Although more than 20 conventional antiseizure medications are available, treatment-resistant epilepsy (TRE*) reportedly affects about 30% of patients with epilepsy.1 Patients with TRE suffer from severe morbidity and have a significantly increased risk of sudden unexpected death in epilepsy (SUDEP) and other types of epilepsy-related mortality.2,3 (For those with TRE, the risk of SUDEP may exceed 10% per decade.4) Even patients with “treatment-responsive” epilepsy, when using conventional antiseizure medications, often suffer from serious, potentially life-threatening side effects and breakthrough seizures (i.e., seizures that occur despite the use of medications that have otherwise prevented them) under various conditions. The potential dangers associated with these medications are even more relevant when they are used in multidrug regimens and at high doses. Controlling seizures sooner, more completely, and more safely can lead to improved outcomes.2
These factors and others have prompted some patients with epilepsy and their family members to turn to medical cannabis (marijuana; Cannabis spp., Cannabaceae), in some cases as a last hope. Some of these patients have experienced dramatic relief that was not achieved with the antiseizure medications they were prescribed. In addition, cannabis preparations have allowed some of these patients to reduce or even eliminate the use of other, more dangerous interventions.2,5 (According to Ethan Russo, MD, a neurologist and highly respected medical cannabis expert, most of the conventional antiseizure medications are quite sedating and contribute to psychomotor impairment.)
In the United States, the Drug Enforcement Administration (DEA) continues to classify cannabis and its constituents as Schedule I substances under the Controlled Substances Act (CSA) of 1970. The CSA defines Schedule I controlled substances, which also include heroin and lysergic acid diethylamide (LSD), as “those that have a high potential for abuse, no currently accepted medical use in treatment in the United States, and a lack of accepted safety for use under medical supervision.”
This classification means that physicians cannot legally prescribe or administer any preparations of cannabis. Even in states that have authorized the use of cannabis for medical purposes, physicians can only “certify” or “recommend” that a patient has a qualifying medical condition and may use cannabis for that purpose.6 Twenty-nine states and Washington, DC, have authorized the medical use of cannabis,7 and, in most of these places, seizure disorders are included among the qualifying conditions.8 Medical cannabis is often distributed to patients through dispensaries,6 but, in some places, there are few or no dispensaries, and medical cannabis is difficult or impossible to obtain, even for persons with qualifying conditions. Perhaps because of this and because of success stories like that of Charlotte Figi, many families with members who have epilepsy have relocated to Colorado, where they hope to have similar success with medical cannabis.9
In 2013, CNN’s highly publicized WEED documentary told the story of Figi, a young girl with Dravet syndrome, a rare type of epilepsy that is usually caused by loss-of-function mutations in the SCN1A gene. Dravet syndrome presents in the first year of life and often begins with febrile seizures (fever-related seizures). Figi was suffering from more than 300 generalized tonic-clonic seizures† per week despite the use of antiseizure medications. Her parents, residents of Colorado, eventually began giving Figi an extract of a cannabis chemovar (chemical variety) that is low in tetrahydrocannabinol (THC, the main psychoactive and intoxicating compound in cannabis) and high in cannabidiol (CBD, the most-studied biologically active, psychoactive but non-intoxicating compound in cannabis). They slowly increased the dose, and, eventually, Figi began having only two to three nocturnal generalized tonic-clonic seizures per month. In addition, she was able to wean off other, more dangerous antiseizure medications, and she showed behavioral, cognitive, and social improvements. The cannabis chemovar was renamed Charlotte’s Web after her.5,10
Figi’s case and other similar cases have received significant public attention, but many in the scientific community have remained skeptical about the safety and efficacy of cannabis and its constituents for the treatment of epilepsy. Widespread use of, and experimentation with, artisanal (or homemade) cannabis preparations, which are not highly standardized to specific cannabis constituents, have largely preceded rigorous scientific investigations and clinical trials that are required for US Food and Drug Administration (FDA) drug approval.8 However, encouraging results from recent randomized, double-blind, placebo-controlled (RDBPC) clinical trials that investigated the effects of Epidiolex (GW Pharmaceuticals; Salisbury, United Kingdom), a standardized oil-based CBD oral solution, may help validate the safety and efficacy of at least this specific preparation. The most recent of these trials was published in The New England Journal of Medicine in May 2017.12
Study in The New England Journal of Medicine
Dravet syndrome reportedly affects more than 5,400 people under the age of 20 in the United States. Patients with this severe, lifelong type of epilepsy often suffer from frequent seizures of multiple types.13 Although seizures associated with all types of epilepsy can be resistant to treatment, seizures associated with Dravet syndrome are among the most resistant.2 About 15% of patients with Dravet syndrome die within 10 years of diagnosis due to various factors, including SUDEP, status epilepticus,‡ and seizure-related accidents. There is currently no therapy approved by the FDA for the treatment of Dravet syndrome.13
This RDBPC study investigated the ability of CBD (20 mg/kg per day) to reduce seizure frequency and improve other measures in patients with Dravet syndrome who suffered from seizures that were not controlled by their standard treatment regimen. Patients were randomly assigned to take either the CBD oral solution (Epidiolex) or placebo, in conjunction with their standard antiseizure medication(s). (If approved by the FDA, Epidiolex will be the first therapy approved for the treatment of Dravet syndrome.) The CBD solution contained 100 mg of CBD per milliliter of solution. The placebo solution was identical to the CBD solution except that it did not contain CBD.12
The study consisted of a four-week baseline period, a 14-week treatment period, a 10-day taper period, and a four-week safety follow-up period. During the first two weeks of the 14-week treatment period, the dose was escalated up to 20 mg/kg per day or the equivalent volume (0.2 mL/kg per day) of placebo solution. During the latter 12 weeks of the 14-week treatment period, this dose was maintained.12
All interventions for epilepsy, including a ketogenic diet (a special high-fat, low-carbohydrate diet that may help control seizures in some patients with epilepsy) and vagus nerve stimulation,** were stable for four weeks before screening and were to remain unchanged throughout the study. Patients were eligible if they had been diagnosed with Dravet syndrome, were taking at least one conventional antiseizure medication, and had at least four convulsive seizures during the four-week baseline period.12
At 23 centers in the United States and Europe, 177 patients were screened and 120 were randomly assigned to receive either Epidiolex or placebo. Of the 61 patients assigned to the Epidiolex group, 52 (85%) completed the treatment period. Of the 59 patients assigned to the placebo group, 56 (95%) completed the treatment period. Of the 108 patients who completed the treatment period, 105 (97%) entered an open-label extension study.12
The average age of participants was 9.8 years, with a range of 2.3 years to 18.4 years. Most participants (62, or 52%) were male. Patients had previously tried a median of four antiseizure medications, with a range of zero to 26. During the study, patients were taking a median of three medications, with a range of one to five. The most common medications taken during the study were clobazam (78 participants, or 65%), valproate (all forms; 71 participants, or 59%), stiripentol (51 participants, or 42%), levetiracetam (33 participants, or 28%), and topiramate (31 participants, or 26%). Ten participants (8%) were on a ketogenic diet, and 15 (12%) were undergoing vagus nerve stimulation therapy. The two groups were similar in terms of these characteristics.12
In the Epidiolex group, convulsive-seizure frequency decreased from a median of 12.4 seizures per month (with a range of 3.9 to 1,717) at baseline to 5.9 seizures per month (with a range of zero to 2,159) during the treatment period. This represents a median change of –38.9% (with a range of –100% to 337%) from baseline. In the placebo group, the convulsive-seizure frequency decreased from a median of 14.9 seizures per month (with a range of 3.7 to 718) at baseline to 14.1 seizures per month (with a range of 0.9 to 709) during the treatment period. This represents a median change of –13.3% (with a range of –91.5% to 230%) from baseline. The adjusted median difference in convulsive-seizure frequency between the Epidiolex group and the placebo group was –22.8 percentage points (P = .01).12
During the treatment period, convulsive-seizure frequency decreased by 50% or more from baseline in 43% of patients in the Epidiolex group compared to 27% in the placebo group (P = 0.08). In addition, during the treatment period, three patients in the Epidiolex group were completely free of seizures, compared to no patients in the placebo group (P = 0.08).12
In the Epidiolex group, 37 of 60 caregivers (62%) judged their child’s overall condition to be improved, compared to 20 of 58 caregivers (34%) in the placebo group. This was measured using the Caregiver Global Impression of Change (CGIC) scale, a 7-point caregiver-rated scale that uses three categories of improvement, three categories of worsening, and an option of “no change.”12
During the treatment period, 93% of patients in the Epidiolex group and 75% in the placebo group experienced adverse events (AEs). Among patients who experienced AEs, 84% in the Epidiolex group and 95% in the placebo group experienced AEs that were considered mild or moderate. Serious AEs were observed in 10 patients in the Epidiolex group (16%) and three in the placebo group (5%). Among those who experienced AEs, 75% in the Epidiolex group and 36% in the placebo group experienced AEs that were considered to be related to the treatment. In the Epidiolex group, the most common AEs (each observed in more than 10% of participants) were diarrhea, vomiting, fatigue, pyrexia (elevated body temperature), respiratory tract infection, decreased appetite, convulsion, lethargy, and somnolence. In the Epidiolex group, eight patients withdrew from the study because of AEs, compared to one in the placebo group.12
The study authors suggest that some AEs in the Epidiolex group may have been due to interactions with the antiseizure medications that were used. For example, the majority of patients who experienced somnolence, the most common AE during the trial, were taking clobazam.12
In addition, the study authors wrote that “the lack of a significant reduction in nonconvulsive-seizure frequency suggests that the antiseizure effect of cannabidiol may be specific to convulsive seizures in the Dravet syndrome or that the frequency of nonconvulsive seizures (e.g., brief staring spells) cannot be reliably counted by parents in developmentally delayed children. Nonconvulsive seizure frequency was a secondary end point but not part of the primary efficacy assessment in this trial.”12
Orrin Devinsky, MD, an epilepsy specialist at New York University’s Langone Medical Center and lead author of the study, stated that one of the advantages of choosing a disorder like Dravet syndrome is that, unfortunately, patients have very frequent and severe seizures. “So, for a scientific study, the more frequent the seizures are, the better the chance you can see how the intervention is working,” he said in a video about the study. “If [patients] had a seizure once a year, you might have to follow them for three or four years. In this study, seizures were frequent enough within this 14-week window that we were able to collect a lot of data.”15
One potential limitation of the study, according to the authors, was that the side effects of the Epidiolex and palatability differences between the Epidiolex and placebo may have caused some degree of unblinding.12
Antiseizure Effects of Cannabis and Its Constituents
The use of cannabis-derived therapies to treat epilepsy became less common after the introduction of phenobarbital in 1912 and phenytoin in 1937, and the passage of the Marijuana Tax Act in 1937 (see “History ...” section). However, the discovery of the endocannabinoid system (ECS) in the 1990s helped renew interest in using cannabis-derived therapies for various nervous system disorders, including epilepsy.1 The ECS is a biochemical signaling system that helps maintain normal cerebral and physiological functions. The effects of cannabis and its constituents are mediated primarily by the ECS.16
The ECS is composed of several receptor types, primarily the cannabinoid type I (CB1) receptor and the cannabinoid type II (CB2) receptor. Because THC, CBD, and other plant cannabinoids (phytocannabinoids) are not naturally present in the body, these receptors exist for the endogenous cannabinoids (endocannabinoids), mainly anandamide and 2-arachidonoylglycerol (2-AG), which are produced naturally in the body. The cannabinoids are a class of compounds that have a 21-carbon terpenophenolic skeleton.1,16 THC and CBD, which are not known to be found in any other plant genus, are the most-studied cannabinoids present in cannabis.
Russo, a member of the American Botanical Council’s (ABC’s) Advisory Board, proposed that a “clinical endocannabinoid deficiency” could underlie certain conditions, including migraine, fibromyalgia, and irritable bowel syndrome, which exhibit common patterns, and that these conditions could effectively be alleviated with medical cannabis. He said he thinks this concept could also play a role in some cases of epilepsy, although he is not aware of a specific epilepsy syndrome in which it is a factor (oral communication, June 21, 2017). In fact, some studies have identified defects in the ECS in patients with epilepsy. For example, in one study, patients who had been newly diagnosed with temporal lobe epilepsy had significantly lower levels of anandamide in cerebrospinal fluid than did healthy controls.1
Studies have shown that the ECS plays an important role in modulating seizure activity. In one study, THC completely eliminated spontaneous pilocarpine-induced seizures in rats. In addition, application of SR141716 (Rimonabant), a CB1 receptor inverse agonist (i.e., an agent that binds to the same site as an agonist but exerts an effect that is opposite of that agonist), significantly increased seizure duration and frequency. It was also determined that during a short-term pilocarpine-induced seizure, levels of 2-AG in the hippocampal brain region increased significantly. Furthermore, expression of the CB1 receptor was significantly increased in the hippocampi of these rats, which had had epilepsy for almost one year. This indicates that the increase in receptor expression was prolonged and probably permanent. It is possible that the increases of 2-AG and CB1 expression were meant to counteract glutamate excitotoxicity. (Glutamate is the main excitatory neurotransmitter in the central nervous system, and it plays a role in the initiation and spread of seizure activity.) The implication of these effects is an improvement in neuroprotection.17
CBD may act as a neutral antagonist at CB1, which means it does nothing at this receptor in the absence of an agonist like THC or an inverse agonist like Rimonabant. In addition, CBD is a negative allosteric modulator, meaning that it binds to a separate site on the receptor called the allosteric site and interferes with the activity of THC when THC is present at the primary site (called the orthosteric site). Therefore, CBD can limit some of the undesirable effects of THC, including the psychoactive high, anxiety, and rapid heart rate.18,19
CBD exerts antiseizure effects by means other than the CB1 receptor, but these actions are not fully understood.1 According to Russo, CBD has more than 30 different pharmacological actions. “Fortunately, none of those are bad in terms of producing side effects,” he said. “What we seem to think is that CBD does not work though the sodium channels. Drugs that do [work through the sodium channels] often exacerbate Dravet syndrome, for example, and that’s not the case with CBD.”
CBD’s antiseizure effects may be explained partially by the fact that it antagonizes the G-protein-coupled receptor 55 (GPR55), which reduces the excitability of nerve cells that are hyper-excitable in patients with epilepsy. Another possible explanation is that CBD is an agonist at the serotonin receptor subtype 5-HT1A. This receptor also has antiseizure effects. CBD’s anti-inflammatory and antioxidant properties also likely play a role.1 “I think the answer is going to be that it is not one mechanism of action,” Russo said. “It is multiple mechanisms of action…. In a multifactorial disease, it is better to have multifactorial pharmacological benefits.”
Although THC also has demonstrated antiseizure effects, some have labeled it an impractical antiseizure medication.20 Beyond the obvious concerns surrounding the psychoactive high produced by THC, there are also concerns that it may have irreversible effects on brain development, mainly by interfering with new synaptic connections. According to Russo, these claims stem from either animal studies that used extremely high doses, or from survey work in teenagers who were using cannabis in very high doses, chronically, on a recreational basis.
“There’s a world of difference between that kind of chronic, recreational use at a young age and much lower doses of cannabis, or THC, used therapeutically for whatever indication,” Russo said. “These are not comparable at all. Additionally, the danger of THC, whatever it is, and I think it’s minimal when it’s necessary medically, pales in comparison to the damage that is obviously done by these severe seizures. These severe seizure disorders can be considered a degenerative disease because of what they do to impair development, or even arrest it.”
Epidiolex was formulated without meaningful amounts of THC at least partially because the FDA was averse to the idea of giving the compound to children, according to Russo. (He suspects that many people at GW Pharmaceuticals were also hesitant about the idea, even though children under 10 years of age are quite resistant to the psychoactive effects of THC, he wrote.) Despite this reluctance, some anecdotal evidence indicates that including THC with CBD may allow for seizure control with much lower doses of CBD (e.g., 16.5 mg of CBD/kg per day maximum, compared to 25 mg of CBD/kg per day in some Epidiolex clinical trials). The potential benefit of combining CBD and THC remains to be confirmed in clinical trials.20
In addition, for some patients who were using CBD as an adjunct to conventional antiseizure medications, the addition of other cannabis constituents, such as tetrahydrocannabinolic acid (THCA) and/or alpha-linalool, resulted in improved antiseizure response.8 “What I believe is going on there is a synergy of ingredients,” Russo said. “These epilepsies are very complex disorders, and having multiple mechanisms of action seems to be an advantage.”
According to Russo, CBD seems to be more effective for addressing generalized seizures. “In contrast, cannabidivarin (CBDV) seems to work better for seizures of partial onset, or what used to be called focal seizures [i.e., seizures that begin in one side of the brain],” he said. “So, that might indicate that you would do better with a combination of different cannabinoids, and there are some chemovars available out there that combine CBDV and CBD with a little THC, and they may turn out to be the best of all. That remains to be worked out.”
Comparing whole-plant cannabis preparations to cannabis-derived pharmaceutical preparations, for both safety and efficacy, is important, according to Russo, but it presents challenges. For example, it is difficult to get approval from institutional review boards to conduct formal studies using what many would consider artisanal, or homemade, preparations that lack the standardization and consistency to qualify as pharmaceuticals. Furthermore, pharmaceutical companies usually do not fund these types of studies. “To date, for example, there has never been a comparison of Sativex [a cannabis-derived oromucosal spray used to treat multiple sclerosis-related spasticity that is also produced by GW Pharmaceuticals] to other preparations,” Russo said. “It really becomes a problem of comparing apples to oranges, if the orange isn’t something you can vouch for, in terms of its specific, reproducible contents.”
In addition to these issues, some animal studies have raised the concern that THC, at high doses, may have proconvulsant effects. This situation may be similar to that of other antiseizure medications. For example, carbamazepine has been known to produce tonic seizures when it is excessively present in the blood. Also, using valproate and clonazepam together, although sometimes necessary, may precipitate clinical absence status epilepticus (an absence seizure causes a period of blanking out or staring).20
“When I was in [neurological medical] practice prior to 2003, I had a number of patients who used cannabis, either as their sole drug or as an adjunct to their anticonvulsant treatment,” Russo said. “I never once, in my entire career, saw a situation in which I thought THC precipitated or exacerbated seizures…. I’ve never seen that in humans and it probably should not occur at conventional doses at all.”
It is noteworthy that these patients all most likely would have used cannabis that was THC-predominant, since evidence indicates that almost all cannabis chemovars in North America were devoid of meaningful amounts of CBD until relatively recently.20 According to Russo, CBD is not proconvulsant at any dose.
History of Cannabis as a Treatment for Epilepsy
There is evidence that cannabis may have been used to treat epilepsy dating back about 4,000 years in Mesopotamia. The British archaeologist, Assyriologist, and cuneiformist Reginald Campbell Thompson (1876-1941) dedicated much of his career to studying Assyrian medical texts from the Royal Library of Ashurbanipal, an Assyrian king who ruled from 668 to 626 BCE. This library is part of the mound of Kouyunjik in Nineveh on the Tigris River near modern Mosul, Iraq. More than 600 broken clay cuneiform tablets excavated from the site were medical in nature. These tablets, which are now housed in the British Museum in London, compiled the knowledge of the much earlier Akkadian and Sumerian cultures from the second millennium BCE.20
The tablets contain about 30 references to azallû in Akkadian (ancient Assyrian) and A.ZAL.LA in Sumerian. Thompson believed these references clearly pointed to cannabis. (According to an expert peer reviewer of this article, Thompson’s hypothesis has been contested by many experts.) The plant in question was described as being psychoactive, a source of fiber, insecticidal, and deliverable orally, cutaneously, per rectum, or by fumigation. In addition, it was pounded and filtered, as is done with hashish, and its seed, stem, leaf, and flower were all used. It was also described as a treatment for many indications. Numerous passages in the tablets mention the plant as being a part of different complex, multi-plant mixtures that were used to treat a condition referred to as “hand of ghost.” Although Thompson never identified the condition referred to as “hand of ghost,” later translations of Neo-Assyrian tablets from 718 to 612 BCE indicated this may have referred to nocturnal epilepsy.20
A passage from the Arabic work Solace of the spirit in hashish and wine by 15th-century Damascene authority Taqi al-Din al-Badri retells an earlier account that he attributed to the eminent Persian physician Rhazes (865-925) in which cannabis was used to treat epilepsy. Rhazes supposedly described how the son of the registry chamberlain of Baghdad under the Abbasid powers, who suffered a seizure attack every week, was apparently cured with hashish (used regularly) and music. This story is open to question, however, because of the loss of key manuscripts and because of a literary tradition in which embellishment was sometimes the sincerest form of flattery.20
In another account from the Arabic literature, Ali ibn al-Abbas al-Mayusi, who died circa 982-994, prescribed cannabis to treat epilepsy. The text reads: “the juice of the leaves of cannabis instilled in the nostril serves to treat epilepsy.” This administration route may have been an advantage with acute attacks in which oral administration may have been impractical or dangerous. In this case, it is also likely that THCA would have been the active constituent.20 (An expert peer reviewer of this article noted that the Latin version of the text refers to “semen canapis” [hemp seed], rather than hemp leaves.)
In 1557, Italian physician and naturalist Pietro Mattioli mentioned the use of a cannabis seed decoction to treat epilepsy. He wrote: “For whose doctrine I never consider those silly women, who give a decoction of cannabis seed to children, who are epileptic, because of the harm added.” It is possible that hemp chemovars with cannabidiolic acid (CBDA), if unheated, or with CBD, but not THC, had little benefit.20
Irish physician William O’Shaughnessy, who was in service to the British Crown in India, studied the indigenous uses of cannabis by Ayurveda medicine practitioners. He then experimented on animals and then his patients and, in 1840, reported that he successfully used a cannabis tincture to treat a 40-day-old girl with convulsions. After 20 days, he noted: “The child is now … in the enjoyment of robust health, and has regained her natural plump and happy appearance.” In 1842, O’Shaughnessy lectured in Britain on his successes with Indian hemp, and others later had similar success.20
In 1856, in North America, R.R. McMeens reported that he successfully used a tincture of Cannabis indica to treat four children, including a 7-week-old infant who was experiencing multiple seizures per day for more than two weeks. McMeens wrote: “from the time of its adoption, the patient never experienced another symptom of convulsion.”20
In 1868, Sir John Russell Reynolds, personal physician to Queen Victoria and one of the greatest 19th-century authorities on medical cannabis, reported on the use of cannabis to treat three patients (two adults and one child) with epilepsy, with varying benefits.20 Later, in an 1890 publication, he wrote, “In true, chronic epilepsy I have found [hemp] absolutely useless.” However, in the same publication, he also wrote, “Indian hemp is the most useful agent with which I am acquainted” for treating convulsions that he apparently thought were not associated with epilepsy,21 which indicates nosological confusion (i.e., confusion about how to classify a disease).20
Well into the 20th century, cannabis remained included in Western pharmacopeias, including the US Pharmacopeia (from which it was removed in 1942), but various factors, including a lack of standardization, bioavailability issues, and, ultimately, criminalization, prevented this ancient, multipurpose plant from becoming (or remaining) a mainstream antiseizure treatment.2
The antiseizure effects of cannabis and some of its constituents are by no means new discoveries, but the legal and political landscape has stifled research on the safety and efficacy of cannabis-derived therapies for all indications, including epilepsy. In 1979, Karler et al. wrote: “Because of the therapeutic failures and because of the toxicity associated with the currently used antiepileptics, the search for relatively non-toxic drugs with different mechanisms of action is an obvious goal in epilepsy research. Both the lack of toxicity and the anticonvulsant properties of CBD combine to enhance its therapeutic potential as an antiepileptic.”20
After this observation, however, little progress was made for decades. “There were sporadic studies but [CBD] wasn’t examined systematically until more than 30 years later,” Russo said. “So, that’s a shame.”
The use of cannabis-derived therapies, even non-intoxicating preparations, will likely remain controversial. However, the recent Epidiolex clinical trials, which observed success both in patients with Dravet syndrome12 and Lennox-Gastaut syndrome (a type of epilepsy with difficult-to-control seizures of multiple types),22 may help convince some that these therapies deserve more consideration. “It is important to remember that these kids have been on multiple drugs without control,” Russo said. “So, everything that we have seen in terms of improvement is over and above the best that conventional medicine could provide to them.”
“It is clear that [cannabis] can be made into a medicine that meets all standards, including FDA standards as a pharmaceutical, and we need to get on with it and offer people better alternatives,” Russo added.
* TRE (also sometimes called refractory or intractable epilepsy) occurs when sustained seizure remission is not achieved even after trials of at least two appropriately selected antiseizure medications that are tolerated by the patient at therapeutic dosages.2
† Formerly called “grand mal” seizures, tonic-clonic seizures combine the characteristics of tonic (stiffening) and clonic (rhythmical jerking) seizures. A seizure is “generalized” if it starts in both sides of the brain.11
‡ Status epilepticus occurs when a seizure of any type lasts more than five minutes, or when seizures occur in succession without the patient returning to normal over the course of more than five minutes. It has been shown that the longer a seizure lasts, the less likely it is to stop without medical intervention.14
** Vagus nerve stimulation is a therapy that may help prevent seizures by using a device similar to a cardiac pacemaker to stimulate the vagus nerve, which is the longest and most complex cranial nerve and is associated with many different brain regions and functions.
SIDE BAR: Epilepsy
Epilepsy is a chronic neurological disorder characterized by recurrent seizures, which occur when neurons fire uncontrollably and cause a surge of electrical activity in the brain. There are a number of epilepsy syndromes, which can be diagnosed based on several factors, including the type(s) of seizures, the age of onset, the cause(s) of the seizures (if known), the part(s) of the brain involved, patterns on the electroencephalogram (EEG), and others. The epilepsy syndrome will inform appropriate treatment options, so an accurate diagnosis is important. Epilepsy can be caused by genetic factors, head trauma, stroke, infections of the brain (e.g., cerebral malaria), and many other factors, but, often, the cause is not known.23 In fact, about 60% of cases are idiopathic (i.e., they arise from unknown origins).24
In addition, epilepsy is often progressive and is associated with continued loss of brain tissue and function.3 For almost all patients with epilepsy, quality of life is negatively impacted by both the disorder and the treatments, and there are often devastating personal and economic consequences.2 Furthermore, many patients have cognitive, psychosocial, psychological, behavioral, and sensorimotor impairments, as well as others.3 Additionally, there is an association between epilepsy and autism spectrum disorders (ASD). ASD and epilepsy co-occur in about 30% of individuals with either ASD or epilepsy.25
When seizures occur, there can be many negative effects, including cuts, bruises, burns, head trauma (including concussion) if the patient hits his or her head, broken bones, a bitten tongue, choking, or drowning if the patient is in water.26
It is estimated that epilepsy affects about 50 million people worldwide and accounts for about 1% of the global disease burden. It is also estimated that about 10% of all people will have a seizure in their lifetime, and, of those, about 30% will develop epilepsy.24 In the United States, about 150,000 people will develop epilepsy each year. Epilepsy develops more often in children and in older adults. It is estimated that, in the United States, about 2.2 million people currently have epilepsy.27
Seizures can remit over time. In the past, it was observed that a large majority of patients who had been seizure-free for two or more years while using antiseizure medications remained seizure-free indefinitely after gradually tapering off the medications.28 Benign Rolandic epilepsy is an example of a syndrome that is almost always outgrown over time.
Surgery may be an option for some patients with epilepsy whose seizures cannot be controlled with medications. In some cases, surgery is now being performed on patients whose seizures have been uncontrolled for only one or two years. The types of seizures and the part(s) of the brain involved will determine whether surgery is likely to help. The most common type of surgery is called resection, in which the part of the brain that is responsible for the seizures is removed. A patient’s overall quality of life should be taken into account when considering surgery. However, surgery does not guarantee that seizures will be controlled.29,30
- Friedman D, Devinsky O. Cannabinoids in the treatment of Epilepsy. N Engl J Med. 2015;373:1048-58. doi: 10.1056/NEJMra1407304.
- O’Connell BK, Gloss D, Devinsky O. Cannabinoids in treatment-resistant epilepsy: A review. Epilepsy and Behavior. 2017;70:341-348. doi: 10.1016/j.yebeh.2016.11.012.
- Rosenberg EC, Tsien RW, Whalley BJ, Devinsky O. Cannabinoids and epilepsy. Neurotherapeutics. 2015;12(4):747-768. doi: 10.1007/s13311-015-0375-5.
- Kroner BL, Wright C, Friedman D, et al. Characteristics of epilepsy patients and caregivers who either have or have not heard of SUDEP. Epilepsia. 2014;55(10):1486-1494.
- Dr Sanjay Gupta: Weed -— CNN Special Documentary. YouTube website. Available at: www.youtube.com/watch?v=-SZzgfyXhJI. Accessed June 29, 2017.
- Mead A. The legal status of cannabis (marijuana) and cannabidiol (CBD) under U.S. law. Epilepsy and Behavior. 2017;70:288-291. doi: 10.1016/j.yebeh.2016.11.021.
- 29 Legal Medical Marijuana States and DC. ProCon website. Available at: http://medicalmarijuana.procon.org/view.resource.php?resourceID=000881. Accessed June 29, 2017.
- Sulak D, Saneto R, Goldstein B. The current status of artisanal cannabis for the treatment of epilepsy in the United States. Epilepsy and Behavior. 2017;70:328-333. doi: 10.1016/j.yebeh.2016.12.032.
- Detyniecki K, Hirsch L. Marijuana use in epilepsy: The myth and the reality. Curr Neurol Neurosci Rep. 2015;15(10):65. doi: 10.1007/s11910-015-0586-5.
- Maa E, Figi P. The case for medical marijuana in epilepsy. Epilepsia. 2014;55(6):783-786. doi: 10.1111/epi.12610.
- Tonic-clonic seizures. Epilepsy Foundation website. Available at: www.epilepsy.com/learn/types-seizures/tonic-clonic-seizures. Accessed July 12, 2017.
- Devinsky O, Cross H, Laux L, et al. Trial of cannabidiol for drug-resistant seizures in the Dravet syndrome. N Engl J Med. 2017;376:2011-20. doi: 10.1056/NEJMoa1611618.
- Dravet Syndrome. Greenwich Biosciences website. Available at: greenwichbiosciences.com. Accessed August 14, 2017.
- Status Epilepticus. Epilepsy Foundation website. Available at: www.epilepsy.com/learn/impact/seizure-emergencies/status-epilepticus. Accessed July 12, 2017.
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