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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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Drugs That Induce Seizures

Caffeine, Seizure-inducing Drugs

Assessment 3: Drugs that promote seizures – focus on caffeine

Background – Evaluating Epilepsy

There is an extended list of drugs with potential to induce seizures, and hence, are referred to as  epileptogenic drugs (Grosset and Grosset, 2004).  Drugs on this list include analgesics, antibiotics, antidepressants, and antipsychotics to name a few.  What constitutes an epileptogenic drug is complicated because it depends on variables such as dose, duration of drug use, drug withdrawal, genetic sensitivity and prior history of seizures (Chen et al., 2015).

Working Hypothesis

Epileptogenic drugs do not cause epilepsy which is defined as a disease with re-occurring seizures (focal, generalized, unknown onset) and a complex etiology (Falco-Walter et al., 2017).  Although there is no cure for epilepsy, it is managed in the majority of persons with epilepsy (PWE) with antiepileptic drugs (AEDs).  The prevailing hypothesis is that epileptogenic drugs perturb normal brain activity in favor of heightened excitability (Chen et al., 2015).  Therefore, these drugs either enhance excitatory neurons, inhibit inhibitory neurons or do both to induce excitatory changes conducive to generating seizures (Chen et al., 2015).  Importantly, when the drugs are withdrawn, the seizures stop.

Assessment 3 will focus on one of the most widely used epileptogenic drugs and probably the most controversial:  caffeine and its relative, theophylline.  Subsequent evaluating epilepsy assessments will discuss other epileptogenic drugs:  nicotine, and  antidepressant, anxiolytic and antipsychotic drugs.

Caffeine – Most widely used epileptogenic drug

Caffeine is the” most common and widely used stimulant” (Chrosciñska-Krawczyk et al., 2011).  It is present in coffee, tea, energy drinks, cola drinks, chocolate and some drugs.  Caffeine belongs to the chemical group of methylxanthines with theophylline and theobromine as important additional group members. 

Caffeine affects the brain by influencing several different neurotransmitters that relay information from nerve to nerve.  The most significant action of caffeine at physiological doses is its ability to interfere with some of the actions of the neurotransmitter, adenosine (Monteiro et al., 2016).  Adensosine, an inhibitory neurotransmitter,  mediates effects on sedation and sleep.  As a result of blocking adenosine, caffeine use produces cognitive benefits such as motivation, focus and improved attention, reduced fatigue and improved muscle performance (Monteiro et al., 2016).  These benefits are the main reason for the consumption of caffeine-containing drinks.

Significantly, adenosine is considered “an endogenous anticonvulsant and neuroprotectant of the brain”; among its many defensive activities, adenosine controls seizures and influences the progression of epilepsy (Tescarollo et al., 2020).   Consequently, it is a neurotransmitter that should not be perturbed.

Epileptogenic effects of caffeine

The role that caffeine plays in the induction of seizures and interference with the efficacy of AEDs is controversial.  This is because there is an absence of quality studies in man such as a randomized control trials to provide definitive information. 

Caffeine effects in animal studies

Caffeine and its epileptogenic actions has been studied in some detail in experiments using animal models of epilepsy.  These studies contribute to our understanding of the mechanism of action of caffeine in the brain and its proconvulsant activities and are reviewed below:

Firstly, caffeine at modest to high doses (150 mg/kg and above) lowers the seizure threshold in rodent models of epilepsy (chemically induced) (Chu, 1981; Cutrufo et al., 1992;  Matovu and Alele, 2018; Esmalili and  Heydari, 2019) and in genetically epilepsy prone rats (De Sarro et al., 1997).  One study reported that whereas low doses of caffeine were proconvulsant, a high dose was not (Esmalili and   Heydari, 2019).

Secondly, caffeine administered to seizure models already protected with AEDs increases the dose of AED needed to prevent a seizure.  This effect varies with the specific AED.  In particular acute and chronic administration of caffeine to mice receiving maximal electroshocks reduced the efficacy of a previously protective dose of phenobarbital and valproate (Depakote) (Gasior et al., 1996).  In a chemically-induced seizure in rats, high doses of caffeine diminished  the efficacy of carbamazepine (Tegretol) (Kulkarni et al., 1989).  Overall, the AED most adversely affected by caffeine pretreatment was topiramate  (Topamax) (Van Koert et al., 2018).   Other AEDs such asoxcarbazepine (Trileptal), lamotrigine (Lamictal ) and tiagabine (Gabitril)  were unaffected by pretreatment with caffeine in electroshock seizure model (Chrosecinska-Krawczyk et al., 2009). In other words, a number of AEDs do not work well in the presence of caffeine.

Clinical reports on caffeine

There are no randomized control trials in adults exploring the role of caffeine in seizure susceptibility.  Evidence to date is derived from cases studies and survey studies.  The limited evidence is this:

Firstly, it has been known for nearly 40 years that caffeine improves the efficacy of electroconvulsive therapy used to treat depression (Coffey et al., 1987), confirming its pro-excitability nature.

Secondly, a review of numerous case studies show that consumption of generally high (but not always) quantities of caffeine-containing beverages induce seizures of many types in individuals of all ages (Chrosciñska-Krawczyk, 2011; Van Koert et al., 2018).  Seizures also occur following heavy consumption of energy drinks (Iyadurai  and Chung, 2007).  In one particular case study, a PWE with excellent seizure control experienced an increased frequency when drinking large quantities of Snapple tea. Substitution with decaffeinated tea returned seizure control to normal (Kaufman and Sachdeo, 2003)

Thirdly, as reviewed by Van Koert et al.(2018), one very early report (published in French in 1960) of caffeine administration to hospitalized epileptic patients on  AEDs (mephenytoin or combination of mephenytoin and phenytoin and/or barbiturates) found that a caffeine dose (1/2  that of the AED) increases the number of seizures and EEG activity in those with generalized seizures but not focal seizures.

Fourthly, in normal volunteers, caffeine (300 mg in 3 divided doses) altered the way the body handled the AED, carbamazepine (200 mg) but not sodium valproate (400 mg) (Vaz et al., 1998).    

Fifthly, in a prospective study (Nurses Health Study II) of over 100,000 “women at-risk for incident seizure or epilepsy”, and followed by questionnaire and medical records for 15 years, found no statistical increase in risk of seizures with long term consumption of caffeine (Dworetzky et al., 2010). 

Clinical reports on theophylline, relative of caffeine

Theophylline found in tea, coffee and chocolate (Monteiro et al., 2016) is best known as a bronchodilator used to treat asthma.  This therapy has a long history of inducing “largely focal onset generalized seizures” more common in children under 5. Theophylline-associated seizures are independent of epilepsy status and mostly but not always result from higher than therapeutic doses (Nakada et al., 1983; Bahls et al., 1991; Boison, 2011).   Theophylline-associated seizures are considered a medical emergency. As a result, theophylline is no longer used to treat asthma in PWE.

Application

Animal studies indicate that caffeine is a proconvulsant in seizure models and reduces the efficacy of a number of AEDs.  The problem is translating these results to humans in the absence of rigorous clinical trials that might confirm or refute this information.  However, if scientists believe animal seizure models are valid and data from them can be used to uncover mechanisms of seizures as well as to discover new AEDs, then the caffeine data from animals deserves similar respect.  It is a shame that considering the wide spread use of caffeine, there is no definitive answer available to guide PWE.  Thus it remains prudent for PWE to avoid caffeine-containing drinks and drugs.

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Myths and Misconceptions

Myths/Misconceptions, , ,

Assessment 2 – Objective seizure detection with biosensors

My first assessment for epilepsy evaluation concluded that persons with epilepsy (PWE) unfortunately have little to no ability to reproducibly predict the onset of their own seizures.  Therefore, subjective impressions are of marginal value.  Given that, there is a vital need for devices or instruments with ability to objectively predict a seizure. 

Many devices called biosensors are already available  (see reviews Nagaraj et al., 2015; Ulate-Campos et al., 2016).  The capability of existing biosensors to predict seizures varies with the specific device.  Unfortunately detection and prevention are generally not part of the same device.  Despite the fact that current biosensors (with possibly one exception) are only able to detect seizures, nevertheless, they represent a significant first step to development of something more sophisticated with therapeutic value.  Furthermore, present day biosensors supply information on seizure frequency, important information that PWE are unable to provide due to an inability to recall the seizure (Hoppe et al., 2015).  As a note of caution, biosensors to date are useful only in certain types of seizures and so to be of benefit, appropriate biosensor selection requires accurate seizure type identification (Ulate-Campos et al., 2016).  

How biosensors work

There are numerous biosensors in use that detect seizures but generally they do not as yet predict seizures within a reasonable time frame for adequate intervention.  Some biosensors record muscle movements e.g. surface electromyography (Conradsen et al., 2012), measure change in muscle acceleration called accelerometry  (Beniczky et al., 2013), or measure movement via mattress sensors (Poppel et al., 2013).  Other biosensors record effects produced by activation of the autonomic nervous system.  This includes measurement of sweating (electrodermal activity, EDA), heart rate (electrocardiogram, EKG), respiration, body temperature and combinations of these with sophisticated computer programs (Ulate-Campos et al., 2016). 

The aforementioned biosensors target seizures in which muscle and autonomic nervous system changes are evident and occur before a seizure.  Other biosensors use near-infrared to detect changes in brain blood flow prior to a seizure (Tewolde et al., 2015).  Ulate-Campos et al., 2016 lists the more than 40 available biosensors and their web sites. 

EEG and intracranial electrodes  – important contributions

However, for all seizures, the gold-standard for seizure detection is the electroencephalogram (EEG).  The EEG records the summation of brain wave activity via topically attached electrodes positioned around the scalp.  Unfortunately, everyday use of the EEG is incompatible with daily life. 

Representative EEG brain wave activity

Another approach, intracranial electrode implantation (iEEG), provides continuous long term measurement of brain activity in the seizure prone region.  Results of small studies and clinical trials with the iEEG (Iasemidis et al., 2003; Cook et al., 2013; Spencer et al., 2016; Karoly et al.,2018; Baud et al., 2018) have confirmed the  presence of

a) unique neurological activity termed epileptiform discharges that occur with a regularity of 24 hours (circadian) or over several days (multi-day), and

b) the relation of aspects of these rhythms (phases) with seizures in PWE with low to moderate seizure frequency rate (Baud et al., 2018).

NeuroVista Advisory System is an example of the iEEG that has undergone clinical evaluation. NeuroVista Advisory System employs an assessment system using sophisticated algorithms.  In clinical trials (Cook et al., 2013; Bergey et al., 2015) it performed with reasonable success.  In several cases where seizure prediction fell below pre-designated criteria, optimization of the computer system i.e. its algorithms, dramatically improved predictability of the seizure.  Thus it appears possible to tailor the algorithm to each patient to achieve the best result (Kuhlmann et al., 2018). 

Although the iEEG successfully analyzes prodrome data (see Assessment 1) to predict a seizure and hence supplies information in a sufficient time frame to avert a seizure, it is not without serious concerns.  An implantation of intracranial electrodes is an invasive technique requiring major surgery and carries the risk of infection and related brain problems.

Biofeedback Biosensors – hope for the future

The most desirable biosensor is one that employs a biofeedback loop with both

1) reliable seizure detection and

2) appropriate and effective therapeutic intervention that prevents the seizure. 

Neuropace Responsive Neurostimulation (RNS) (http://www.neuropace.com)  device is an example of a biosensor with a biofeedback loop.  The device is implanted in the brain and detects epileptiform discharges and delivers neurostimulation to suppress the seizure.  Results of a two year clinical trial with 191 medication- resistant PWE, showed significant decline in seizure frequency (Heck et al., 2014).  The PWE enrolled in this trial had intractable partial-onset epilepsy.  The development of the Neuropace RNS is a significant achievement for select PWE.  However, the biggest limitation is the requirement of major surgery for implantation of this device.

Characteristics of the ideal biosensor

The ideal biosensor would monitor seizure-related external biological phenomena such as EKG, EDA, muscle movement blood flow etc., as discussed above and accurately assess the data to predict a seizure.  Additionally, seizure detection would be linked with effective seizure prevention measures.  This could take the form of a) an alert  to a caretaker to give appropriate therapy, b)  neurostimulation or c) minipump infusion of appropriate mediation (Ulate-Campos et al., 2016).  Additional characteristics of the ideal biosensor include safety and efficacy without false alarms, user friendly instrumentation, ease of care, wireless transmission of data and full compatibility with daily life (Hoppe et al., 2015).

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Questions for readers

Comments on this blog are welcome.  Experience with biosensors would be appreciated.

Myths and Misconceptions

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Assessment 1 – Are seizures predictable? What are the triggers?

Preface 

Epilepsy is a serious neurological disease, usually with an unknown origin.  In the USA population, this disease affects about 1.2% of individuals. It is a disease that produces random seizures of varying duration, magnitude and frequency.  Approximately 30% of persons with epilepsy (PWE) derive no benefit from anti-epileptic drugs. Many others are poorly served by these medications (Thijs et al., 2019).  For this group, the ability to identify the seizure trigger(s), so as to intervene and prevent the seizure, is of the highest priority.  Therefore, it is important to know whether the current science convincingly show seizure predictability with identifiable and reliable initiators.

Science from diverse disciplines

Definitions of seizure symptoms – which ones are important for reliable predictions?

To evaluate epilepsy, it is important to first understand some established terminology. The scientific literature has categorized the “symptoms to anticipate seizures” (Kotwas et al., 2016) as falling into 3 distinct categories as follows: 

     a) auras,

     b) premonitory or prodromes, and

     c) precipitating factors. 

If reliable, each provides a different degree of potential benefit for PWE.

Auras

First, auras are symptoms that occur in some PWE immediately prior to the seizure.  In the presence of an aura, seizure events are already in play and the ability to prevent the seizure is nil.  However, it could allow for PWE to seek safety e.g. lying down to prevent a fall or calling for assistance (Schulz-Bonhage and Haut, 2011). 

Prodrome

Secondly, the prodrome symptoms occur 30 minutes to 6-12 hours prior to a seizure.  Examples of reported symptoms are :”mood disorders; symptoms such as irritability, anxiety, depression, fear, anger, excitability and reduced tolerance” and “non-specific ‘funny feeling’, headache, and cognitive disturbances; bradypsychia, speech disturbances and attentional deficits” (Scaramelli et al., 2009; MacKay et al., 2017).  The prodrome permits intervention with  potential to negate a seizure and has been examined repeatedly in drug-resistant PWE.

Precipitating Factors

Thirdly, precipitating factors are symptoms that occur 24-12 hours prior to a seizure and if correctly identified could enable the PWE to change behavior, location, activity etc.  Symptoms include “stress, stressful events, sleep deprivation, symptoms of depression, anxiety, fatigue (Kotwas et al., 2016).

Of the three categories, the second category, the prodrome, offers the best time frame to prevent a seizure and it is the time frame of interest of many investigators (MacKay et al., 2017). 

Seizure prodrome predictions with subjective analysis lack credibility

There exists numerous studies (see reviews Illingworth et al., 2014; Kotwas et al., 2016; Mackay et al., 2017)  and several clinical trials (Privitera et al., 2019; Jeppesen et al., 2019) that have investigated the extent of subjective seizure prediction in PWE resistant to anti-seizure medications.  Studies employed questionnaires, interviews and electronic diaries to assess the ability of PWE to predict their seizures.  The results suggest that a small subset of PWE have the ability of seizure prediction.  However, these studies lack scientific rigor.  This means that the data were collected retrospectively (as a recall) and the time between “predictive” symptom(s) and seizure was unknown.  The most meticulous assessments use electronic diaries (see review MacKay et al., 2017).  However, even with this approach, multiple choice answers were supplied for each question relating to events prior to a seizure.  PWE reported their seizures without electronic verification (such as with an electroencephalograph (EEG) recording).  Results were further honed by selecting epileptics who had a high degree of confidence in their ability to predict their seizures and of these, only 9 out of 20 achieved this with their electronic responses.  Additionally, many studies were faced with a diversity of epilepsy disorders that confound results.  Despite the high level of interest in this topic and urgent need to know definitively the predictability of a seizure, results of studies to date with a subjective approach of surveys, questionnaires and diaries are unconvincing.

References for this assessment can be found in the PDF download.

Assessment 2 will examine seizure prediction with biosensors and what the future holds for this approach.

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