinical trials in man.  Despite the fact that many trials ended more than 7 years ago, results for only two of these compounds, vitamin E and melatonin, are publically available. 

Vitamin E

Vitamin E is a fat soluble anti-oxidant found in nuts, plant-based oils (e.g. olive, sunflower) and avocados, for example.  Two clinical trials using vitamin E as an add-on to anti-seizure medication produced contrasting results.  The first study of 12 patients with epilepsy reported that vitamin E, daily for six months significantly reduced seizure frequency in 10 of the 12 patients (Ogunmekan and Hwang, 1989).   In contrast, daily use of vitamin E for 3 months in 43 patients was without effect on seizure frequency or severity (Raju et al., 1994).  Both studies used what clinicians consider to be very high doses of vitamin E (more than 15 times the recommended daily allowance).

Melatonin

Melatonin is a sleep regulating hormone produced by the pineal gland in the brain.  It is commercially available in extended release form to enhance sleep duration and quality.  Additionally, due to its structure, it acts as an anti-oxidant.  Since epilepsy is associated with sleep disturbances (Sleep Disturbances and Epilepsy – Adversaries), the use of melatonin as an add-on therapy for drug resistant (intractable epilepsy) is reasonable.

There have been six published clinical trials evaluating melatonin in epilepsy.  Five of the 6 studies pertain to children and evaluated melatonin efficacy in 6-37 youngsters with epilepsy for generally a 3 month period.  Melatonin significantly improved sleep characteristics and improved seizure severity in 2 of the 5 studies.  Due to the small number of participants, it is impossible to know why positive results occurred in some but not all studies.  One study in adults with generalized epilepsy found melatonin added on to therapy of valproate for 8 weeks improved both sleep characteristics and reduced the seizure frequency and severity (Verma et al., 2021).  Although larger than trials with children, this trial evaluated only 52 patients.

Yin-Yang of Oxidative Stress

Conclusions

There is considerable experimental data supporting the hypothesis that oxidative stress is instrumental in creating an abnormal environment that continues to perpetuate seizures and maintain the disease state.  Clinical evaluations of more effective antioxidative compounds would be worthwhile.  The positive results of melatonin in adults is a good start that needs confirmation with a larger study.

Select References

Keskin Guler, S et al., Antioxidative-oxidative balance in epilepsy patients on antiepileptic therapy: A prospective case-control study. Neurol. Sci. 5:  763–767, 2016.

Lin T-K et al., Seizure-Induced Oxidative Stress in Status Epilepticus: Is Antioxidant Beneficial? Antioxidants 9: 1029, 2020

Morimoto M et al., Oxidative Stress Measurement and Prediction of Epileptic Seizure in Children and Adults With Severe Motor and Intellectual Disabilities. J Clin Med Res. 8(6):  437-444,2016.

Ogunmekaan AO, Hwang PA.  A randomized, double-blind, placebo-controlled, clinical trial of D-alpha-tocopheryl acetate (vitamin E), as add-on therapy, for epilepsy in children. Epilepsia. 30(1):  84-9, 1989.

Parsons ALM et al., The Interconnected Mechanisms of Oxidative Stress and Neuroinflammation in Epilepsy. Antioxidants  11:  157, 2022.

Pecorelli A et al., NADPH oxidase activation and 4-hydroxy-2-nonenal/aquaporin-4 adducts as possible new players in oxidative neuronal damage presents in drug-resistant epilepsy. Biochim Biophys Acta.  1852(3):  507-19, 2015..

Raju GB, Behari M, Prasad K, Ahuja GK.  Randomized, double-blind, placebo-controlled, clinical trial of D-alpha-tocopherol (vitamin E) as add-on therapy in uncontrolled epilepsy. Epilepsia. 35(2):  368-72,1994.

Verma N et al.,  Effect of add-on melatonin on seizure outcome, neuronal damage, oxidative stress, and quality of life in generalized epilepsy with generalized onset motor seizures in adults: A randomized controlled trial.  J Neurosci Res. 99(6):  1618-1631, 2021.

Sleep Disturbances and Epilepsy – Adversaries

Epilepsy Topics, Sleep disturbances, , , , ,

Assessment 11 – A complex relation exists between sleep disturbances and epilepsy.  Despite recognizing this reciprocity for well over a century, researchers are just now defining the adversarial effects of sleep disturbances on seizure frequency and severity of epilepsy on the one hand, and, on the other hand, the equally harmful effects of epilepsy on quality of sleep.  This blog will present the current understanding on the bidirectional relation of sleep disturbances and epilepsy

Introduction

Many important biological activities exhibit a cyclic function, known as circadian rhythms.  The most widely known circadian rhythm is the sleep-wake cycle.  This cycle exhibits a regularity of  7-9 hours of sleep, alternatively considered a transient unconscious state, and 14+ hours of conscious wakefulness.  The cyclic nature is tightly regulated by a plethora of genes, some aptly called clock genes.

Sleep is essential.  It provides a restorative benefit for our organs. Furthermore, It is necessary for the consolidation of long term memories. It is critical for removal of toxic metabolic waste products that accumulate in the brain during the day.  

Measurements of brain wave activity show that sleep occurs in several stages numbered 1-4. Light sleep spans stages 1 and 2; deep sleep develops in stages 3 and 4.  Stage 4 is followed by a period of rapid eye movement (REM) that is associated with dreaming.   Humans experience these stages (1-4, REM) over 90 minutes or so, resulting in about 7 repeats per night.  The more time spent in stages 3, 4 and REM, the fewer awakenings, the better rested one feels, and the greater the health benefit.

Sleep Disturbances

Sleep disturbances may take several forms.  They are 1) obstructive sleep apnea (OSA), a condition of reduced airway support and subsequent serious perturbations of oxygen and carbon dioxide levels, 2) insomnia, an inability to maintain sleep and 3) poor quality of sleep with frequent awakenings and reduced deep sleep (stages 3,4) and REM sleep. 

Sleep disturbances lead to complaints of excessive daytime sleepiness, reduced cognition and accidents.   Untreated OSA results in additional negative changes such as an increased risk for hypertension, diabetes, and heart disease.  Sleep disturbances also may exacerbate epilepsy and vice versa, epilepsy may worsen sleep disturbances.

Research Findings

Effects of Sleep Disturbances on Epilepsy

Sleep disturbances and epilepsy are intertwined.  To what extent and why is not entirely clear.  The most well-known finding supporting a relation of sleep disruptions and epilepsy is one used clinically to provoke seizures.  That is the state of sleep deprivation.  A night without sleep increases the likelihood of recording a daytime seizure with the 20 minute clinical EEG test.  In other words, sleep deprivation provokes seizures. It is used clinically to verify their presence. However, unraveling the mechanism of this empirical observation represents a challenge that is just beginning to be met.

Prospective Trial – Seizure Susceptibility Influenced By Sleep Deprivation

Sleep disturbances may initiate the onset of epilepsy.  A 10 year prospective population study (Harnod et al., 2017) that tracked medical records of  those (~ 277,000 individuals) half with and half without sleep disturbed breathing support this observation.  Harnod et al (2017) showed “the cumulative incidence of epilepsy was higher in the sleep disturbed breathing cohort than in the comparison cohort”.  The authors also concluded  that “Sleep deprivation increases seizure susceptibility and often provokes epileptic seizures”.  The data are impressive but regrettably they lack key information relating to patient confirmation, epilepsy type, seizure frequency and other confounding factors such as smoking.

A polysomnographic study is the medical term for a sleep study.  Polysomnography measures brain waves (EEG), blood gases (oxygen and carbon dioxide) and quantifies the number of reduced/absent breathing episodes per night (see detail at https://www.mayoclinic.org).  Therefore, polysomnographic studies provide quantitative data.

Result from these studies, reported individually or summarized in a meta-analysis(Lin et al., 2017) indicate that the prevalence of one of the most serious sleep disturbances, obstructive sleep apnea (OSA), is about 30% in patients with epilepsy treated with antiseizure drugs and higher in those with drug-resistant epilepsy.  Importantly, treatment of OSA in patients with epilepsy with continuous positive airway pressure (CPAP) not only corrects OSA but also reduces seizure frequency.   

Effects of Epilepsy on Sleep

According to several studies using a questionnaire, patients with epilepsy report a higher number of sleep complaints compared to those without epilepsy.  Complaints included insomnia, excessive daytime sleepiness and disturbed breathing such as obstructive sleep  apnea.  The complaints were 25-50% higher in patients with epilepsy compared to those without epilepsy

Night Time Seizures

Epilepsy impacts sleep in several ways.  Firstly, night time seizures, most common in frontal lobe epilepsy but occasionally occurring in other types of epilepsy, directly disrupt sleep.  It may cause insomnia or poor quality sleep. 

Discharges Between Seizures

Secondly, data from patients with an implantable brain recorder/stimulator device to reduce seizure frequency and severity, shed light on the indirect effects of seizures on sleep.  Recall from Assessment 8, continuous brain recordings in patients with epilepsy revealed the cyclic nature of epilepsy with seizure reoccurrence in intervals of days, weeks, months. Data show that abnormal brain waves termed interictal epileptiform discharges (IEDs) occur in between seizures in patient with epilepsy.  Interestingly, IEDs peak during sleep hours, specifically appearing during stages 1-4.  Their presence modifies normal sleep waves in those stages. In contrast, REM sleep suppresses IEDs.  It is unknown why this is.  One suggestion is that the character of normal brain waves in sleep stages 1-4 (synchronous and slow) is permissive for reception of irregular discharges such as IEDs. 

Anti-Seizure Medications

Thirdly, there is early recognition that some antiseizure drugs in certain types of epilepsy may enhance sleep disturbances and hence indirectly worsen the epilepsy by disturbing sleep character.  This issue is correctable with an alternative medication, shifting time of drug use and defining the sleep disturbance with a polysomnographic study.

Link between sleep and epilepsy

The results of numerous studies in animal models and in humans with epilepsy point to a common link between sleep disturbances and epilepsy.  Specifically, Bonilla-Jaime H. et al.,  (2021) reviewed an extensive body of evidence that supports the hypothesis that the common factor between sleep disturbances and epilepsy may be neuroinflammation.

Neuroinflammation

Neuroinflammation refers to a profusion of harmful changes in the brain initiated and maintained by a wealth of pro-inflammatory mediators.  Dying neurons and associated neurons called astrocytes and glial cells are the source of these mediators.  In measuring pro-inflammatory mediators, scientists conclude that both sleep disturbances and epilepsy promote neuroinflammation and the two together create a vicious cycle.  In other words, epilepsy worsens sleep disturbances and sleep disturbances worsen epilepsy through this pathway of neuroinflammation.

This is a milestone discovery with opportunities for new therapies for epilepsy.  Several therapies already have the backing of clinical trial results.  For example, use of continuous positive airway pressure (CPAP) restores normal breathing in patients with epilepsy and  OSA, and importantly, decreases seizure frequency and severity.  Another therapy, the ketone diet (see Assessment 9) decreases neuroinflammation and reduces seizure frequency in certain types of epilepsies.  Possible future therapies are anti-inflammatory medications to prevent and/or minimize neuroinflammation and additionally, therapies for insomnia and poor sleep such as cognitive behavioral therapy.

Conclusions

Unraveling the relation between sleep disturbances and epilepsy is important.  The modest amount of work to date defines an adversarial reciprocity between sleep disturbances and epilepsy with each worsening the other.  However, defining a common pathway such as neuroinflammation offers hope of someday diminishing both sleep disturbances and epilepsy. Clearly, future large clinical trials could provide definitive progress.

Proposal: Sleep Disturbances and Epilepsy related through neuroinflammation

Select References

Bonilla-Jaime H. et al., Sleep Disruption Worsens Seizures: Neuroinflammation as aPotential Mechanistic Link. Int. J. Mol. Sci. 22:  12531, 2021.

Harnod T, Wang Y-C, Lin C-L, Tseng C-H.  High risk of developing subsequent epilepsyin patients with sleep-disordered breathing.  PLoS ONE 12(3):  e0173491, 2017.

Lin Z, Si Q, Xiaoyi Z. Obstructive sleep apnoea in patients with epilepsy: a meta-analysis. Sleep Breath 21(2): 263-270, 2017.

Marlow BA et al., Treating obstructive sleep apnea in adults with epilepsy A randomized pilot trial. Neurology 71:  572–577, 2008.

Pavlova MK et al., Proceedings of the Sleep and Epilepsy Workshop: Section 2 Comorbidities: Sleep Related Comorbidities of Epilepsy.  Epilepsy Currents 21(3):  210-214, 2021.

Scharf MT et al., Obstructive sleep apnea risk in patients with focal versus generalized epilepsy. Epilepsy & Behavior 111:  107190, 2020.

The Subscalp EEG Recording – promising technology 

Diagnostics, Epilepsy Topics, ,

Introduction

Subscalp EEG recording is a technological advancement positioned to revolutionize diagnostics, treatment and understanding of epilepsy.

Over the past 7 years or so, several investigatory groups have developed subscalp EEG recording systems. These systems consist of electrodes that can be implanted under the skin of the scalp.  Electrodes are attached to external data collection and analytical systems.  These systems allow continuous EEG monitoring 24/7 for months and potentially for years. 

Unmet Need

There is a unmet need for accurate long term measurements of seizures.  To provide a correct diagnosis of epilepsy and develop optimal therapy, the physician needs information on exact seizure frequency, location, and brain wave activity prior to and after a seizure. As discussed in Blog 8 (Intracranial EEG recording), implantation of electrodes directly in the brain continually assesses brain wave activity and has provided significant insights in the cyclic nature of the disease.  However, intracranial recordings necessitate major surgery and, therefore, are available for only a small number of patients with epilepsy.  On the other hand, scalp EEG (electrodes placed on top of the scalp) coupled with video monitoring, although not invasive, supply continuous seizure assessment for no more than 14 days, at best.

Ultra-long term EEG recording lies between intracranial recording and scalp recording.  It has potential to not only determine seizure frequency and location but to confirm the cyclic nature of epilepsy, thereby significantly adding to insights from intracranial EEG recordings.  Furthermore, subscalp EEG systems appear capable of predicting future seizures, thus allowing for preemptive suppression.

However, keep in mind, this technology is in its initial stages but has great promise.

Validation of Subscalp EEG Recording

While there are many foreseeable uses of continuous subscalp EEG recordings, the first use is for long term acquisition of seizures and pre/post seizure activity in patients with epilepsy. 

There are 6 systems in clinical validation phases (clinical trial completion, ongoing or about to begin).  Two systems, the 24/7EEG SubQ (https:// www.uneeg. com/ en/ epilepsy/products/subq) and the Minder have completed small clinical safety/feasibility studies (see Weisdorf et al., 2018; 2019; Sterling et al., 2021). 

The 24/7EEG SubQ system

The 24/7EEG SubQ system consists of  a) subcutaneously implanted electrodes and b) a data collection system composed of a transceiver (transmitter/receiver combo), data storage device and power supply.  The first study with this system (4 patients with temporal lobe epilepsy) was a feasibility (proof-of-concept) study.  Results showed that SubQ EEG recordings were similar to standard scalp EEG recordings.  Specifically, the SubQ system measured seizures, pre-seizure activity, sleep brain wave activity and some unrelated activity.  These are all findings comparable to standard EEG recordings. 

The most outstanding characteristic of the subscalp recording is, unlike standard scalp EEG measurements, its ability to gather data over long periods of time.  The second clinical trial with the SubQ device implanted in 9 patients with temporal epilepsy and monitored EEG activity for the target time of 3 months (achieving a minimum of 9 weeks of recording for each patient).  This is clearly a milestone since it is the first study to demonstrate “ultra-long” EEG monitoring with a minimally invasive device and without disruption of daily activities of living.

The Minder System

Another subscalp EEG system, the Minder completed an 8 months study with 5 patients with epilepsy. The components of the Minder system are electrodes capable of monitoring brain activity in both hemispheres and collecting data by telemetry to a processor placed behind the ear.  A smart phone receives the data and stores it in the cloud. 

Subscalp EEG data from the Minder compared favorably with standard video/scalp EEG data obtained at specified times during the study.  These results confirm the feasibility of a minimally invasive implanted subscalp EEG system such as the Minder for long term monitoring of focal seizures.

Adverse Effects of Subscalp EEG Recording

Adverse effects from subscalp devices described above are mild.  Expected pain and soreness at the site of surgical implantation lasting about a week occurred in most patients.  However, few experienced pain and soreness beyond one week.  Some experienced mild headaches unrelated to the surgery.

Limitations of Subscalp EEG Recordings

Firstly, the collection of thousands of hours of brain wave activity creates an analytical nightmare.  In summarizing the data to reasonably handle it, some data may be lost.  Efforts to develop intelligent algorithms are in development so that all data can be treated equally.  Secondly, the position of the implanted electrodes may miss seizures originating deep in the brain. Thus some patients with epilepsy may not benefit from subscalp EEG devices.  Thirdly, completed safety and feasibility studies necessarily involved a small number of select patients (those with temporal lobe epilepsy).  Therefore, for confirmation of the generalized benefit of subscalp EEG for most patients with epilepsy, larger scale studies with patients with diverse types of epilepsy are required.

Conclusions

Subscalp EEG recording systems represent a relevant and dearly needed advancement over the short term EEG recordings of the standard scalp EEG.  Subscalp EEG systems provide ultra-long term recordings. These recordings provide accurate determinations of seizure frequency and location, information essential for optimal drug therapy or future surgical decisions.  Especially attractive is the fact that subscalp EEG systems require minimal surgery for implantation and once implanted do not disrupt everyday activities.

There are at present 6 subscalp EEG systems, 2 of which successfully demonstrated safety and feasibility  in patients with temporal lobe epilepsy.  This is a significant start.  The limited results thus far are indeed very promising.  Continued development and clinical assessment can promote and expand a transforming new technology to better serve patients with epilepsy.  This blog will provide updates on subscalp EEG systems from future clinical trials.

Comparison of EEG Technologies

References (http://pubmed)

Duun-Henriksen J et al., A new era in electroencephalographic monitoring? Subscalp devices for ultra–long-term recordings. Epilepsia.61:  1805–1817, 2020.

Stirling RE et al., Seizure forecasting using a novel sub-scalp ultra-long term EEG monitoring system. Front. Neurol. 12:713794, 2021.

Weisdort S et al., High similarity between EEG from subcutaneous and proximate scalp electrodes in patients with temporal lobe epilepsy. J Neurophysiol 120: 1451–1460, 2018.

Weisdort S. et al., Ultra‐long‐term subcutaneous home monitoring of epilepsy—490 days of EEG from nine patient. Epilepsia. 60:  2204–2214, 2019.

Ketogenic Diet: Can It Cure Epilepsy?

Epilepsy Topics, Ketogenic Diet, , , ,

Introduction to the Ketogenic Diet

Assessment 9 – Anti-seizure medication is the standard therapy for patients with epilepsy as discussed in an earlier blog ( Assessment 6 – Epilepsy Medication – Need to Know Information). Despite the availability of over 20 some anti-seizure drugs, approximately 30-35% of patients with epilepsy gain no benefit from these medications.  These patients are considered to have resistant epilepsy.  Options for resistant epilepsy are few.  However, one such option is the ketogenic diet.  This blog will describe the ketogenic diet, its effect on seizures and its limitations.

Background

The composition and efficacy of the ketogenic diet was published close to 100 years ago in a paper by Peterman (1928).  It is named the classic ketogenic diet (CKD) to distinguish it from the more recently developed variations of this diet.  In many respects, the CKD is similar to starvation/fasting diets in vogue to treat epilepsy some 2000 years ago. 

Classic Ketogenic Diet (CKD)

Components of the Classic Ketogenic Diet

CKD is a diet that is very high in fats and very low in carbohydrates and proteins.  Adherence to the CKD requires consumption (as a percentage of daily calories) of 80-90% fats, 6-8% protein and 3-4% carbohydrates.  The dietary goal of the CKD is to convert normal metabolism driven by the use of sugars for energy to one driven by the use of fats for energy.  The result is a decline in blood levels of sugar and insulin and an elevation in blood levels of fats and their metabolic products, termed ketone bodies.  Ketone bodies (e.g. hydroxybutyrate, acetoacetate and acetone) are fats readily utilized by the brain.  Although poorly understood, the outcome is seizure suppression.

Modified Ketogenic Diets

As you can imagine, the CKD with its incredibly high fat content requirement is unappealing and to some quite unpalatable.  Patients that do not immediately respond to the diet, readily give up on it.  Generally after 2 years, only 30% of patients remain on the diet.  Hence, over the years, scientists developed modifications of the CKD. 

The established variations are a) modified Atkins Diet (MAD), b) the low glycemic index treatment (LGIT), and c) the medium chain triglyceride diet (MCTD).  Compared to CKD, these modified diets permit a significant reduction in consumption of fats and allow an increase in protein and carbohydrate consumption.  Specifically, the percentage of calories from fat is reduced to 60% or less. Protein is increased to 10-25 %. Similarly, carbohydrates is increased to 10-19%.  Although not studied as extensively as the CKD, these diets are more palatable. So far, the results of studies to date indicate that efficacy is close to that shown with the CKD.

Actual Dietary Benefits – Seizure Reduction

Children/Adolescents with Resistant Epilepsy  

Since 1928, as reviewed by Wells et al., (2020)  results of many studies (observational trials, randomized clinical trials and meta-analyses) show that adherence to the ketogenic diet significantly decreases seizure frequency in children and adolescents with resistant epilepsy.  In particular, from 2008 to 2017, 7 randomized clinical trials tested the efficacy of CKD or one of its variants.  The trials differed in number of patients (48-145), age of participants (1-18 years) and duration (3- 16 months).  Nevertheless, patients consuming ketogenic diets compared to those on a normal diet experienced significant reductions in seizure frequency.  Depending on the trial, 38% to 100% of patients on ketogenic diets experienced greater than a 50% reduction in seizure frequency.  Additionally, a smaller number  of patients became seizure free.

Adult Patients with Resistant Epilepsy  

There are few studies on the use of ketogenic diets in adult patients with resistant epilepsy.  A summary analysis of several small clinical trials with adults (18-86 yrs) with drug resistant epilepsy, concluded that CKD was efficacious in adults.  In particular, 53%  of patients experienced greater than 50% reduction in seizure frequency. Thirteen percent of patients were seizure free on the diet.  There is a need for confirmation with larger trials.

Mechanism of Seizure Reduction

There is no convincing evidence as to how an increase in ketone bodies serves to suppress seizures and in some cases to cure epilepsy.  Study results in animals suggest that ketone metabolism unlike sugar metabolism promotes

a) anti-inflammatory activity and neuronal protection and repair,

b) suppresses production of mediators that excite nerves and enhances production of mediators that inhibit abnormal nerve activity,

c) influences gut bacteria to produce effective brain relevant compounds, and changes brain metabolism to optimize function of favorable nerve genes. 

 At present, there is no evidence in man that these pathways predominate during adherence to ketogenic diets.

Adverse Effects Of the Ketogenic Diet

Appearance of adverse effects is one reason patients discontinue the ketogenic diet.  To be fair, this is not the only reason. Lack of efficacy and poor palatability of the diet are generally more important. Not surprisingly, a series of gastrointestinal-related changes are the main complaints with consumption of ketogenic diets.  Specific adverse effects include constipation, diarrhea, abdominal pain, gastroesophageal reflux, and hunger.  Other adverse effects, not as common occur with long term use (greater than one year). They are kidney stones, reduction of bone mineral content, and abnormal blood lipid profile e.g. elevation of triglycerides/low density lipoprotein (LDL) and decrease in high density lipoprotein (HDL).  However, abnormal blood lipids did not result in cardiovascular disease.  As expected, modified CKDs e.g. diets noted above, result in fewer and less severe adverse effects. Hence patients achieve greater tolerance and adherence

Summary

Ketogenic diets remain an option for patients of all ages with resistant epilepsy.  For those responding to these diets, seizure frequency declined by half or more and some patients become seizure free.  Compared to the classic ketogenic diet, the modified diets encourage greater adherence. Patients experience fewer adverse effects and efficacy is nearly equal to the classic diet.  Considering these observations, it seems incredibly important for scientists to determine exactly how ketogenic diets work to suppress seizures.

Reference used for this blog are available on request and found on pubmed.com.

Assessment 8 – Nature of Epilepsy

Pathophysiology of epilepsy, ,

Introduction

The electroencephalogram known as the EEG is one of the main clinical tools used by neurologists to capture a seizure so as to make a  diagnosis of epilepsy (Assessment 7).  The EEG is a 20 minute procedure in which electrodes are placed on the scalp and brain wave activity is recorded and analyzed.  It has many flaws.

EEG limitations

The EEG  has serious limitations, chief of which is its short duration. Therefore, the EEG is unable to detect most seizures since most seizures, occur randomly.  In lieu of an EEG seizure, physicians rely on the patient and/or family observations of seizure activity for a diagnosis.  Thus, physicians make a selection of anti-seizure medication without hard evidence of seizure type and brain location.  Although this empirical approach may eventually lead to seizure suppression for the patient, albeit with side effects, it does not advance the field of epilepsy.  Treating the symptoms of epilepsy does not add to understanding the disease in order to find a cure.

Insights from intracranial EEG recordings

Cyclic Nature

Brain wave recordings gathered over a period of years in patients with epilepsy have revealed new and important insights into the nature of epilepsy.  Basically, these findings show that epilepsy creates a brain where abnormal brain waves (interictal epileptiform activity) occur in cycles of 7, 15, 20-30 days or more. 

What this means is that abnormal brain wave activity flows over the brain like ocean waves, rising to a peak and then falling to a baseline.  Cycle length is unique to each patient with epilepsy.  Importantly, these cycles are predictive of a seizure. This is because it is the rising number of abnormal brain waves of a cycle (the upswing of the cycle) that is associated with seizure onset.  Therefore, as the number of abnormal brain waves in each cycle increases to its peak so does the risk of seizures.  The waning number of abnormal brain waves of each cycle is not related to seizure risk. The section below describes the supportive experiments.

These are incredibly significant revelations. Firstly, cyclic brain wave activity exists in epilepsy. Secondly, the upward swing to the peak of each cycle is the time of greatest risk for seizures.  Therefore, cycle intervals are unique for each patient with epilepsy. Each cycle predicts the next round of seizures (since it follows the rise in wave number per cycle).  The knowledge of this relation between cycle and seizure could allow for adequate intervention and prevention.

Source of Insights

These findings appear in a publication by Baud MO et al. Under-sampling in epilepsy: Limitations of conventional EEG. Clinical Neurophysiology Practice 6 : 41–49, 2021.  Since copyright laws prevent reproduction of Baud’s figures, it is recommended that the reader obtain the free publication through PubMed (https://pubmed.ncbi.nlm.nih.gov/).  The representative EEGs with superimposed seizure events provide visual confirmation of these findings.

These findings are important. Two hundred patients with generalized epilepsy of unknown cause (idiopathic) resistant to antiseizure medication participated in Baud’s clinical study.  To suppress their uncontrolled seizures they chose an FDA approved intracranial neurostimulator (RNS_System.NeuroPace, Inc).  The device captures the abnormal brain waves (interictal epileptiform activity) described and can respond with a counter stimulation to neutralize the seizure.  

Sixty percent of the patients in Baud (2021)’s study exhibit cyclic rhythms as described above.  This is certainly a significant number of patients to propose cyclic brain waves rhythms as a basic characteristic of idiopathic generalized epilepsy.  However, in the future, it is important to evaluate patients with different types of epilepsy to determine if these cycles also occur across all epilepsies.

Future Challenges 

The hurdle to more wide spread research is how to obtain years long data without  implantation of electrodes directly into the brain.  Intracranial electrode implantation is major invasive surgery and hence, a choice of last resort.  Since these observations would never have been obtained in a 20 minute diagnostic EEG, there is clearly a need to develop external devices with the same sensitivity and accuracy as intracranial devices that would be suitable for long term use. 

Summary

The exciting findings of Baud et al (2021) uncovered significant novel characteristics in the brains of patients with epilepsy.  Results of years long brain recordings of patients with idiopathic generalized epilepsy show abnormal brain wave activity that continuously cycles over intervals of weeks or months.  As the number of abnormal waves increase so does the risk of seizures.  This is an incredible insight and if confirmed in other types of epilepsy, provides the first step toward understanding the disease of epilepsy.

Assessment 7 – Value of Diagnostics for Epilepsy

Diagnostics, , , ,

Epilepsy is a disease defined by the presence of two or more seizures, separated by more than 24 hours.  However, in order to identify the appropriate anti-seizure drug for seizure suppression, a diagnosis of epilepsy is more complicated than the definition implies.  There are 4 sources of potentially valid information that together should yield the most accurate diagnosis.  The diagnostics for epilepsy are:

a) seizure history provided by the patient;

b) digital data from an electroencephalogram (EEG) which records seizure activity or, in the absence of a seizure, the presence of abnormal discharges;   

c) analysis from magnetic resonance imaging (MRI) showing presence of a tumor, scar tissue, or abnormal anatomical lesions related to site of seizure origin;

d) genetic assessment matching one or more of the known genetic errors associated with specific types of epilepsy.

What is the value of the information gathered from these sources?

1. Seizure History

Seizure history is important but can be lacking in specifics.  This is because many patients have little to no recollection of their seizures.  This starting point for a diagnosis is not particularly helpful in identifying the epilepsy type and thus, it is not helpful at all in selection of the appropriate antiseizure medication.

2.  EEG

The EEG was developed over a century ago.  Electrodes, placed on the scalp, record summated electrical activity primarily from the outer portion of the brain (the cortex).  Electrodes are precisely positioned to receive defined recognizable brain wave activity.  The EEG recording itself generally takes 20 minutes but considerable time is required to position the electrodes and also to remove them.  During the actual recording, procedures such as light stimulation or hyperventilation are used to “evoke” a seizure.

Advantages of diagnostics for epilepsy: 

Whereas the EEG usually does not record a seizure in progress, its ability to detect abnormal discharges, (called interictal epileptogenic discharges or IEDs), is significant because the presence of IEDs have been found to signal a high risk of having a future seizure.  The EEG many record local IEDs (expressed in one hemisphere) or general IEDs (expressed in the entire brain). This information contributes to a more accurate diagnosis and hence is one clear benefit of the EEG.  Additionally, the EEG is helpful in monitoring the progress of seizure suppression with drugs or surgery. Anti-seizure drugs has previously been discussed (Assessment 6 – Epilepsy Medication – Need to Know Information)

Limitations of Diagnostics for Epilepsy: 

As revealed by years of intracranial recording (surgical implantation of electrodes) in patients with epilepsy, it is apparent that the EEG has limitations.  Its short duration, lack of sensitivity and tendency for over interpretation are some of its limitations.  It has also failed to identify the multiday cyclic nature of epileptic activity. 

The short duration of the EEG test fails to capture the majority of  in-progress seizures and many patients show no evidence of IEDs.  Although in a hospital setting, the EEG may be used continually for several days, this is not routinely practiced.  To avoid obtaining incorrect data, technical expertise is required for electrode placement.  Despite this, sensitivity is diminished due to distance of the electrodes (on the scalp) from the origin of the brain activity (somewhere in the brain) and the inability of electrodes to record all brain wave activity but only a sampling of those reaching the outer layer of the brain.

3.  MRI

The MRI is one of several imaging techniques with success in identifying abnormalities in the brain in persons with epilepsy (see https://medlineplus.gov/mriscans.html ) for details on MRI imaging.  In cases of epilepsies resistant to drug, surgical protocols require prior imaging procedures.

Imaging techniques include the MRI, the positron emission tomography (PET) and MRI spectrometry, to name a few.  The MRI uses magnetic energy to define the location of structures in the brain.  The stronger the magnet, the better the resolution of the individual structures in the brain.  The PET scan adds to the MRI with the use of a radioactive tracer.  This tracer localizes to areas of high metabolism as in tumor or indicates areas of low metabolism as in epileptic lesions.  The MRI spectrometry is a supplemental test only.  It measures brain compounds known to indicate the presence of a seizure lesion.  Abnormal levels of specific compounds add to MRI data of structural changes, pinpointing a epileptic lesion.

Advantages of Diagnostics for Epilepsy: 

The MRI in association with other imaging tools (PET, Spectrometry) provide essential information for epilepsy patients resistant to drug therapy.  These patients may be candidates for surgical therapy.  High quality data from imaging techniques assist with accurate surgery but only facilities with extensive experience in imaging and treating patients whose epilepsy is not suppressed with antiseizure drugs, produce these desired outcomes.

Limitations of Diagnostics for Epilepsy: 

Outpatient use of the MRI technology generally contributes little to the initial diagnosis of epilepsy.  Most clinics lack expertise on recognition of epileptogenic lesions and additionally do not employ the optimal MRI protocols to capture these lesions.  Technologists may also lack the clinical information to alert them to the reason for the MRI and hence fail to seek expert help.  

4.  Genetic Analysis

Epilepsy is considered to have a heritable component.  Identification of the genes involved in epilepsy should provide greater understanding of this disease and lead to better therapy.  The International League Against Epilepsy Consortium on Complex Epilepsies initiated a large analysis (meta-analysis) of the genome (DNA content) of persons with epilepsy compared to controls.  The most recent work (2018) included over 15,000 epilepsy cases and over 29,000 controls.  This study identified 16 different chromosome locations that relate with confidence to epilepsy.  These chromosome positions reveal many genes already associated with epilepsy such as the ion channels on nerve cells but also importantly, many new genes not previously identified as a cause of epilepsy.

Advantages of Diagnostics for Epilepsy: 

Routine genomic testing in epilepsy could be a step closer to precision medicine. Genomic testing would allow for a precise diagnosis, and a more rational selection of anti-seizure medication.  This type of testing opens the door for discovery of novel drugs and has potential to determine exactly which genes play a role in specific types of epilepsy.

Limitations of Diagnostics for Epilepsy: 

Analysis of genomic-wide testing is complicated and the variety of different forms of epilepsy are equally complex.  To date, most of the identified genes are “associated with genetic generalized epilepsy” (ILAE Consortium).  Considerable research commitment will be needed to unravel the genetic influence on epilepsy and then to reveal how the environment interacts with these genes.

Summary

There exists 4 different types of information (patient assessment, EEG, MRI, genetic analysis) that should provide an accurate diagnosis of epilepsy.  Unfortunately, their limitations outweigh their assets.  Thus, a diagnosis of epilepsy may be absent, delayed or incorrect and consequently, antiseizure therapy may be inappropriate.

Assessment 6 – Epilepsy Medication – Need to Know Information

Therapeutic anti-seizure drugs, ,

Here are 4 summary statements, supported by research, that hopefully will provide a useful overview of epilepsy medication for persons with epilepsy (PWE) and parents of children with epilepsy.  This blog will expand on each statement and indicate why this information is important to know.

1.  There are no drugs that treat the root cause of epilepsy; there are more than 25 FDA approved drugs that treat seizures, the symptoms of epilepsy.

2.  Drug selection should be based on seizure type but in many cases, seizure type is unknown.  Generally, in both instances, physicians prescribe drugs based on their familiarity with a specific drug.

3.   Drugs in clinical use act to suppress seizures in one of four ways.  Thus, when a drug fails to work, an alternative drug with a different mechanism of action would be a reasonable next step.

4.  No drug has a single action and all drugs used to treat PWE produce adverse drug reactions, many of which reduce quality of life.

1.  Epilepsy Drugs versus Seizure Drugs

Previous blogs (Assessments 3,4,5) discussed prescription drugs that induce seizures either during treatment of epilepsy and other conditions or on withdrawal of therapy.  This blog will discuss prescription drugs that control seizures and hence are the pharmacological treatment of epilepsy.  These drugs, of which there are more than 25, are termed anti-epileptic drugs (AED) but as noted by Sills and Rogawski, (2020), since they have no ameliorating effect on the disease of epilepsy but solely inhibit seizures, a better name is anti-seizure drugs (ASDs).  None of the drugs in clinical use correct the main cause of epilepsy.  Thus, at present, there is no cure for epilepsy, only possible relief from its symptoms.

It is important to know that only the symptoms of epilepsy are treated with medication and rarely will the disease go away.  It is truly sad that epilepsy which has been diagnosed since the Middle Ages (Brigo et al., 2018) remains, today, without a cure!

2.  Anti-Seizure Drug (ASD) Selection 

Seizures are categorized as focal, generalized, unknown or unclassifiable.  This is according to the International League Against Epilepsy (ILAE) guidelines (Scheffer et al., 2017).   Correct identification of a seizure is essential because data for drug efficacy is based on results of randomized controlled clinical trials in which a specific drug is evaluated against a specific seizure type.  A mismatch between seizure type and appropriate drug leads to inadequate therapy.  As noted by Kim (2020), “the diagnosis of the patient must first be accurate, in terms of the cause, seizure type, and epilepsy syndrome.”  Unfortunately, many seizure types are difficult to diagnose and unlike most other diseases, diagnosis of epilepsy relies on the patient’s history of the seizure.  Additionally, ASDs are not efficacious for all type of seizures and some, such as absence seizures are more difficult to treat (Kim, 2020).

Anti-seizure drugs (ASDs) as a monotherapy (single drug use) are effective in about half of all patients with epilepsy (PWE).  Twenty percent of PWE require additional drugs (polytherapy) and the remaining 30% are ASD-resistant, in which none of the available drugs suppress seizures (Verrotti et al., 2020). 

Selection of ASDs should be based  on drug “efficacy, tolerability and safety provided by solid evidences from well-designed randomized clinical trials (RCTs)” (Santulli, 2016).  However, survey results of PWE and their physicians (Groenewegen et al., 2014) imply that drug choice, in addition to safety and efficacy is based on the physician’s knowledge and experience with a specific drug.  This represents a possible source of bias (Santulli (2016). 

Persons wih epilepsy should ask their neurologist why they are taking a specific drug.  Ideally, for example, they should hear a discussion of the clinical trial results such that this drug suppresses their seizure type and not that their physician has considerable  experience with this ASD.

3.  Familiarity with anti-seizure drugs aids in successful treatment

Anti-seizure drugs  are divided into 4 groups according to the way in which they block seizures.  Scientists have worked hard from 1938 (advent of first clinically tested drug, phenytoin) to the present to understand the pathology of the seizure and develop ways to effectively interrupt them (Perucca, 2019).  They have successfully identified 25+ drugs with variable degrees of success in preventing seizures.  Additionally, they have developed a number of animal models with reproducible seizures to test novel anti-seizure drugs (Perucca, 2019).

Scientists have learned that seizures are identical to normal nerve activity except that seizures break loose of biological controls.  The result is unleashed neuronal activity and disruption of normal brain function.

Thus, anti-seizure drugs act to restore normal neuronal activity by restraining excessively high abnormal nerve function.  They essentially dampen this run-away nerve action and let alone the underlying normal nerve function.

Anti-seizure drugs target aspects of basic neuronal physiology.   Some anti-seizure drugs block ion channels that carry information throughout the nerve; others act to enhance the inhibitory neurotransmitter, gamma-amino-butyric acid (GABA) or inhibit an excitatory neurotransmitter, glutamate.  Anti-seizure drugs are listed below, grouped according to the way they act in the brain, called their mechanism of action. 

It is important to know that if an anti-seizure drug with a specific mechanism of action fails to suppress seizures, there exist other drugs with different mechanisms of action that would be the appropriate next anti-seizure drug to try.

4.  Adverse drug reactions (ADRs)

No drug has a single action.  All drugs have undesirable side effects termed adverse drug reactions (ADRs) and anti-seizure drugs are no exception.  Results of a 3 year prospective, cross-sectional, observational study of ~1000 patients with epilepsy found that ADRs occurred at a rate of ~2 per patient (Kumar et al., 2020).  ADRs increase with use of more than one anti-seizure drug.  Interestingly, Kumar et al., (2020) found no correlation between ADRs and the mechanism of the anti-seizure drug.  Thus, all anti-seizure drugs produce ADRs.  It remains unresolved as to the origin of ADRs but considering they target basic nerve activity in the brain and elsewhere, the existence of ADRs with use of anti-seizure drugs is not surprising.

ADRs that are least tolerated relate to behavioral/psychiatric side effects.  These ADRs include somnolence, ataxia (instability in standing/walking), sedation, aggression, depression, mood swings, psychosis, anxiety, suicidal thoughts, irritability, aggression, tantrums  and cognitive impairment (memory loss) (Chen et al., 2017; Kumar et al., 2020).  Other ADRs of lesser concern but still serious, are physiological or physical side effects such as diarrhea, nausea, skin disorders, and eye disorders (Witt, 2013; Kumar et al., 2020; Verrotti et al.,.2020). 

ADRs reduce quality of life and remains a major reason patients with epilepsy stop taking their medication.  This outcome is especially evident when seizure suppression is less than 100% (Chen et al., 2017).

Summary

On the one hand, considerable progress has been made in development of many efficacious anti-seizure drugs that target seizures in specific ways.  However, on the other hand, 30 % of patients with epilepsy receive no benefit from these drugs and 20% require use of more than one anti-seizure drug, elevating the risk of intolerable adverse drug reactions.  Furthermore,  none of the anti-seizure drugs in clinical use treat the root cause of the epilepsy.  Although current investigations seems interested in drug discovery and development to cure epilepsy, additional effort is needed in this direction (Perucca 2019).

Anti-seizure Drugs – Grouped according to how they work in the brain

Inactivators of sodium channels include the following drugs:

  • Phenytoin (Phenytek, Dilantin),
  • Carbamazepine (Tegretol),
  • Lamotrigine (Lamictal),
  • Fosphenytoin (Cerebyx),
  • Eslicarbazepine acetate prodrug – S-licarbazepine active metabolite (Aptiom, Zebinix),
  • Cenobamate (Xcopri),
  • Rufinamide (Banzel),
  • Lacosamide (Vimpat),
  • Topiramate (Topamax, Trokendi XR),
  • Oxcarpazepine (Trileptal)

Inactivators of calcium channels include the following drugs:

  • Ethosuximide (Zarontin),
  • Zonisamid (Zonegran),
  • others with multiple targets: Levetiracetam (Keppra XR, Spritam broad spectrum),
  • Gabapentin (Gralise, Horizant, Neuraptine), Pregabalin (Lyrica)

Activator of potassium Kv7channels include the following drug: 

Retigabine (Trobalt, Potiga) discontinued 2017 due to limited use and toxicities.

Enhancement of inhibitory neurotransmission

  • benzodiazepines: Diazepam (Diastat),  Lorazepam (Ativan), Clonazepam (Klonopin),  Clobazam (Onfi)
  • Tiagabine (Gabitril)
  • Vigabatrin (Sabril)

Attenuation of excitatory neurotransmission

Perampanel (Fycompa) 

Modulation of neurotransmitter release

  • Levetiracetam (Keppra XR, Spritam broad spectrum),
  • Brivaracetam (Briviact),
  • Gabapentin (Gralise, Horizant, Neuraptine),
  • Pregabalin (Lyrica)
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Prescription drugs – potential for seizures

Psychotropic Medications, Seizure-inducing Drugs, , , ,

Assessment 5 – Prescription Drugs

Introduction

There is an extensive list of prescription drugs that induce seizures (Zacarra et al., 1990; Grosset and Grosset, 2004).  Most, but not all drugs on this list, act to influence the brain in one way or another.  For example, these drugs may reduce anxiety, depression, or psychotic behavior or alternatively, may stimulate activity of the brain.  However, some drugs such as antibiotics, surprisingly, do not fit in this category, yet are capable of inducing seizures (Sutter et al., 2015 Wanleenuwat et al., 2020). Previous blogs discussed potential seizure induction with caffeine and nicotine use (http://assessment 3 and http://assessment 4).

Basically, drugs with a history of seizure induction have the potential to remove normal inhibitory influences on the brain or enhance excitatory influences, both of which produce outcomes of inappropriate nerve activity termed seizures.  

Ways drugs induce seizures

In general, drug-dependent seizures occur following use of a) higher than therapeutic drug doses (overdose) (Chen et al., 2015), b) use of drugs for prolonged periods (years) (Hill et al., 2015) or c) an abrupt withdrawal of a drug (Robertson and Sellers, 1982).  Furthermore, according to Thundiyil et al, (2010) in a prospective observational study, there are many factors which can exacerbate drug-induced seizures such as “stimulant exposure, suicide attempt, initial hypotension, and admission acidosis or hyperglycemia”.  These conditions not only complicate drug-induced seizures but may also lead to death.

This blog will focus on the seizure-inducing potential of drugs categorized as psychotropic medications.  They include a) antidepressants, b) antipsychotics and c) anti-anxiety drugs. These are drugs with ” high epileptogenic potential”, that is ability to stimulate seizures (Lee et al., 2003).

Specific drugs: Antidepressant drugs

Hill et al., (2015) completed one of the most extensive evaluations of the effects of antidepressants on seizure induction.  In the UK, this group evaluated records from 200,000 depressed patients (20-65 years of age) over a 5 year period to determine the time of first diagnosis of epilepsy/seizures while taking anti-depressant medication.  Only individuals without a prior epilepsy/seizure diagnosis were included in this study. 

Hill et al.,(2015) reported a significant increase in seizure induction with” all antidepressant drug classes”.  Hill and his associates  determined that 8 of the 11 most commonly prescribed antidepressants (see Table 1 for a list of these drugs) are associated with a first diagnosis of epilepsy/seizures.  The top three antidepressants are trazodone (Desyrel), lofepramine (Gamanil, Lomont, Tymelyt) and venlafaxin (Effexor).  The exceptions, that is antidepressants with no relation to induction of seizures, are sertraline (Zoloft), escitalopram (Lexapro) and mirtazapine (Remeron).   Interestingly, the risk of seizure induction with antidepressant use is low if drugs are used for one year or less, the duration recommended by the FDA.  Long term use, as in this study, up to 5 years is associated with a significant risk of a first diagnosis of epilepsy or seizures.

Antidepressants and mortality

Josephson et al., 2017  (electronic health records of >2 million individuals; 0.6% with epilepsy and followed for 6 years) found that use of antidepressants termed serotonin receptor uptake inhibitors (SRI) which include drugs like Effexor and Prozac, in patients with epilepsy (PWE) is associated with increased mortality, not decreased mortality as expected.  Furthermore, use of 2 or more antidepressant prescriptions whether in PWE or otherwise, is statically associated with an ” elevated risk of all-cause mortality”.  The authors indicate that their data does not prove a cause and effect relationship.  Because of the limited number of PWE, the authors were unable to determine whether increased mortality was due to seizure-related deaths.  Clinical trials are needed to determine the adverse effects of long term use of antidepressants.

Antipsychotic drugs

Antipsychotic drugs are prescribed for the treatment of psychosis (mania, paranoid states, acute schizophrenia, bipolar disorder and dementia).  Hedges et al, (2003) concluded that antipsychotic drugs have the potential to lower seizure threshold and hence induce seizures.  This applies to the older original antipsychotic drugs such as chloropromazine as well as the later second generation drugs such as Clozapine (Clozaril).  Specific reports (Alper et al., 2007; Uvais and Sreeraj, 2018) indicate that Clozapine and Olanzpine (Zyprexa) induce seizures in a dose-related manner.  It is speculated that antipsychotics induce seizures by inhibition the neurotransmitter, gamma-amino-butyric-acid (GABA).

Case study reports provide much of the data on antipsychotics and seizures.  Whereas this is important information, it lacks the rigorousness of results obtained from randomized clinical trials.  To date, no clinical trial has examined the effect of antipsychotic drugs on seizure induction, other than that which is reported in phase 4 clinical trial for FDA drug approval (accordingly, less than 1% experience seizures).  Nevertheless, caution is advised since other factors such as ” history of seizure activity, concurrent use of other drugs that lower seizure threshold, rapid dose titration, slow drug metabolism, metabolic factors and drug-drug interactions” (Hedges et al., 2003), may play a role in facilitating seizure induction with antipsychotics.

Anti-anxiety drugs

Anti-anxiety drugs belong to a class of drugs termed benzodiazepines.  This class includes one of the most commonly prescribe drugs, alprazolam (Xanax) (Ait-Daoud et al., 2018)  (see Table 1 for similar drugs).  As a class, these drugs are widely prescribed and are used for the treatment of panic disorders, obsessive-compulsive disorders, sleep disorders, muscle spasms, pre-anesthetics preparation and are also used as a standard drug choice for the treatment of convulsive disorders such as epilepsy and seizures (Goodman and Gilman, 2005).  Benzodiazepines act by binding to and stimulating a select subset of GABA receptors to facilitate the anti-anxiety  and anti-convulsive effects.

Evidence of adverse effects appeared early on, since their advent some 60 years ago of the original anti-anxiety drugs,  Librium and Valium.  In particular, it was clear that potentially serious withdrawal symptoms occurred with drug stoppage.  Importantly, abrupt withdrawal of a drug from the benzodiazepine class leads to seizures (Robertson and Sellers, 1982).  Withdrawal symptoms may be mild (headache) to severe. Specifically, “seizures, mania and death from convulsions” (Calcaterra and Barrow, 2014; Brett and Murmion, 2015) may occur.  Generally, severe withdrawal symptoms are evident after prolonged use.  Therefore, short term use of benzodiazepines not exceeding 6 months, is recommended (Brett and Murmion, 2015).

Conclusions

Antidepressants, antipsychotics and anti-anxiety drugs have the potential to induce seizures.  This comes from several comprehensive medical record assessments and a wealth of case reports.  The available data suggests that seizures occur primarily during long term use of antidepressants and antipsychotic drugs and on abrupt withdrawal of anti-anxiety drugs.

There remain many unanswered questions:

1.  There is suggestive evidence that abrupt drug withdrawal even after short term use of an anti-anxiety drug may precipitate seizures.  Unanswered: What is the minimum duration of anti-anxiety drug use for which seizure induction will not occur following discontinuation?

2. The literature suggests that drug-induced seizures are different from epilepsy.  However, Hill et al., (2015) reported that a number of patients, with no prior history of epilepsy,  received  a first diagnosis of epilepsy while on antidepressants.  Unanswered question:  Is this observation important enough to warrant confirmation by additional studies?

3.  The literature suggests that long term use of psychotropic drugs is highly associated with seizure induction.  Unanswered:  If psychotropic drugs are generally prescribed for extended periods of time, would a clinical trial be appropriate to determine the adverse effects of long term use of psychotropic drugs?

4.  Unanswered questions:  Should individuals with a prior history of epilepsy and seizure free without medication for years be prescribed psychotropic medications in the future?    Can psychotropic drugs reactivate epilepsy?

Advice

Much of the seizure-inducing potential of psychotropic drugs can be reduced with short term (12 months or less) use and a prolonged (months) withdrawal when no longer needed.   Lack of knowledge or contrary actions clearly elevate the chance for seizures or epilepsy.

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Drugs That Induce Seizures

Nicotine, Seizure-inducing Drugs, ,

Assessment 4 – Does nicotine provoke seizures?

Background

Nicotine Use; Possible source of Seizures?

My previous blog discussed the effect of caffeine consumption on the possible induction of seizures (Assessment 3).  Another widely used substance is nicotine which reportedly has the potential to induce seizures under some conditions.  The main route of nicotine use is by inhalation in smoking  tobacco.  Alternative routes include absorption in the oral cavity with chewing tobacco, snuff, nicotine gum and lozenges, and as anti-smoking aids, vaping with E-cigarettes, and transdermal absorption with a nicotine patch.  How does nicotine use relate to seizures?

Seizures and Nicotine – Confounding Issues

The scientific literature on seizures and nicotine, comprehensively reviewed up to 2014 by Rong et al.,  emphasizes the following confounding issues: 

1.  Impossible to separate nicotine from toxins in smoke

It is incredibly difficult to determine whether nicotine in smoking tobacco can provoke seizures because in the act of smoking tobacco, the smoker not only absorbs nicotine, the addictive component of tobacco, but also absorbs over 7000 other compounds (Rong et al., 2014).  Among these, some cause seizures e.g. carbon monoxide; arsenic; cresol, some prevent seizures e.g. acetone and the remainder are unstudied.  So it is not only nicotine that might provoke a seizure but anyone of a number of inhaled compounds of smoke.  Hence, it is impossible at present to sort this out.

2.  Indirect effects of smoking on health may induce seizures

A second consideration is that long term smoking produces harmful changes in the heart, blood vessels and lungs, causes inflammation and blood clots and initiates cancers.  These changes secondarily may induce seizures, and are highly probable with a stroke.   Therefore, smoking (not necessarily nicotine alone) may indirectly elevate the risk of seizures.

3.  No convincing studies on seizures and just nicotine alone

Nicotine use, other than smoking, should provide insights into the direct effects of nicotine on seizures.  However, sadly, there are no large scale interventional studies that have investigated this.

Scientific literature (nicotine and seizures) – up to 2014

There have been two prospective studies with the objective of defining the risk of smoking to seizures (see review Rong et al., 2014).  The first of these by Dworetzky et al.,( 2010) using data from the Nurses’ Health Study II, assessed the effect of chronic cigarette smoking by women 25-42 (over 110,000 participants at start in 1989) on the risk of seizures or epilepsy.  Participants answered a questionnaire every two years and self-reported seizures over a 15 year period.  Only responses with seizure verification by medical records were included.  The researchers reported a “doubling in the risk of seizures and a modest non-significant increase in epilepsy in current smokers compared with never smokers that appeared to be independent of stroke”.  Whether this was strictly due to nicotine was not determined.  

The second study (de Carvalho et al., 2012) reported the relation of smoking to seizures in a specific systemic autoimmune disease, primary antiphospholipid syndrome.  Of the 88 individuals with primary antiphospholipid syndrome, approximately 10% experienced epileptic seizures.  Chronic smoking was the only factor statistically associated with their seizures.

In contrast, several case histories of individuals diagnosed with autosomal dominant nocturnal frontal lobe epilepsy are benefitted by use of nicotine patches (Rong et al., 2014).  In these few cases, nicotine patches were comparable to antiepileptic drugs and diminished seizure frequency.   

Results of animal studies tell a different story.  By different routes, (into the brain ventricles of cats),  (subcutaneously, intraperitoneally into rats and mice), nicotine induced seizures, reduced the efficacy of antiepileptic drugs or potentiated known proconvulsant compounds or electric shock.  Doses were considered high (generally 3mg/kg or higher). 

Interestingly, studies that chronically exposed rats to cigarette smoke or administered low doses of nicotine (0.8 -2 mg), observed a protective effect against chemically-induced seizures (kainic acid  or high dose nicotine).  In other words, in animal experiments, low doses of nicotine prevent seizures while high doses (greater than obtained with routine smoking) induce seizures.

Relation of nicotine use and seizures – up to present

A small pilot retrospective study of Chinese males (278) with various types of diagnosed epilepsy analyzed the effect of smoking on seizure frequency ( Gao et al., 2017) .  While the  data show a trend that smoking reduces the frequency of seizures, the type of study design and small size limit reliability of this report.  

In contrast, in a comparison of nonsmoking epileptic patients with smoking epileptic patients, Johnson et al.,(2019) showed that smokers had a higher risk of a seizure than non smokers in the past year.  Although the study validated smoking with a biochemical test, the cross-section study design, small number of participants and weak validation of seizures in the preceding year, limit reliability of this study.  Thus to date, there are no convincing data regarding the effect of smoking on seizures in man.

In animals, injection of cigarette smoke condensate (CSC) into the cerebral ventricle of the rat induced seizures comparable to those produced by intraventricular injection of kainic acid, a known proconvulsant.  Interestingly, the effect of the CSC could be block by pretreatment with atropine, a classic  inhibitor of the nicotinic acetylcholine receptor.  This is the receptor that nicotine activates to produce its  stress reducing effects (Xiao et al., 2020).  These findings strongly supporting a mechanistic role of nicotine in the induction of seizures (Laadraoui et al., 2018).  Iha et al.(2017) identified the seizure-sensitive brain regions affected by intraperitoneal injection of a high dose of nicotine (4mg/kg nicotine) in mice and rats.  Selectively removing these areas negated the seizure-inducing effects of nicotine.  These results strongly suggest that the nicotine in animal models is a potential cause of seizures.  Unfortunately, there is no corroborative data in man. 

Vaping and Seizures

Electronic nicotine delivery systems (ENDS) e.g. e-cigarettes are marketed as a means to quit smoking.  Seizures are associated with use of ENDS as summarized in 122 voluntary reports (Faulcon et al., 2020).  Sixty-two percent indicated seizures occurred within 30 minutes after last use; 85% indicated seizures occurred within 24 hours of last use.  According to Benowitz (2020) these reports lack  biological plausibility for the following reasons:  a) timing of seizures (30 minutes-24 hours) does not relate to the presence of nicotine (minutes), b) description of nicotine poisoning differs from voluntary reports, c)  impossibility of relating recurrent seizures to last use.  It is possible that other components, added drugs or e-cigarette components may be responsible for reported seizures.

Summary

Does nicotine consumption by any route induces seizures? 

Animal studies show low doses of nicotine protect against seizures while high doses induce them.  However, contradictory results also exist.  Generally, except with toxic overdosing, the high doses used in animals are never achieved in man with smoking or other routes. 

Thus, the bottom line is that in man there is no reliable data to indicate either way whether smoking presents a risk to seizure induction or is, in fact, protective.  Furthermore, these is no data at all on the effect of chewing tobacco, snuff, patches, lozenges or gum on seizure induction.

Unfortunately and regrettably, the available science is incomplete and inadequate to convincingly state whether nicotine use a) induces seizures, b) suppresses seizures or c) is without effect in man. 

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