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Reference

Thiele, et al,. “Cannabidiol in patients with seizures from Lennox Gastaut Syndrome (GWPCARE4): a randomized, double-blind placebo-controlled phase 3 trial,” Lancet, 2018, Jan., 390 (10125):1085-1096.

Epilepsy

Seizure alert dogs: can they really sense seizures of their owners?

Virginia Thornley, M.D., Neurologist, Epileptologist

March 28, 2018

Introduction

Seizures are a result of recurrent electrical impulses in the brain causing repetitive symptoms pertaining to that area. At times, patients will not know when they occur.

Scientific studies

Seizure alert dogs are used to detect seizures that are undetectable to humans which may be either through olfactory senses or a change in the behavior. In one study, patients utilizing the seizure alert dog were studied. Seizure frequency was monitored for 48 weeks including a baseline of 12 weeks after entry into the study. With this mode, there has been a seizure reduction of about 43% compared to baseline. 9/10 patients had a 34% reduction in seizure frequency (1).

One study suggested that dogs have the innate sense of sensing their owners’ seizures. In 63 patients, 29 had pet dogs, 9 stated their dogs could sense their seizures (3).

In some studies of skeptical value, there is no proven benefit, although the presence of pseudoseizure may be a factor, meaning neurological symptoms that appear as seizures but are psychogenic in etiology may throw the seizure alert dogs off. Although some studies may indicate lack of benefit, mode of training may play an influence in the detection. The seizure alert dog likely takes cues from the heart rate or olfactory cues to detect seizures (2).

Downsides to seizure alert dog services

Recipients of service dog must meet certain criteria. This service is usually not covered by medical insurance and patients may avail of this service through assistance programs for a minimal fee.

The service dogs themselves may suffer from stress related to the work required for service. In addition, most dogs train between 6 months and 2 years after which service may be of value for about 7 years. The patient must also forge a bond with their service animal. Becuase it is often not covered by insurance and it may be cost prohibitive, some patients have started training their own dogs for seizure detection. The different levels of training may not be standardized or adequate.

References

Strong, et al, “Effect of trained seizure alert dogs on the frequency of tonic-clonic seizures,” Seizure, 2002, Sep., 11(6):402-405.
Brown, et al, “Can seizure-alert dogs predict seizures?” Epilepsy Res., 2011, Dec., 97(3):236-242.
Dalziel, et al, “Seizure-alert dogs: a review and preliminary study,” Seizure, 2003, Mar., 12 (2):115-120.
Strong, et al, “Seizure alert dog-fact or fiction?”Seizures, 1999, Feb., 8 (1):62-65.

Epilepsy

Epilepsy surgery in temporal lobe epilepsy due to mesial temporal sclerosis: the timeline in investigative work-up from the neurologist’s office to the O.R.

Virginia Thornley, M.D. Neurologist, Epileptologist

March 27, 2018

Introduction

Temporal lobe epilepsy is one of the most common types of seizures. The most common cause and one of the most successfully treated causes of temporal lobe epilepsy treated through surgery is mesial temporal sclerosis. This article focuses on mesial temporal sclerosis and does not include discussions of other types of temporal lobe epilepsy due to other causes such as tumors, cystic lesions or head injury or non-lesional temporal lobe epilepsy. In order to identify a patient, the symptoms are generally stereotypical which suggest localizing towards one focus. An early age of identification may portend a better outcome since frequent temporal lobe seizures may cause the development of circuitry to the opposite side causing another focus to develop on the opposite temporal lobe. In addition, it is important to control temporal lobe epilepsy because of the location of the seizures are in the hippocampus which is important in memory. Many patients complain of poor memory which will continue to progress should seizures remain poorly controlled. Epilepsy surgery is the definitive treatment for temporal lobe epilepsy in mesial temporal sclerosis.

Identification

To identify an appropriate candidate for surgery, the patient should have stereotypical seizures which localize towards one focus. While the focus may cause contralateral clinical symptoms, automatisms of the limb are generally ipsilateral to the focus. Once a patient has been identified, further diagnostics tests are needed in order to confirm this focus including a routine electroencephalogram and an ambulatory 48-72 hour EEG which can be performed out-patient. The only downfall with an ambulatory EEG is that it is subject to the artifact, since the electrodes may be displaced causing poor adherence of the electrode to the scalp causing resistance manifested as artifact and a poor recording. However, it is still a good screening test to determine whether there may be a single focus versus multiple regions affected. Temporal lobe epilepsy may be seen with high voltage epileptiform spike and wave. It may be accompanied by focal delta slowing within the temporal lobe, suggesting temporal lobe dysfunction due to recurring seizures. If a patient is deemed an appropriate candidate, a referral may be made to an epilepsy center where more in-depth investigations are performed.

Admission to an epilepsy center

Expect to stay at least 1 week or more in order to allow the capture of typical seizures and to obtain an adequate sampling of ictal periods and pinter-ictal periods during wakefulness and sleep. A team of specialists is involved with the work-up including a clinical epileptologist who manages the medications and clinical aspect, a clinical neurophysiologist who interprets the video EEG monitoring and correlates it with the clinical symptoms, a neuropsychologist who performs the WADA testing and a slew of clinical EEG technicians who ensure that the electrodes are properly attached throughout the hospital stay. In-depth conferences are held to review the studies of the patients and evaluate which patients are suitable epilepsy candidates. Sometimes, multiple admissions are necessary before seizures can be captured.

Hospitalization

During admission, seizures are captured and correlated with the electroencephalographic recordings to determine the focus. More than one focus correlates with a poor outcome, a single focus is necessary. The clinician may provoke seizures by tapering medications safely in the hospital setting. Other techniques include sleep deprivation and encouraging any triggers. The full spectrum of clinical seizures must be captured in order to ensure adequate localization. Bitemporal foci portend a poor outcome.

Neuroimaging

A high-quality MRI of the brain using epilepsy protocol with thin cuts through the temporal lobes of 1.5mm to 2mm is essential. Coronal views are the best way to visualize the hippocampi to evaluate for hippocampal sclerosis which characterizes temporal lobe epilepsy. Usually, the hippocampus affected is much smaller than the contralateral one with hyperintensity on T2. As a result of excessive seizures, burning off of the cells in the hippocampus occurs so that is it is now atrophic. Although an MRI of the brain may have already been obtained pre-work-up, a higher resolution and exceptional quality brain MRI is likely to be repeated. This will serve as the visual point on which the neurosurgeon operates. Seeing a sclerotic hippocampus gives a high correlation with mesial temporal sclerosis.

Ictal SPECT

Spectroscopy is obtained in-house, where hexamethylpropylenamine oxime (HMPAO) injection is done 30 minutes before an ictus. When the patient has a seizure, the HMPAO perfuses to the area of interest showing where the seizure localizes. Images are obtained. This test has an added value of further localizing the focus. The drawbacks, however, include not being able to predict when a seizure is about to occur and missing the ictus. It is not unusual for this test to be repeated for it to be meaningful. In addition, it can only be done during office hours so that nocturnal seizure will be missed due to lack of adequate staff.

Magnetoencephalography

This is a costly examination which may not be available in some epilepsy centers. It uses a 3-dimensional modality for localizing the focus. The MEG dipoles are superimposed on the MRI images.

WADA testing

A neuropsychologist examines the patient’s memory and language by temporarily putting the opposite side of the brain to sleep through injection of amobarbital into the internal carotid artery. Short-term memory and language are examined. The neuropsychologist must determine that there is adequate memory on the contralateral temporal lobe for temporal lobe surgery to be successful. If both temporal lobes are impaired in terms of memory, the patient will suffer from poor memory following the surgery. Other tests are done by the neuropsychologist to check for cognition, any personality disorders and assess for evidence of mood disorders.

Electrocorticography

This is one of the final steps in the investigation where the cranium over the temporal lobe of interest is removed and electrodes are placed directly on top of the cerebrum. Depth electrodes are placed in order to capture epileptiform discharges buried deep inside the hippocampus which cannot be adequately detected by electrodes laying on top of the temporal lobe. The seizures are recorded and a more accurate mapping of the seizure focus is obtained.

Discussions

Once all the appropriate investigations are obtained, if all the data points towards a single focus then the patient is deemed an appropriate candidate. Epilepsy conferences are usually held and reviewed by all the specialists involved in the care. Some patients may proceed directly into surgery after mapping. Others may need to go home and return back for another admission to undergo epilepsy surgery. A patient who is still questionable may need to return for more in-depth recording, this may occur in non-lesional epilepsy where the information is not strong enough to justify surgery. The goal of epilepsy surgery is to resect the dysfunctional epileptogenic zone while preserving the functioning surrounding cortex.

After care

Once the surgery is performed, the patient will need to be on anti-epileptic agents for at least 2 years of seizure freedom. In appropriately investigated patients, a favorable outcome of seizure freedom may reach as high as 60%.

Epilepsy

The deleterious effect of caffeine on epilepsy and anti-epileptic agents

Virginia Thornley, M.D., Neurologist, Epileptologist

March 25, 2019

Introduction

Caffeine (1,3,7-methylxantine) is one of the most commonly ingested stimulants in the world. It is not uncommon for someone to ingest a daily consumption of 200mg of caffeine a day. It is ubiquitously found in soda, coffee, tea, and chocolate. It is the bane of every neurologist who treats migraine and patients with insomnia. It acts as a stimulant and many people use it to counter fatigue induced by lack of sleep. Students consume it to stay up at night for late night studying in order to ace their tests the next day. Millions of people ingest caffeine on a regular basis to get through the full work day.

Caffeine worsen seizures

It has been found in animal models to lower the seizure threshold. At low doses, it reduces the efficacy of anti-epileptic agents. At more than 400mg of caffeine per day, in rodent models it is found to induce seizures. In experimental data, use of caffeine is found to lower the seizure threshold. In mouse models, at lower doses below the seizure-inducing effects, it is found to counter the protective beneficial effects of anti-epileptic agents such as carbamazepine, phenytoin, valproate, and phenobarbital as well as newer agents such as topiramate. There seems to be no effect of caffeine on newer agents such as tiagabine, oxcarbazepine or lamotrigine. There is clinical data confirming that ingesting high doses of caffeine correlates with greater number of seizures.

Dark cocoa and seizures

Dark chocolate is also found to be a proconvulsant, but little is known about the mechanism of action. Dark chocolate is rich in caffeine. In one mouse study, the effect of high intake of dark chocolate on the susceptibility of hippocampal cells to seizures was examined. Dark cocoa appeared not to affect mood behavior but improved motor coordination. However, electrophysiologic studies showed enhancement of bursts of epileptogenic potential within the dentate gyrus of the hippocampus. There was a reduction in GABA-alpha receptors suggesting that consumption of dark chocolate may alter the synaptic aspect of epileptogenesis in the temporal lobe.

These findings suggest that high consumption of caffeine especially dark cocoa can increase seizure frequency in animal models and in clinical studies. It seems to act as a proconvulsant and reduces receptors that are necessary for inhibiting seizures.

Reference

Chroscinska-Krawzyk, et al, “Caffeine and anticonvulsant potency of anti-epileptic drugs: experimental and clinical data,” Pharmacol. Rep., 2011, 63(1):12-18.
Cicvaric, et al, “Sustained consumption of cocoa-based dark chocolate enhances seizure-like events in the mouse hippocampus,” Food Funct., 2018, Mar., 1, 9(3):1532-1544.

Amyotrophic lateral sclerosis, Epilepsy, Glaucoma, multiple sclerosis, pain, Parkinson's disaese, Peripheral neuropathy, Tumor

Medical marijuana: dispelling myths and fallacies behind cannabidiol and tetrahydrocannabinol

Virginia Thornley, M.D. Neurologist, Epileptologist

Introduction

The endocannabinoid system is found naturally in the brain. It is responsible for the sense of well-being one gets after running a 5-mile course. It does not work through endorphins or adrenaline, as some people may think. It works at the level of the endocannabinoid system. There is a community of CBD producers and consumers and it is in this mysterious world that it is well-known to be used in many medical conditions, still shunned by the majority of the medical community, Congress and even patients in general. The 2 most commonly known are cannabidiol and tetrahydrocannabinol. Cannabidiol has medical properties and has a weak affinity to the CB1 receptor which is predominantly found throughout the central nervous system, which is likely why it is found to work in numerous neurological conditions. Tetrahydrocannabinol (THC) is a well-known cannabinoid most notoriously known for the euphoria of kingpins seen on movies propagated by pop culture. Unfortunately, these connotations overshadow the well-known medicinal benefits. Cannabinoids have been used for centuries even in the B.C. period. It was part of the American pharmacopeia in the 1980’s until it was banned in the 1930’s. Slowly, these products are gaining popularity as a treatment for many medical conditions, primarily neurological because the CB1 receptor is so abundant in the nervous system, due to patients becoming more and more frustrated with the adverse effects and ineffectiveness of conventional treatments. In Europe, a combination of THC and CBD have been used in multiple sclerosis patients since 2010. Animal studies and cell line culture studies demonstrate many potential mechanisms in which CB1 receptors, CBD and THC may be beneficial at the cellular level in many diseases, mechanisms are still being elucidated. It is most commonly used for chronic pain and epilepsy. As with any medication, it may or not be effective for everybody.

How it works–the nitty gritty

Cannabidiol has none of the psychoactive properties as THC. One needs 100 times the amount of CBD to have the same intoxication as THC. Therefore, it works well for those who are reluctant to go this route but who have found conventional medications which do not provide effectiveness, they are simply not cutting it. Because very little is know about its titration, medical marijuana can seem like entering into the world of an apothecary, or such as that found in the medieval days when potions are concocted. Physicians who use it in their treat it similar to a medication and the guidelines are similar start low and go slowly. Tetrahydrocannabinol is more potent and at higher doses works more effectively for pain control and seizures. THC is used at relatively low concentrations in order to effect its medical properties, at higher concentrations one may run into side effects which offsets its medical value. There are different ratios of CBD:THC, different ratios correspond to different symptoms treated. CBD is required in conjunction with THC in order to offset the potential side effects of THC. Tolerance does not build in the system such as that seen with opioids, although if one is medical marijuana naive, the lowest dose possible is ideal. There are no side effects of respiratory depression such as that seen with other medications for pain such as opioids.Consult with your treating physician.

Current legal state of affairs

Currently, there are many states that recognize the medical value of medical marijuana with medical marijuana laws allowing the opening of licensed dispensaries. However, the same cannot be said for the federal law. In some states, the carrying of THC on your person can result in fines and imprisonment. Despite marijuana laws enacted, qualified physicians are at risk for being questioned by authorities, its recommendation and use is not for the faint of heart on the part of physicians and patients. Cannabidiol comes from hemp oil and is not considered illegal. However, anyone who even has 1% hemp oil in their product can still label that product as cannabidiol, which may be the reason why some patients are not getting the full medical effects when bought from the flea market or a vitamin store. Tetrahydrocannabidiol which is more well-known for its recreational use and concomitant psychoactive properties at very high doses is federally illegal in many states. Many states often have registries so patients who require this may obtain an ID and verify they are under the care of a qualified physician. It can take a few months to obtain an ID because many patients are often at the end of their ropes in terms of effectiveness of medications. Many patients wish to come off opioids or do not like the idea of needing higher and higher pain medications for their chronic illnesses. It may serve as a great antidote for the current opioid crisis that is well-documented in the news or overdocumented in the news. Many mothers order products online from other countries to counteract the illegalities of their states in order to help their child who may be using 4 potent anti-epileptic agents and is now like a zombie because of the number of medications. While physicians are leery suggesting anything that is in category 1, its medical value cannot be disputed. There is too much evidence tipping it towards the other side of the scale. As tPA was in its infancy of use and physicians were hesitant using it due to its hemorrhagic adverse effect and is now the standard of care for stroke protocols, medical marijuana will likely find its way back into the pharmacopeia, the amount of medical evidence is far too compelling to ignore.

In conclusion

In short, when used wisely, cannabidiol is a non-intoxicating effective treatment for many medical conditions especially neurologic, as evidenced by thousands of years of history of its use and current animal models, clinical trials and wider clinical experience in Europe. When cannabidiol is combined with low concentrations of THC, the medical effect is even greater with the entourage effect without the stigmatized psychoactive effects that are usually associated with THC.

Epilepsy, Glaucoma, pain, Peripheral neuropathy, Tumor

Medical Marijuana: why the huge disconnect between physicians, laws, policies, and patients?

Virginia Thornley, M.D., Neurologist, Epileptologist

March 11, 2018

Introduction

A patient comes to you asking “Doc, my seizures are getting worse, I really hate the side effects of my medications, I really want to go a different route. Have you heard about medical marijuana?” You start sweating profusely, fidgeting in your seat, thinking of every single reason why not to recommend it and come up with the standard response, “uh, well, I’m not qualified to recommend it and it’s not FDA approved, plus we don’t really know much about it there could be so many side effects.” And then we have the oldie but goodie response, “there’s not enough large randomized control trials to recommend it.” This scene plays 100,000 times over if not a million times over in physician offices across the country. Patients who are disillusioned with adverse effects of medications are looking towards alternative therapy. As surprising as it sounds, patients with chronic pain do not want to get intoxicated by opioids. In fact, some want to be tapered off of them or refuse them all together. Patients with end-stage cancer at the terminal stage of their lives wish to live a comfortable and humane existence without the need for more chemotherapeutic medications or pain medications that consistently make them feel like a zombie. While other patients with epilepsy may be on 4 different anti-epileptic agents and can no longer function or have a good quality of life because of side effects. There are two sides to every coin.

Why you should be educated on cannabidiol and THC use in medical conditions

If patients do not get their answers from their trusted physicians who they trust with their well-being, their health, the temples of their souls, they will go to great lengths in procuring this knowledge. This is via various sites on the internet some of the dubious nature others are from high quality companies that have been in business even before this seeming treatment fad started. Or, the information may be obtained from their brother-in-law’s friend’s hair stylist who is now pain-free after going through a long course of pain medications including ablative treatments, physical therapy, and acupuncture and has a physician who does recommend it. Like it or not, cannabidiol and tetrahydrocannabinol are alternative treatment options and are gaining more and more traction. To ignore it is to be complacent with the changing direction and landscape of medicine. As patients become more and more disillusioned by the limitation of conventional treatments, attention is directed towards alternative regimens. It is not just for the yoga-practicing patient looking for more natural methods, one sees the sweet 83-year-old gentleman who must be someone’s grandfather with the chronic hip pain of 50 years who have failed opioids and is simply looking for pain relief.

Is there any evidence that it works?

The endocannabinoid pathway is found naturally in the system. It is responsible for the runner’s sense of wellbeing one gets after a 5-mile run and the pleasant mood you get after a 1-hour work-out with Zumba. There are 2 receptors in the system CB1 receptor which has the highest number of brain cells and the CB2 receptor which is found predominantly in the immune system. There are 2 common cannabinoids cannabidiol and tetrahydrocannabinol which exert various medical effects. Cannabidiol (CBD) has a weak affinity for the CB1 receptor and one needs 100 times the amount to get the same euphoria that one gets from tetrahydrocannabinol, the bane of every ER physician. Unfortunately, the side effects of euphoria of THC have preceded its popularity as a medical product. Little do we know it was once used for hundreds of years as a medication before the psychoactive properties were exploited for recreational purposes. In urologic culture cell lines, it is found that cannabinoids may reduce proliferation of cancer cells and reduce the pro-inflammatory microenvironment that is necessary for metastatic conditions (1). Human studies are still needed to determine a reduction in tumor loads. THC receptors are found in retinal cells and may be found to reduce intraocular pressure in glaucoma (5, 6). Cannabidiol is found to bind to the 5HT1 receptor which reduces anxiety. THC has been well-established in the mouse model to promote the inhibitory control of excitatory pathways in the hippocampus, where seizures commonly arise (8). There is an increase in CB1 receptors after prolonged seizures suggesting a compensatory response. It has been used in combination and found in several randomized control trials to reduce the frequency of seizures by as much as 36% in medically refractory patients (2). It is well-established that cannabinoids reduce pain refractory to conventional medications (3). It has been found in bench research to be an antioxidant and have anti-inflammatory properties (4, 7). Some studies cite side effects of somnolence, nausea, dysphoria, however, it is not clear what was the quality of cannabinoids or dosages were used. At high doses, while THC can reduce pain it may also result in side effects, which is why it is usually used in combination with CBD which ameliorates the side effects of THC. In addition, cannabidiol by itself has no euphoria and it takes 100 times the amount to achieve intoxication seen with THC use. Synthetic products will have more side effects than products that are organic meaning only of natural materials.

Given the huge amount of evidence in several different medical conditions (3), the results should overwhelmingly be towards a push in using cannabinoids more frequently. However, because of the cynicism of the public, physicians even of patients, who have been exposed more frequently to the harmful psychoactive side effects, the benefits are far overshadowed. More clinical randomized controlled trials are needed. Most literature cites small numbers of patients enrolled in studies or review multiple medical centers where the conditions are not uniform. In addition, some of the patients that would benefit the most are the least in numbers such as those with rare neurological conditions such as Dravet syndrome or Lennox-Gastuat syndrome.

In conclusion

As it still stands, many states still do not recognize the medicinal value of cannabidiol or tetrahydrocannabinol. In some states, medical physicians are not allowed to recommend it and put themselves at risk for FBI questioning in even suggesting its use. It is not uncommon for patients to move states or order from other states or countries to procure this liquid gold that is supposed to work wonders. Only time will tell if this is a passing fad and if there are long-standing side effects, however, as of current standing, medical marijuana is here to stay. As far as the literature goes, there are beneficial results but it is a cautionary tale as more studies in large human trials are still needed. As with any new preclinical data, the preclinical status may get ahead of itself and human trials do not replicate the desired results. But from the small clinical trials in seizures, pain, nausea, anxiety, and loss of appetite, the results are promising while more research is needed for anti-tumor effects in humans.

As with any medication, there will be clear-cut side effects just as with any other medication which is why more studies are needed to determine the least amount with the least amount of side effects. In some studies, amounts upwards of 50mg/kg (2) is used the high amounts likely responsible for causing side effects, which is far higher than that cautioned by medical marijuana dispensaries. It will take patients time to wrap their heads around taking guidance from a fresh-faced 20-year-old millennial at the spa-like dispensary which is currently the norm at most dispensaries, who likely knows much more than even most medical professionals. It seems it will take even longer in Congress to understand the potential benefit of cannabinoids from a medical standpoint especially with the present opioid epidemic. Countries in Europe have far surpassed the United States when it comes to cutting-edge treatments. Perhaps, it will take even longer for the medical community to see the medical potential with their exposure to the sinister side of tetrahydrocannabinol seen in patients in the ER for non-medical reasons, which may be one of the most challenging stumbling blocks.

References:

Ghandhi, et al, “Systemic review of the potential role of cannabinoids as anti-proliferative agents for urological cancer,” Can. Urol. Assoc. J., 2017, May,-April., 11(3-4):E138-E142.
Devinsky, et al, “Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial,” Lancet Neurology, 2016, Mar., 15(3):270-280.
Petzke, et al, “Efficacy, tolerability, and safety of cannabinoids for chronic neuropathic pain: a systemic review of randomized controlled studies,” Schmerz, 2016, Feb., 30(1):62-88.
Rajan. et al, “Gingival stromal cells as an in vitro model: cannabidiol modulates genes linked with amyotrophic lateral sclerosis,” Journal of Cellular Biochemistry, 2017, Apr., 118(4):819-828.
ElSohly, et al, “Cannabinoids in glaucoma II: the effect of different cannabinoids on intraocular pressure on rabbits,”Current Eye Research, 1984, Jun., 3(6):841-50.
Jarvinen, T., “Cannabinoids in the treatment of glaucoma,” Pharmacology and Therapeutics, 2002, Aug., 95(2):203-20.
Carroll, et al, “9-Tetrahydrocannabinol exerts a direct neuroprotective effect in human cell culture model of Parkinson’s disease,” Neuropathology and Applied Neuropharmacology, 2012, Oct., 38(6):3535-547.
Kaplan, et al, “Cannabidiol attenuates seizures and social deficits in a mouse model in Dravet syndrome,” Proceedings of the National Academy of Science, 2017, Oct.

Closed head injury

Closed head injury: electroencephalographic changes in post-concussive syndrome

Virginia Thornley, M.D., Neurologist, Epileptologist

March 10, 2018

Introduction

A concussion occurs commonly as high-speed vehicular accidents become more common in today’s fast-paced world. In addition, it occurs frequently in sports-related activity such as football or boxing. The brain is composed of millions of connections and though a patient may complain of several neurological complaints, it is not often manifest in neuroimaging studies, except perhaps diffusion tensor imaging. More often than not, a good clinician can diagnose symptoms of post-concussion syndrome based on neurological symptoms and a preceding event. During injury, there is shearing of thousands of axons diffusely throughout the brain. The contrecoup effect of the injury occurring over the frontotemporal poles produces damage causing a myriad of neurological symptoms. On EEG, non-specific changes can be found corresponding with the degree of injury. There is slowing of the posterior dominant rhythm and excessive theta rhythms which eventually clears after weeks or months of recovery (1). Some patients, however, are left with recurrent symptoms such as post-concussion headaches, or dizziness or sensations of discomfort. On EEG, some studies show post-concussion symptoms correlating with bursts of theta rhythms.

EEG findings in a few minutes spanning more than 6 months

In animal studies, the EEG shows high voltage sharp waves followed by diffuse background suppression which can last a few minutes. This is followed by diffuse slowing that normalizes after 15 minutes in one study occurring between 10-60 minutes (2). Over a few hours to weeks, there are increased theta and delta rhythms and reduced ratio of theta to alpha frequencies. there was an increase in delta activity in the posterior regions. There are brief periods of reduced delta: alpha ratios. In one study called the “Belfast studies,” amnesia was evaluated in 73 patients at 24 hours and 6-week follow-up with EEG and brainstem auditory evoked potentials (BAEP). It was found that amnesia did not have EEG correlate but correlated with abnormal BAEPs suggesting amnesia was derived from brainstem dysfunction rather than cortical dysfunction. Over weeks to months, there are reduced alpha and increased delta rhythms are noted. In the Belfast studies, there was more persistent left temporal slowing, which seemed to correlate with chronic symptoms when it persisted beyond 6 months. After more than 6 months, there were increased delta activity and fewer alpha rhythms (2).

Other EEG findings in closed head injury and part-seizure like activity

In one retrospective study of 3 groups of veterans at a Veteran Affairs Medical Center, 30 comprised of normal subjects with normal EEGs, 30 had EEG’s with non-paroxysmal theta delta slowing and 38 patients had theta bursts. The patients with episodes of theta bursts seemed to have corresponding partial seizure-like clinical symptoms. Patients with head injury reported episodic symptoms across all 3 groups. These findings conclude that clinicians may want to evaluate patients for seizure-like activity in the context of closed head injury and presence of bursts of theta activity (3).

Reference

Nuwer, et al, “Routine and quantitative EEG in mild traumatic brain injury,” Clinical Neurophysiology, 2005, Sep., 116(9):2001-2025
Haneef, et al, “Electroencephalography and quantitative electroencephalography in mild traumatic brain injury,” Journal of Neurotrauma, 2013, Apr., 30(8):653-656.
Roberts, et al, “Theta bursts, closed head injury, and partial seizure-like symptoms: a retrospective study,” Applied Neuropsychology, 2001, 8(3):140-7.

Epilepsy

Cannabidiol: mechanisms and efficacy in medically refractory epilepsy

Virginia Thornley, M.D., Neurologist, Epileptologist

March 9, 2018

Introduction

One of the most challenging therapeutic goals are to keep patients with epilepsy seizure free. Once a patient is found to be medically refractory, it is not unusual to find patients on 3-4 medications for seizure control. However, oftentimes, the means to the end is often wrought with its own challenges with patients suffering side effects placing their quality of life secondary to the medical control of their condition. More and more patients and their families are turning towards a more naturalistic approach including diet and cannabidiol use which has fewer side effects as a means to control seizures. The literature is fraught with a paucity of scientific data with small clinical trials, animal models, and anecdotal data. Larger clinical randomized control trials are pursued.

Mechanisms of Cannabidiol and THC

In the brain, there is the natural endocannabinoid system. Endocannabinoids are released after exercise referred to as the runner’s high which contributes towards our sense of well-being. In the endocannabinoid pathway, cannabidiol has a low affinity to the CB1 receptor and modulates THC tetrahydrocannabinol by blocking CB1 receptor. It is thought to modulate THC by blocking the CB1 receptor acting as an inverse CB1 agonist (2). This may be the mechanism behind combining CBD with THC, CBD modulates the side effects of THC making it less available to exert its effects. Delta9THC is found to work at the level of the CB1 receptors which are rich in the brain and CB2 receptor which is more predominant in the immune system. THC can bind to other targets exerting inflammatory properties. CBD has less binding capabilities to CB1 receptors and is thought to exert its effect by working through other mechanisms such as voltage-gated potassium and sodium channels and the GRP55 in controlling seizures. Cannabinoids are lipid binding or lipophilic making it less available within the system making it challenging to deliver (3).

Cannabidiol clinical trials

In one study, 216 patients were enrolled and followed 3 months after administration of the first dose cannabidiol. Initially, the dose was 2mg/kg which was titrated up to 50mg/kg. 76% were enrolled in the safety profile study and 64% were enrolled in the efficacy profile study. In the first group for safety, 20% had Dravet syndrome and 19% had Lennox-Gastaut syndrome. Side effects were noted in 79% of the patients in the safety group. These include somnolence, diarrhea, seizures (11%), fatigue and reduced appetite. Five disenrolled due to adverse effects, 30% had serious side effects including 1 death of consisting sudden death syndrome. 12% had serious side effects including status epilepticus which may have been related to cannabidiol use. The median reduction of seizures was 36.5%. The study concluded that cannabidiol may be an effective strategy for reducing seizures in medically refractory seizures. The flaw with the study is that the doses at the higher end may have been too high for the patients to tolerate, a lower titrated dose may have been equally effective in controlling seizures and minimizing side effects. Nevertheless, the results were promising as it proves to be beneficial in controlling some of the seizures.

References

Devinsky, et al, “Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial,” Lancet Neurology, 2016, Mar., 15(3):270-280.
McPartland, et al, “Are cannabidiol and 9 delta tetrahydrocannabivarin negative modulators of the endocannabinoid system? A systematic review,” British Journal of Pharmacology, 2015, Feb., 172(3):737-53.
Gaston, et al, “Pharmacology of cannabinoids in the treatment of epilepsy,” Epilepsy Behavior, 2017, May, 70(Pt B):313-318.

Epilepsy

Ketogenic diet and its variants, modified Atkins diet and medium-chain triglyceride ketogenic diet and control of seizures

Virginia Thornley, M.D, Neurologist, Epileptologist

March 6, 2018

Introduction

In the past decade, different modifications of the ketogenic diet have evolved given the high intolerance to the side effects of the classic ketogenic diet and poor adherence to the strict regimen. Other variants have had similar effects in achieving control of seizures. The ketogenic diet remains a viable treatment option in patients medically refractory to conventional agents and should not be discounted as part of the armamentarium of the epileptologist or neurologist who treats patients with seizures.

Studies and classic ketogenic diet

In one small trial of febrile related seizures, 7 children with medically refractory febrile infection-related epilepsy syndrome (FIRES)were followed, 6 had less frequent and less severe seizures. On average, 4 antiepileptic agents were weaned (1). FIRES is a febrile related convulsion syndrome that starts during childhood where febrile seizures are thought to induce a cytokine reaction that occurs post-infectiously(2). In one remarkable study of 77 patients with refractory status epilepticus, only one patient had a shortened acute phase in response to ketogenic diet, 2 to anesthesia and 1 in response to IVIG, all other treatment modalities including conventional IV medications failed to shorten the acute phase (6).

In several case reports of pediatric patients in status epilepticus, the ketogenic diet was used to stop the continuous seizures. In 10 patients in one case series, all 10 pediatric patients were in continuous status epilepticus. 4 patients had focal partial status epilepticus while 6 had generalized status epilepticus. The patients had a mean duration of seizures of 18 days. The mean time for achievement of ketosis was 7 days of which 9/10 patients stopped having continuous seizures during that timeframe(4).

Modified Atkins diet and seizure control

In one study of 14 patients, the modified Atkins diet seemed to be better tolerated than the ketogenic diet. The diet was well-tolerated by 86%. 7 (50%)remained on the diet after 6 months and 36% had a 50% reduction in seizures 21% were seizure free. Strong ketosis appeared to be key in controlling the seizures (5).

Medium chain triglyceride ketogenic diet

In another variation, the medium-chain triglyceride ketogenic diet, ketones have been challenged as the substrate for control of seizures. It has been shown that medium-chain fatty acids can work through the AMPA receptors where the excitatory neurotransmitter glutamate binds, as the mechanism for controlling seizures and by changing the bioenergetics of the mitochondria (3).

References:

Gofshteyn, et al, “Cannabidiol as a potential treatment for febrile infection-related epilepsy syndrome in acute and chronic phases,” Journal of Child Neurology, 2017, Jan.,32(1):35-40.
Gaspard, et al “New onset refractory epilepticus (NORSE) and febrile infection-related epilepsy syndromes (FIRES): state of the art and perspective,” Epilepsia, 2018, Feb., doi:10:1111/epi. 14022 (Epub ahead of print)
Augustin, et al, “mechanism of action for the medium-chain triglyceride ketogenic diet in neurological and metabolic disorder,” Lancet Neurology, 2018, Jan., 17(1):84-93.
Appavu, et al, “Ketogenic diet treatment for pediatric super-refractory status epilepticus,” Seizure, 2016, Oct., 41:62-65.
Kang, et al, “Use of modified Atkins diet in intractable childhood epilepsy,” Epilepsia, 2007, Jan. 48(1):182-186.
Kramer, et al, “Febrile infection-related epilepsy syndrome(FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children,” Epilepsia, 2011, Nov., 52 (11):1956-1967.

Epilepsy

Ketogenic diet and its variants modifed Atkins diet, low glycemic index treatment: effectiveness, side effect profile in patients with epilepsy and incidental weight loss

Virginia Thornley, M.D., Neurologist, Epileptologist, February 26, 2018

Doctors first took notice of the ketogenic diet working in patients with epilepsy in the 1920’s. But the exact mechanism remains unclear. One study elucidated that the ketone bodies are one of the reasons why the ketogenic diet works in patients with epilepsy. Ketosis occurs during a natural fasting state. In the ketogenic diet using high fat, the by-products of beta-oxidation of fatty acids which are beta-hydroxyacetate and acetoacetate in the blood do not correlate with patients who are doing better. Medium chain triglyceride fatty acids, which are a part of a variation of the ketogenic diet, are shown to suppress the AMPA receptors which subserve the excitatory neurotransmitter glutamate and may change energy use of the cell through mitochondrial processes (1).

Ketogenic diet and adverse effects

Some patients have difficulty adhering to the diet which makes it difficult to use. Common side effects because of the high-fat content are diarrhea, constipation, nausea, transient increase in lipemic values. Variations of the ketogenic diet are sometimes used to offset these side effects and reduce the non-compliance.

Some ketogenic variants

Ketogenic diet variants include modified Atkins diet, low glycemic index treatment, and medium chain diet. The ketogenic diet consists of 4:1 ratio of fat to carbohydrates shifting metabolism to the use of ketone bodies as a source of energy. A lower ratio is sometimes employed called the modified ketogenic diet with a 3:1 or 2:1 ratio of fat to carbohydrates. In the modified ketogenic diet, the palatability is improved and avoids the gastrointestinal symptoms associated with the ketogenic diet such as nausea. With the modified Atkins diet, carbohydrates are restricted to 10-20 grams a day, or a 1-2:1 ratio of protein to fat plus carbohydrates. In the low glycemic index treatment, carbohydrates are limited to 40-60 grams while 50-60% of the diet is fat and 20-30% is from protein. The medium-chain triglyceride diet employs oils as a supplement such as coconut oil. The palatability of these diets improve patient compliance and lessen the side effects of the ketogenic diet. Some patients also used the diets to incidentally lose weight in addition to treating seizures (2).

Effectiveness of the ketogenic diet and ketogenic diet variants

One study summarizing studies on patients using the classic ketogenic diet found that 50% of patients out of 206 had a >50% reduction of seizures using the classic ketogenic diet. Older patients seemed to benefit less. In the modified Atkins diet, seizures were reduced in younger patients with more frequent seizures. Patients tended to drop out because of the side effects, lack of perceived effectiveness and because of the restrictions in the diet. Patients greater than 12 years old were less adherent to the diet (3).

It is possible that the protective effects of the ketogenic diet are related to the medium chain triglyceride fatty acids and not the ketone bodies.