I recently came across a couple of interesting threads that suggested the possibility of entirely new techniques in the management of epilepsy. One of these came by way of a suggestion from a very helpful Gumshoe denizen, and the other was incorporated in a compelling story about the potential benefits and also potential hazards of brain implants.

To make sense of either of these relatively recent developments, we’ll need to work up a bit of background about epilepsy itself.

Identification of epilepsy as a disease, coupled with at least a degree of understanding of the fundamental cause of epilepsy, goes back at least 2500 years. The word “epilepsy” comes from the Latin word “epilepsias,” meaning 
“a taking hold of or seizing.” The individual affected by an episode of epilepsy appears to be seized by something that causes the symptoms. Hippocrates in his work “On the sacred disease” not only described major and minor epileptic seizures, but also identified the origin of these seizures as the brain, since there were no evident external causes. He also described what we now term premonitory auras, distinguished between different types of seizures, and discussed the influences of age, temperament, and the menstrual cycle.

In English, the word has been around at least since the 16th century. Shakespeare used it in Othello (Act IV, sc. 1): “My Lord is fain into epilepsy. This is his second fit.” And in Lear (Act II, sc. 2): “A plague upon thy epileptic visage.”

My Oxford English Dictionary gives the definition as “A disease of the nervous system, characterized (in its severer forms) by violent paroxysms, in which the patient falls to the ground in a state of unconsciousness, with general spasm of the muscles and foaming at the mouth. The English name is falling sickness, now little used.”

The OED is not a medical dictionary; still, that definition does seem to date from the age of Shakespeare. Beyond the type of seizure described in the OED, epilepsy occurs in many forms. Elaine Wylie, MD, editor of The Treatment of Epilepsy: Principles and Practice (a standard text) gives 142 pages just to the description of the many forms which epilepsy takes.

These range from seizures that are termed “simple partial seizures,” which can be as minor as involuntary flexion and extension of a hand without loss of consciousness, to more complex and consequential seizures. Absence seizures, known as “petit mal” seizures are brief loss of consciousness without loss of postural control. In other words, the patient does not fall to the ground foaming at the mouth.

“Grand mal” seizures, called generalized tonic-clonic seizures, are the seizure type in about 10% of persons with epilepsy. These are the seizures that the OED was describing in its definition. In the tonic phase, the muscles contract throughout the body, including the muscles that result in breathing. The patient emits a loud moan, and the oropharynx fills with secretions (which produce the foaming at the mouth). The patient may become cyanotic from lack of oxygen, meaning that the skin takes on a bluish hue. As the jaw muscles contract, the patient may inflict serious bites on his/her tongue. The tonic phase lasts about a minute and is followed by the clonic phase, with muscle relaxation, unresponsiveness, and flaccidity. Patients often experience bladder and/or bowel incontinence. Impaired consciousness can last several hours.

In the US, about 2.2 million people, or 0.7% of our total population have been diagnosed with epilepsy. The percentage of people who report having had at least one episode of epilepsy is more than double that figure – 1.65%. The incidence of epilepsy is about 150,000 new cases per year. The incidence of new cases is considerably higher in young children and older adults. According to the CDC, there are about 3 million adults and 470,000 children in the US with epilepsy.

Unlike many other diseases, epilepsy does not appear to get worse over time. It is a condition that can affect a person for life, with occurrences at varying frequencies. Some individuals experience an epileptic seizure every few months, perhaps once a year, or even less frequently. Others have seizures much more often.

The greatest dangers from epilepsy are the consequences of the seizure itself. Many patients with epilepsy injure themselves seriously as they fall when the seizure hits them. A major fear is that the seizure will occur when they are driving an automobile. In some cases, the person with epilepsy will experience a premonitory symptom which he/she has learned precedes the onset of the seizure. In some such cases, the patient may have sufficient time to pull over and stop the car before losing consciousness and also losing control over his/her muscles. Obviously, it would be impossible to drive a car safely while having an epileptic seizure.

The laws of many states require that a person be seizure-free for a specified time in order legally to drive a motor vehicle. The time varies from six months to a full year. Verifying whether or not an individual has experienced a seizure in a specific time interval is not easy, but persons with epilepsy are especially wary of the chance of having even the slightest accident, whether or not they are in the process of experiencing a seizure.

A high proportion of persons with epilepsy report that they feel stigmatized due to their condition, even if the actual seizures take place at long intervals. The experience of having an epileptic seizure in a public place brands them permanently as “epileptics.” They may feel humiliated as being reduced to a state of utter helplessness, displaying the symptoms of their seizure in public. The term “epileptic” itself may be humiliating, as though it reduces their personhood to that single characteristic. It is one thing to be a person with epilepsy, who is from time to time affected by epileptic seizures, and another thing to be an “epileptic,” whose affliction is the sum total of his/her identity.

Established management strategies

The way epilepsy affects its victims necessarily complicates the management of this disease. Unlike almost every other disease I can think of, epilepsy manifests its harmful symptoms only occasionally. When a person with epilepsy is not having a seizure, there are no symptoms requiring treatment. In some cases there are brain abnormalities that in some way result in seizures, but surgically correcting these is by no means the preferred course of managing epilepsy.

Disease management usually involves targeting the cause of the disease in some way. If it’s an infection, we try to identify and attack the pathogen. As we know, many factors can contribute to heart disease, and we can address those factors and mitigate their harmful effects. Cancers are difficult to treat, but we usually have a pretty good idea of where they are and we can try to eliminate them.

Epilepsy is quite another matter. When Hippocrates pronounced that the cause of these seizures had to be in the brain because there was no obvious external cause, he was intuitively right, at least mostly. However, there are other causes of events that look very much like seizures. Many people occasionally experience vasovagal syncope, an event where a signal conveyed by the vagus nerve causes an abrupt drop in blood pressure such that the person rapidly and momentarily loses consciousness, very much mimicking some forms of epileptic seizures.

When Hippocrates identified the brain as the origin of seizures, he did not have the benefit of electroencephalograms (EEG), or computerized tomography (CT) scans, or magnetic resonance imaging (MRI), or positron emission tomography (PET). All of these are used in trying to identify the specific brain activities that result in seizures. Brain imaging can sometimes reveal wave patterns that are related to epilepsy even when the patient is not experiencing a seizure. And lesions or abnormalities in brain structure can be detected in some brain scans. The information gained in brain imaging is important in decision about drug treatment for epilepsy.

There are many other potential causes of events that look very much like epileptic seizures. For example, babies born to drug-addicted mothers often experience seizures in the few weeks after birth. As the concentration of drugs in their bodies diminishes, they go through withdrawal symptoms, which can mimic epileptic seizures. Trauma, brain tumors, illicit drug use, alcohol withdrawal, and other factors can trigger non-epileptic seizures. Zeroing in on the cause of seizures is critical to the management of epilepsy.

In most patients with epilepsy, drug treatment either prevents seizures or effectively controls them when they occur. However, it is not feasible to employ drug treatment only when a seizure occurs. Patients must take the drugs at the specified doses and intervals whether or not they experience seizures, in order to prevent the seizures from occurring and minimize their consequence if they occur despite drug treatment. In some cases, if patients have been seizure-free for two years or more, they can discontinue the anti-epileptic drug (AED) – at least, until they experience another seizure.

There are many AEDs, and many of them have been around for a fairly long time. Phenobarbital is by far the oldest epilepsy drug, and its effectiveness has not been much exceeded by newer drugs. Drugs based on valproic acid (Depakote and others), as well as topiramate (Topamax), benzodiazepine agents such as phenytoin (Dilantin), diazepam (Valium), lorazepam (Ativan), clonazepam (Klonopin) are also in wide use. There are a few newer drugs, including gabapentin (Neurontin), pregabalin (Lyrica), and lamotrigene (Lamictal). All of these drugs have side effects such as dizziness, fatigue, nausea, and other such common effects. Most of these side effects would be of little consequence, except that they are linked to drugs that need to be taken continually in order to ward off an event that might occur as seldom as once a year. (By the way, if you Google “new drugs for epilepsy,” one of the most robust sources that comes up is from 2006.)

Currently, PubMed lists 1,633 studies in epilepsy. This contrasts with 357,351 studies in prostate cancer and 692,364 studies in breast cancer, suggesting that there isn’t a high degree of expectation that new management techniques for epilepsy are on the horizon. Most of the studies that have anything at all to do with drug treatment are investigating such matters as the effects of some of the well-established drugs on specific treatment-resistant types of epilepsy.

Anticipating epileptic seizures

The greatest danger from an epileptic seizure has to do with what the patient is doing at the moment the seizure strikes. If he/she is lazing in a recliner, the seizure is not likely to result in any permanent harm. On the other hand, if he/she is passing an eighteen-wheeler on I-95 when the seizure occurs, the outcome could be catastrophic.

Some people with epilepsy learn to recognize premonitory symptoms early enough to remove themselves from a dangerous situation – they can go and sit in that recliner, wait for the seizure, and resume their normal activity after the seizure passes. These premonitory symptoms can present as strange odors or as oddities in their perception.

However, the brain activity that produces the seizures commences some time ahead of the seizure itself, and if that brain activity could be detected in advance of the seizure, the patient could take the necessary precautionary measures – go to bed, pull over to the side of the road, or whatever is possible at the moment.

Here’s the first paragraph from a recent (2017) commentary in EBioMedicine entitled “Seizure Prediction is Possible – Now Let’s Make it Practical.” (Stacey WC. https://org/10.1016/j.ebiom22018.01.006)

“People living with uncontrolled epilepsy face the constant fear of seizures. The mental toll of anticipation and uncertainty surrounding the random occurrence of seizures may actually be more stressful than the embarrassment, injury, or death caused by the seizure itself. In a recent US poll of patients and caregivers by the Epilepsy Foundation, the unpredictability of seizures was the most impactful aspect of epilepsy, and there is great interest in providing warning to patients when seizures are more likely – a “seizure warning” device (Dumanis et al 2017). However, whether such a device is feasible, both scientifically and practically, has been an unanswered question.”

The possibility of seizure prediction is based on the relationship between brain-wave patterns and seizures, which has been studied since digital electroencephalographs (EEGs) became a fundamental part of neurology in the 1990s. The idea was that patients with epilepsy might have a device implanted which would record the EEG patterns and transmit these to a device that read the patterns and determined whether these patterns resembled those in the brain of a person who was experiencing a seizure or was about to experience a seizure.

There appears to be evidence of detectable signs that appear in advance of a seizure. Some changes in behavior have been detected by family members hours or even days before ictus. (“Ictus,” by the way, is a word used to specify the sudden onset of a seizure, or sometimes the onset of a stroke. It refers to a rhythmic beat that imposes itself over the natural flow of events.) Some dogs are alert to the signs of an impending stroke. An article in Brain Sciences cites a review that found that in 31% of patients with dogs, the dogs were able to respond to the seizure, and 10% of the dogs could provide a warning approximately three minutes in advance of the seizure, and another study of 22 patients with “seizure-response dogs”, the dogs exhibited seizure alerting behavior an average of 31 minutes in advance of ictal onset. (DiLorenzo J. Brain Sci 2019, 9, 156;doiL10.3390/brainsci9070156)

It is not being suggested that persons with epilepsy should acquire “seizure-response dogs” and keep these excellent animals always in close proximity so as to be able to take the necessary precautions in advance of a seizure. But if dogs can recognize the signs of an impending seizure, that surely means that there are such external signs, and that such signs could surely be detectable by means of a device that would be always close to the source of these signs.

A small US company called NeuroVista developed a device specifically to detect such signs and communicate them to the patient. It consisted of 16 electrodes implanted in specific areas of the brain, which communicated with an implanted device which had the capacity of translating the impulses into the brain wave patterns as recorded on an EEG, and assessing whether these brain wave patterns were signs of an impending seizure. In order to accomplish this, a data set of brain waves patterns from 200 patients were recorded and analyzed, such that the patterns that predicted a seizure could be recognized in real time. The implanted device had the capacity to communicate with an external device which could then transmit information to the NeuroVista computer system, which would in turn send a warning to the patient if a seizure was impending. The external device was about double the size of a cell phone, which the patient could wear in something like a holster. The patient was supposed to keep this device on his or her person at all times. The seizure warning consisted of a flashing red light and a fairly loud beep.

NeuroVista ran a small clinical trial in Australia to test this device. The trial enrolled 15 subjects. The description of the trial on the NIH website is as follows:

“Epilepsy Device: Seizure Advisory System — Phase 1

“The purpose of this prospective, single-arm, unblinded, multicenter clinical study is to evaluate the safety and effectiveness of the NeuroVista Seizure Advisory System (SAS) in patients with medically refractory epilepsy. A total of 15 subjects will be implanted at up to three study sites.
This research project aims to evaluate the effectiveness of the SAS based on how well it provides subjects with signals (or “advisories”) that they can see and hear to predict their “likelihood” of having a seizure. It does this by monitoring signals in the brain. A secondary purpose of the study is to learn whether the advisories improve subject quality of life or that of their caregiver.

“The SAS is made up of three main components that work together to monitor the subject’s brain signals and then relay their information to the subject: the leads, the implantable telemetry unit (ITU), and the personal advisory device (PAD). The leads will be placed on different areas of the subject’s brain to record electrical signals. The leads are tunneled down the neck to an ITU that is implanted in the chest, similar to a pacemaker. The ITU wirelessly transmits information to the PAD, which is carried like a pager. It records and processes brain signals and may be able to advise subjects when a seizure is likely or unlikely to occur.

“Following implantation with the SAS, subjects will return for five study visits for neurological examinations and quality of life assessments. Throughout the study, subjects must maintain their SAS; which includes daily recharging and data card replacement.”

The study was only a partial success. Of the 15 patients enrolled, 4 did not make it to the Advisory Phase, in which the Seizure Advisory System’s performance was to be evaluated. One patient had the device removed due to discomfort, and in three other patients, the device failed to predict seizures with high likelihood, which was the standard set for success in the trial. One more patient had to have a lead removed due to an infection. However, all of the remaining 10 patients met the overall “high likelihood” standard for seizure prediction. In two of the 10 patients, all of the seizures were within the specified time limits for the “high likelihood” standard. The mean seizure advance warning time was 114 minutes, which is certainly enough time for the patient to avert the most dangerous consequences of a seizure and more than enough time for the patient to take an oral antiepileptic drug to prevent the onset of a seizure. (DiLorenzo J. Op Cit.)

One of the patients in the study, Rita Leggett, was the subject of a piece in The New Yorker. (Kenneally C. “Mind Machines,” The New Yorker 4/26-5/3/21,pp.38-43. Leggett had the surgery to implant the NeuroVista device in Melbourne, Australia in November, 2010. She was patient number 14 in the trial described above.

Leggett had had epilepsy since she was born. The New Yorker article described some of her epileptic seizures as follows:

“Her seizures had taken many forms. At school, she would zone out, coming to only when a teacher threw something at her or her classmates jeered. Once, as an adult, she was drying dishes when, with a small shout and no warning, she sent a dinner plate flying into the air and then, oddly, managed to catch it again. Not all the seizures were so mild. There was a time when she fell down some stairs and awoke days later in the hospital, her jaw so badly broken that surgeons had had to take a piece of her rib to reconstruct it.”

In her case, the device worked quite well. On the first occasion when it warned her of an impending seizure, she was at a hairdresser’s, and she had about 15 minutes to get out of the salon and go home to get safely in bed.

Leggett felt that the device had transformed her into an entirely new person. Prior to having the device implanted, she felt that she never had a self that she could entirely trust. With the device implanted, she felt that she and the device had “become one.”

However, this valuable symbiosis did not last. Three years after the implantation of the Seizure Advisory System, Leggett’s neurologist had to give her a piece of bad news. NeuroVista had run out of funding for the SAS and could no longer support it. Without the communication between Leggett’s implanted device and the processors at NeuroVista, the device would no longer be able to give Leggett seizure warnings. The implanted device would have to be removed. When she was on her way back from the Royal Melbourne Hospital, where the device was removed, she said that she felt as if she had left a part of herself behind.

However, Leggett has experienced a significant change in her response to seizures since the removal of her device. Prior to her experience with the device, her mind was muddled for a considerable time after her seizure, and she had been unable to notice and remember the signs that she experienced before the seizure, which could have acted as a warning signal if she recognized them. Her experience with the device taught her how to recognize what she calls a funny, flip-floppy feeling that frequently preceded a seizure. Now, when she has that feeling, she takes an anti-seizure pill. She is now essentially seizure-free.

It’s not clear what NeuroVista is up to these days. From what I can tell, they are down to four employees and doing work mostly in the area of erectile dysfunction – not a hint of anything about epilepsy.

However, entirely aside from the fate of NeuroVista and their SAS, the concept of detecting signs of an impending seizure by means of some kind of implantable device appears to be alive and well, although as far as I can tell, there are no devices yet in the trial stage. But the need is real, and the capacity to detect neural signals is real, so we can hope to see real progress on this front relatively soon.

Epilepsy is not the only condition for which devices implanted in the brain are being investigated. Deep brain stimulation was approved for Parkinsonism more than 15 years ago, and currently trials are under way to evaluate devices implanted in patients with dementia and several psychiatric conditions including anorexia, schizophrenia, depression, obsessive-compulsive disorder, and Tourette’s syndrome.

I acknowledge that there is a deeply-felt desire on the part of the health-care sector to explore any and all possible ways of addressing illness, whether physical or mental, and this desire is worthy. At the same time, there is a desire to see what the most advanced technology can accomplish in any area, including brain function. The risks of implanting devices in the brain must be considered carefully, especially if there are other possible pathways to achieve the same goals, such as the one discussed below.

Managing seizure activity with music

Doc Gumshoe learned about this approach to seizure control from a clue supplied by a long-time Gumshoe citizen. It’s been known for about 30 years that seizure activity decreased significantly when patients with epilepsy were exposed to one piece of music in particular – Mozart’s Sonata in D major for Two Pianos, K. 448.

What makes it current is the publication of a detailed paper which attempts to explain how and why this particular piece of music reduces epileptic seizure activity. The paper, “Musical components important for the Mozart K 448 effect in epilepsy,” was published this year in Nature Scientific Reports. (2021;11:16490 https://doi.org10.1038/s41598-021-9522-7)

The lead author, Robert J. Quon, is a PhD candidate at Geisel School of Medicine, Dartmouth-Hitchcock Medical Center. One of his principal collaborators was Michael Casey, PhD, a professor of music and computer science at Dartmouth.

What Quon and his team specifically studied was how music affected specific brain actions, termed interictal epileptiform discharges (IEDs), which are experienced in conjunction with seizures by persons with epilepsy. IEDs arise from the brief, synchronous firing of groups of neurons that are typically involved with epileptic networks. They are known epileptic biomarkers and are associated with seizure frequency and impaired cognition.

The presence of IEDs does not necessarily predict an impending seizure. Instead, IEDs are a continuing characteristic of the neuronal activity of a person with epilepsy, and the intensity and frequency of IEDs is likely related to the frequency and severity of seizures.

A meta-analysis of several studies of the effect of that specific Mozart composition on IEDs showed that approximately 84% of subjects had significant reductions of IEDs during K 448. As far as is known, the only other musical composition that results in this effect at all is Mozart’s Piano Sonata in C Major K 545. Other compositions tested included Beethoven’s “Für Elise” and a string version of K 448; these did not result in any change in IEDs.
Prior to the K 448 study, Quon and his team showed that exposing subjects with refractory epilepsy and high baseline IED rate to a 40 Hertz tone could also reduce IEDs. For reference, a 40 Hz tone is about 3 E’s below middle C. But, they point out, this low note is not especially pleasant to listen to for an extended time.

The 16 subjects in the study were undergoing clinical monitoring for refractory epilepsy. Subjects had electrodes implanted in the left and right brain hemispheres to detect IEDs. This method of detecting brain activity is referred to as stereo EEG.

All subjects demonstrated significant reductions in IED rates during 90 seconds of exposure to K. 448. The significant reductions were seen only with K. 448 for the full 90 seconds. Shorter exposures resulted in non-significant reductions, nor did modified versions of K. 448 result in significant reductions. The median reduction in IED rates observed in the study was 66.5%. In another study where the exposure to K. 448 continued over a period of one month, the reduction in IED rates was 79.4%, while in other studies using scalp EEG, which is less sensitive than stereo EEG, the median IED reduction was 32%. There is also variation in IED rates depending on the patient treated. Those with refractory epilepsy experienced a smaller reduction in IED.

The study reported that there was no carry-over of the reduction of IED rates after a 90 second exposure, while other studies in which exposure to K. 448 was considerably longer reported significant effects on seizure frequency in the post-treatment follow-up.

The Mozart work is organized by contrasting melodic themes, each with its own harmony. This was compared with the opening of Richard Wagner’s Prelude to the first act of Lohengrin, which has been called “the first piece of hypnosis by music.” It consists of static chords, which are held for long periods before small shifts in instrumentation and harmony take place. Other musical selections were also employed in the study, including Chopin’s Bolero in C, Op. 19, and Listz’s Piano Sonata in B minor, as well as popular music selections, which were in some cases chosen by the study subjects themselves. Only Mozart’s K. 448 had any effect on IED and seizure mitigation.

Quon said that the study “sought to untangle how auditory stimuli may exert its therapeutic effects, with the dream of creating novel, adjunctive therapies necessary for epilepsy.”

One of the objectives of the study was to learn what it is about the structure of Mozart’s K. 448 that has this effect on a neural activity that leads to seizures. Quon’s study is not without a few gaps, the chief one being a failure to identify those crucial characteristics of K.448. Lesser issues: we only learn in the depths of the paper that it was only the first 90 seconds of the work that were used in the trial. Mozart’s K. 448 is a three movement work. The second movement, Andante, is slow, pensive, and non-rhythmic, while the third movement, Allegro, goes like a bat out of hell (at least in the Barenboim/Argerich recording). And, by the way, which recording was used in the trial?

However, identifying the specific elements of K. 448 that led to a reduction in IEDs and thus to a reduction in the risk of seizures will certainly be the objective of further studies. The ultimate goal, of course, is a non-invasive, non-drug means of managing seizures. Without the least doubt, arriving at this goal would be a major victory in the campaign to end epilepsy.

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Not a word about you-know-what in this dispatch from the desk of your Doc Gumshoe. But there continue to be developments. At the risk of triggering another deluge of comments in all flavors, I will return to that subject (among others!) in the next opus. Best to all, and thanks again for all the comments! Michael Jorrin (aka Doc Gumshoe)

[ed. note: Michael Jorrin, who I call Doc Gumshoe, is a longtime medical writer (not a doctor) who writes for us about medicine and health a couple times a month. He has agreed to our trading and disclosure restrictions, but does not generally write directly about investments. His ideas, thoughts and words are his own, and you can see all his past pieces here.]