Epilepsy

The effects of barometric pressure changes and other climate factors on the frequency of seizures

Virginia Thornley, M.D., Neurologist, Epileptologist

June 3, 2018

Introduction

It is not common for a patient to complain of seizures seeming to increase immediately before a hurricane or a big storm. Do these changes truly correlate with outside environmental factors? This article seeks to review the literature to determine the cause and mechanisms of how weather risk factors might affect epilepsy and frequency of seizures.  There is a paucity of information of barometric effects and weather changes on exacerbation of seizure frequency.

Changes in atmospheric pressure correlated with seizures 

Atmospheric pressure is defined as the weight of the atmosphere. At sea level, it is 101,325 pascals, 14.5969 pounds/square inch or 1013.3 millibars. It is also referred to as barometric pressure.

In one article studying 191 patients, with an increase in atmospheric pressure variability, seizures were noted to increase. The atmospheric pressure was obtained from metropolitan weather stations in Seattle. The maximum, minimum and changes were correlated with the number of seizures being monitored in a telemetry unit over 2005-2006. Patients with known epilepsy had an odds ratio of 2.6 (p=0.02) if the atmospheric pressure varied over 5.5mBar (1).

Higher temperatures correlated with more febrile seizures

In another study of 108,628 pediatric patients from January 2005-December, 2015 were studied regarding the effect of barometric pressure on the frequency of seizures. They were classified as febrile seizures, afebrile, epilepsy or status epilepticus. 53% presented as febrile seizures while 5.9% presented as status epilepticus. Mean atmospheric pressure was 1015.5hPa over the 11 year period. The mean temperature was 14.7 degrees Celsius with a variation of 8.3 degrees Celsius throughout the day.  The study demonstrated febrile seizures were influenced by the temperature. At lower temperatures, the emergency room visits were less while at higher temperatures the visits increased (2).

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Low barometric pressure, high air humidity increases seizures, high ambient temperature improved seizures

In another study where temperature, barometric pressure, and humidity were correlated with seizure frequency, 604 patients were studied between 2006-2010. The study showed that with a 10.7hPa lower atmospheric pressure there was an increase in seizures by 14%. Those with less severe seizures had an increase of 36%. Relative humidity of >80% correlated with increased seizures of 48%. A high ambient temperature of more than 20 degrees Celsius reduced seizures by 46% (4).

Cold temperature worsen seizures

In a study of 30 patients ages (19-54), patients with epilepsy appeared to have more active seizures during the seasons of spring, autumn and winter and less during summer of about 7%. During stable weather, it was 43% patients and unstable weather 63% had seizures. EEG’s changes occurred more frequently during winter. During winter seizures increased by 40%, in spring it increased 40% and spring by 43.3% (3).

In summary

While anecdotally, there is a correlation of exacerbation of seizure frequency to weather changes, the literature shows mixed results and some of them are small in number. One study showed a correlation of changes of more than 5.5mBar in barometric pressure leading to increased seizures frequency, another showed that it is the reduction in the atmospheric pressure itself that increased seizures. 1 study showed that high humidity may increase seizures. 2 studies showed that cold temperatures worsened seizures, while 1 study showed that higher ambient temperature worsened febrile seizures.

The data that was demonstrated is not uniform in the acquisition of information and there is a large variety of conditions. One study was primarily taken from ER visits another was information from inpatient video EEG monitoring units where the subset of patients may be completely different. In addition, there is a wide heterogeneity in etiologies of seizures which comes into play. Regardless, patients know their own symptoms, usually, if something is noted to trigger an event is it probably real.

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Reference

  1. Doherty, et al, “Atmospheric pressure and seizure frequency in the epileptic unit: preliminary observations,” Epilepsia, 2007, Sep., 48 (9):1764-1767.
  2. Kim, et al, “The effects of weather on pediatric seizure; a single -center retrospective study,” Sci. Total Environ. , 2017, Dec., (609):535-540.
  3. Motta, et al, “Seizure frequency and bioelectric brain activity in epileptic patients in stable and unstable atmospheric pressure and temperature in different seasons of the year–a preliminary report,” Neurol. Neurochir. Pol, 2011, Nov.-Dec., 45(6):561-566.
  4. Rakers, et al, “Weather as a risk factor for epileptic seizures: a case-crossover study,” Epilepsia, 2017, Jul., 58(7): 1297-95.
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synthetic cannabinoids

The fatal effects and mechanisms of synthetic cannabinoids including JWH compounds used recreationally

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

May 31, 2018

Introduction

Advocacy groups are well-versed and even the public is aware of the increasing popularity of medical marijuana use for medical purposes. Medical marijuana that is all organic all natural with no synthetic materials with high quality have the best-tolerated effects compared to synthetic products. However, with many research studies ongoing, there is the darker side of the equation from which the stigma first grew, its intent for recreation and subsequent abuse. Producers trying to evade the law have come up with far more potent and potentially deadly synthetic cannabinoids which escape detection through laboratory means.

There are spurts of news items regarding the increasing use of synthetic marijuana known as the street name “spice” or “K2.” It first became known in 2008 when the European Monitoring Center for Drugs and Drug Addiction (EMCDDA)  identified it as dangerous synthetic cannabinoids from herbal incenses with a remarkable affinity to the CB1 and CB2 receptors which were insidiously abused. These substances were left unchecked because they were initially difficult to identify through biomarkers or testing leading scientists to urgently study these compounds (3).

Typically, presentations occur in groups of patients in the emergency room arising from a single source of distribution at a time. There can be a variety of symptoms because of admixed substances. They have arisen in popularity because they may not be detected by conventional drug testing. Synthetic cannabinoids produce more intense psychoactive effects and by the same token more intense side effects. In animal models, synthetic cannabinoids are 2-100 times more potent than tetrahydrocannabinol in terms of analgesic, anti-inflammatory, anti-seizure effects. It is also thought to be more potent for anti-cancer growth. Because of this, while the beneficial effects are more prominent, by the same token, medical and psychoactive emergencies may result due to its more intense effects through the endocannabinoid pathway. With the added effect of excessive use, this only magnifies the potentiation of effects.

This is likely also the reason why synthetic cannabinoids used medically may provide more benefit, but by the same token are less tolerated and more side effects are noted.

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JWH-018 or K2 or Spice and mechanisms

The synthetic cannabinoid “K2” or “Spice” is also known as JWH-018. Dangerous effects of K2 and other synthetic cannabinoids, because they work through the CB1 and CB2 receptors, are potentiations of the usually mild effects of phytocannabinoids from the Cannabis sativa plant. This can lead to changes in the levels of dopaminergic, serotonergic and GABAergic neurotransmitters in the system causing symptoms. There is a high affinity of synthetic cannabinoids to the CB1 receptor through which psychoactive properties of cannabinoids are manifest. It produces similar effects to delta-9-tetrahydrocannabinol which is the psychoactive metabolite from the Cannabis sativa plant but is much more potent. Synthetic cannabinoid metabolites may still remain active and exerts long-lasting effects in addition to the effects of the parent compound. The CB1 receptor is predominantly found in the nervous system while the CB2 receptor is found mostly in the immune system and in other organs to a lesser extent. Synthetic cannabinoids interact with the CB1 receptor pre-synaptically which is a G-coupled protein. Synthetic cannabinoid agonists interact with the CB1 receptor and modulate voltage-gated channels that inhibit sodium, potassium and N-sodium channels and P/Q-type sodium channels thereby reducing the membrane potentials (5).

Synthetic cannabinoids were originally manufactured as a therapeutic agent to exert effects on the cannabinoid receptor.

It is extensively metabolized by cytochrome p450 and activates the cannabinoid receptors (CBR). The most significant cytochrome is CYP2C9 (1) which is found predominantly in the gastrointestinal tract and liver. CYP2C9*1 is the wild type while CYP2C9*2 and CYP2C9*3 are the more common variants. It was found that CYP2C9 *2 tended to metabolize JWH-018 3.6 times more than CYP29C*1 which is likely why there is variation in toxic effects among different individuals when abused (1).  Genetic polymorphisms may lead to potentiation of the effects.  Other synthetic cannabinoids include JWH-073, CP-47 and 497 (3).

6 other synthetic cannabinoids that have been identified

Six synthetic cannabinoids were characterized from illicit drugs including MMB- and MDMB-FUBINACA, MN-18, NNEI, CUMYL-PICA, and 5-Fluoro-CUMYL-PICA. The toxic effects include cardiotoxicity, seizures and renal damage (2).  These have greater effects compared to those of THC. The study shows that synthetic cannabinoids are being manufactured and used as substitutes for THC with greater effects and potentiation (2).

There are hundreds of other synthetic cannabinoids that have been identified.

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Dangerous side effects of synthetic cannabinoids

Synthetic cannabinoids affect the gastrointestinal and neuropsychiatric systems and additionally can cause cardiogenic effects. Adverse effects include tachycardia, chest pain, myocardial ischemia, hypertension, confusion, agitation, hallucination, seizures, cerebrovascular vasoconstriction, stroke, and nausea. There have been other reports involving arrhythmias, psychosis, memory loss, cognitive impairment and even fatality (5).

In one study of 141 patients, there were atypical symptoms of psychomotor retardation, hypotension, bradycardia. 75% of blood samples had possibly XLR-11. 24 urine sample came back positive for synthetic cannabinoids, 74% had XLR-11, while 35% had carboxamide indazole derivatives. There were no JWH compounds, opioids, sedative-hypnotics, or imidazoline receptor agonists detected. It is not clear if there may be other undetectable psychotropic agents that may have been mixed causing the unusual symptoms not typical for cannabinoids.  In addition, these were patients that came from a nearby psychiatric facility where potentially other neuropsychotropic agents may have interacted (4).

In summary

Clinicians should recognize the clinical symptoms from synthetic cannabinoids and possible adverse side effects as it is emerging as one of the popular drugs of abuse. Once it was discovered there was a ban on synthetic cannabinoids decreasing the wide usage but there has since been a resurgence. They potentiate their pharmacologic effects at the CB1 receptor 2-100 times that of tetrahydrocannabinol but by the same token may cause medical and psychiatric emergencies.

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References

  1. Patton, et al, “Altered metabolism of synthetic cannabinoid JWH-018 by human cytochrome p4502C9 and variants,” Biochem. Biophys. Res. Commun., 2018, Apr., 6, 498 (3):597-602.
  2. Gamage, et al, “Molecular and behavioral pharmacological characterization of abused synthetic cannabinoids MMB- and MDMB-FUBINACA, MN-18, NNEI, CUMYL-PICA, and 5-Fluoro-CUMYL-PICA,” J. Pharmacol. Exp. Ther., 2018, May, 365(2):437-446.
  3. Brents, et al, “The K2/spice phenomenon: emergence, identification, legislation and metabolic characterization of synthetic cannabinoids in herbal incense products.” Drug Metab. Rev., 2014, Feb., 46(1):72-85.
  4. Sud, et al, “Retrospective chart review of synthetic cannabinoid intoxication with toxicologic analysis,” West J. Emerg. Med., 2018, May, 19(3):567-572. doi: 10.5811/westjem.2017.12.36968
  5. Castaneto, et al, “Synthetic cannabinoids: epidemiology, pharmacodynamics and clinical implications,” Drug Alcohol Depend., 2014, Nov., 1:12-41

 

 

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cannabidiol, Epilepsy

Scientific and clinical evidence of cannabidiol (CBD) and seizure control: mechanisms, randomized controlled clinical trials, open label trials and animal models

Virginia Thornley, M.D., Neurologist, Epileptologist 

@VThornleyMD

May 22, 2018

Introduction

There are numerous scientific studies that have studied the effect of cannabidiol by itself on seizure control encompassing animal models, longitudinal observational studies, case series and currently randomized double-blinded placebo-controlled clinical trials. It is difficult to ignore the wealth of information regarding the medical value of cannabidiol with a significant role in the treatment of epilepsy.

The endocannabinoid pathway and cannabinoids

The endocannabinoid pathway is found naturally within our system, comprising of receptors, transporters, and endocannabinoids. It is responsible for the sense of well-being one gets after running referred to as the “runner’s high,” and not endorphins, serotonin or noradrenergic neurotransmitters as their molecular sizes are too large to pass through the blood-brain barrier. There are 2 types of receptors, CB1 and CB2 receptors. CB1 is found predominantly within the nervous system and is the receptor on which tetrahydrocannabinol works and it is through this binding where psychoactive properties arise. There are two metabolites within the endocannabinoid pathway, anandamide for which tetrahydrocannabinol (THC) is a phytomimetic and 2-arachidonoyl-glycerol for which cannabidiol is a phytomimetic. Cannabidiol (CBD) acts as an inverse agonist on the CB1 receptor, with a weak affinity. 100 times of cannabidiol is needed to get the same psychoactive properties as tetrahydrocannabinol. When CBD is combined with THC the side effects of paranoia, hyperactivity and agitation become less because it is an inverse agonist of the CB1 receptor. In many animal studies, cannabidiol has anti-inflammatory, anti-oxidative and neuroprotective actions within the nervous system (8).

Mechanisms by which cannabidiol works 

It is thought to modulate the neurotransmitter system. Endocannabinoids are increased as a result if hyperexcitability in the nervous system. CBD can regulate intracellular calcium during hyperexcitability states in the hippocampus in the temporal lobe. CBD can regulate NMDA (N-methyl-D-aspartate) receptor transmission and increase serotonergic 5HT-1A (5-hydroxytryptamine)receptor transmission and reduces GABA, 5-HT1A, and norepinephrine synaptic uptake (9). Cannabidiol is thought to be neuroprotective through its role in controlling intracellular calcium. Excess calcium can activate a cascade of neurochemical events leading to cell degeneration and death through lipases, endonucleases, and proteases. In one study in rat models, there was a suggestion that treatment of seizures was not just at the neurotransmitter level but also modulates the oscillatory nature, neuronal loss and post-ictal lethargy of the status epilepticus model.

Scientific evidence in animal models

Animal studies show that the effectiveness of cannabis is at the level of the CB1 receptor. With the deletion of the CB1 receptors in the forebrain excitatory neurons in the mice model, Kainate-induced seizures were more prominent. The presence of CB1 receptors in the hippocampal gyrus seems to protect against Kainate-induced seizures. Viral-induced CB1 overexpression resulted in less Kainate-induced seizures, CA pyramidal cell 3 cell death. This demonstrates that the presence of the CB1 receptor can limit seizures and reduces gliosis and apoptosis (4).

 

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In animal studies, the CB1 receptors increased 1 week after pilocarpine-induced seizures in the CA1-3 striatum oriens and the dentate gyrus. Patients with temporal lobe epilepsy had reduced Anandamide and increased CB1 receptors suggesting an up-regulation of the CB1 receptor as a homeostatic mechanism in the presence of seizures which can reduce excitatory neurotransmitters (4). This compensatory mechanism may be impaired with long-standing seizures and hippocampal sclerosis and refractoriness to pharmacologic measures.

Case series report

In a small study on patients with tumors with seizures, in 3 patients who were medically refractory were started on cannabidiol (Epidiolex) to treat seizures. 2 out of the 3 had improvement in seizures while all 3 had improvement in the severity in the University of Alabama (2).

Evidence in longitudinal observational studies

In one study of 57 patients, ages 1-20 years old, CBD:THC was given at a ratio of 20:1 with the CBD component of 11.4 mg/kg/day. The patients were followed longitudinally for 3 months with a follow-up time of 18 months. 56% or 26 patients had <50% reduction of seizures. No difference was noted between the causes of the seizure and the type of cannabis used. Younger ages of 10 years old and below had a statistically better outcome compared to an older age. Those with higher doses of CBD of >11.4mg/kg/day had a statistically better outcome compared to 11.4mg/kg/day and below. There were side effects in about 46% of patients leading to stopping the protocol. These studies suggest that cannabidiol enriched treatment may be beneficial in seizure control particularly in the pediatric population.  (1).

Open-label studies

In an open-label trial, 214 patients were studied between the ages 1-30, with pharmacoresistant epilepsy. There were 162 in the safety follow-up of 12 weeks, 137 were in the efficacy analysis. For the safety group, 33 had Dravet syndrome and 31 had Lennox-Gastaut syndrome. The rest had medically refractory seizures from different causes. Side effects were mild to moderate including diarrhea, lack of appetite, somnolence, fatigue, and convulsion. 5 had a cessation of treatment related to adverse effects. Serious events were reported in 48 patients with 1 death unrelated to cannabidiol. 20 had severe adverse effect including status epilepticus. The median number of seizures at baseline was 30 which was reduced to 15 per month with a 36.5% reduction of motor seizures (7).

Evidence in randomized controlled clinical trials 

In a multi-country study was performed on Dravet syndrome and effect of cannabidiol in a randomized double-blind trial of cannabidiol versus placebo and in young adults between the ages of 2-18. Dravet syndrome is an epileptic syndrome involving myoclonic epilepsy during childhood which may progress attributed to an SCN1A gene abnormality. There was a 4 week baseline period followed by a 14 week treatment period. The dosages of cannabidiol were increased gradually to 20mg/kg/day. Those in the cannabidiol group was matched to a placebo control. The endpoints were the percentage of change and Caregiver Global Impression of Change (CGIC). In 23 center in the U.S. and in Europe, 120 patients underwent randomization, mean age was 9.8 years old. 108 completed treatment. The median number of drugs was 3 and the most commonly taken were clobazam, valproate, stiripentol, levetiracetam, and topiramate. The most common type of seizures was generalized tonic-clonic followed by secondary generalized tonic-clonic seizures. 114/118 children presented with developmental delay. Adverse reactions were mild to moderate including somnolence, diarrhea and loss of appetite. Elevated liver enzymes were found in those taking valproate likely related to drug-drug interactions. The reduction of seizures was considered meaningful while no change in non-convulsive episodes was noted. In the cannabidiol group, convulsive seizures reduced from 12.4 seizures to 5.9 per month while the placebo control group had a reduction of seizures from 14.9 to 14.1 which was not statistically significant. A reduction of more than 50% of seizures occurred in 43% of patients in the cannabidiol group and 27% in the control cohort. 3 patients in the cannabidiol group and no one in the placebo group became free of seizures. 62% of caregivers thought the condition improved in the cannabidiol group as opposed to 34% in the placebo group (5).

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Another randomized placebo-controlled trial in Lennox-Gastaut syndrome was done using cannabidiol versus placebo. Lennox-Gastaut Syndrome is characterized by multiple seizure types with a slow spike and wave of 2.5 Hz or slower on EEG.  This study covered 30 clinical trial centers between the ages 2-55 with 2 or more seizures per week over 28 days. 225 patients were randomized with 76 in the group for cannabidiol at 20mg/kg/day, 73 in the cannabidiol group at 10mg/kg/day and 76 in the placebo cohort. The reduction in median of drop attacks was 41.9% in the 20mg cannabidiol group, 37% in the 10mg cannabidiol group and 17.2% in the placebo group which was statistically significant. Side effects were somnolence, diarrhea and poor appetite which was dose-related. 9% had higher liver function tests. The study concluded that addition of cannabidiol of either 10mg/kg/day or 20mg/kg/day in addition to standard anti-epileptic agents resulted in a significant reduction of seizures(6).

Cannabidiol as an add-on adjunct for refractory seizures

In another study in Slovenia, add-on cannabidiol was given to 66 patients who were deemed medically refractory at a dosage of 8mg/kg/day. 32 or 48% of patients experienced fewer seizures of more than 50% reduction. 14 (21%) were seizure free. No patient had to worsen and 15 or 22.7% there was no effect. Patients reported less robust seizures, less recovery time and less time duration of the seizures as positive outcomes. Adverse effects were seen in 5 patients or 0.07% of patients. They concluded that there are some beneficial effects of cannabidiol as an add-on adjunctive treatment in controlling medically refractory epilepsy(3). However, this study focused on cannabidiol as an adjunctive treatment, not as monotherapy.  Regardless, there are some beneficial aspects as evidenced in this study (3).

In summary

There is growing evidence that cannabidiol which is the non-psychoactive component of the Cannabis sativa plant is effective in treating intractable seizures, from the mouse model to randomized controlled clinical trials, which can no longer be ignored. There are mostly mild to moderate side effects involving the gastointestinal and neuropsychiatric system, although severe adverse outcomes include status epilepticus. There were no fatal outcomes associated with the use of cannabidiol. The real question are the long-term side effects and drug-drug interactions which can be studied once the cannabidiol is well-established as a conventional agent in the future.

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References:

  1. Hausman-Kedem, M., et al, “Efficacy of CBD-enriched medical cannabis for treatment of refractory epilepsy in children and adolescents – an observational longitudinal study,” Brain Dev., 2018 Apr., pii:S0387-7604 (18)30112-8 doi: 10.1016/j.braindev2018.03.013. (Epub ahead of print)
  2. Warren, et al, “The use of cannabidiol for seizure management in patients with brain tumor-related epilepsy,” Neurocase, 2017, Oct.-Dec., 23 (5-6):287-291.
  3. Neubauer, D., et al, “Cannabidiol for treatment of refractory childhood epilepsies: experience from a single tertiary epilepsy center in Slovenia,” Epilepsy Behav., 2018 Apr., 81:79-85. doi:10.1016/j.yebeh.2018.02.009. (Epub ahead of print)
  4. Rosenberg, et al, “Cannabinoids and epilepsy,” Neurotherapeutics, 2015, Oct., 12 (4):747-768.
  5. Devinsky, O., et al, “Trial of cannabidiol for drug-resistant seizures in the Dravet Syndrome,” New England Journal of Medicine, 2017, 376: 2011-2020.
  6. Devinsky, et al, “Effect of cannabidiol on drop seizures in the Lennox-Gastaut Syndrome,” NEJM, 2018, May,  378:1888-1897.
  7. Devinsky, et al, “Cannabidiol in patients with treatment-resistant epilepsy: an open label interventional trial,” Lancet Neurology, 2016, Mar., 15 (3):270-8.
  8. Fernandez-Ruiz, et al, “Prospects of cannabinoid therapies in basal ganglia disorder,” British Journal of Pharmacology, 2011, Aug., 163 (7):1365-1378.
  9. Do Val-da-Silva, et al, “Protective effects of cannabidiol against seizures and neuronal death in a rat model of mesial temporal lobe epilepsy,” Front. Pharmacol., 2017, 8:131.
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