Posts Tagged Epilepsy

[NEWS] Novela Neurotech to Present nEureka® for Epilepsy Platform at CapCon 2020 Venture Conference – EIN Presswire

NEWS PROVIDED BY Novela Neurotech September 23, 2020, 19:30 GMT

nEureka® for Epilepsy: an all-in-one platform for remote epilepsy monitoring.
nEureka® for Epilepsy: an all-in-one platform for remote epilepsy monitoring. Click to zoom

nEureka® is a telehealth Data-as-a-Service platform transforming costly episodic care to personalized, efficient, and accessible remote care for epilepsy.

ALAMEDA, CALIFORNIA, UNITED STATES, September 23, 2020 /EINPresswire.com/ — Novela Neurotech, a Data-as-a-Service company developing personalized remote epilepsy care using connected consumer data, will showcase its nEureka® for Epilepsy platform at the virtual CapCon 2020 Venture Conference, Sep 29 to Oct 1, 2020.

Over 3 million people in the U.S. are diagnosed with epilepsy, which is characterized by unpredictable seizures. Although a chronic neurological condition, the current status quo for epilepsy healthcare relies on punctuated clinical visits—often three months apart—which delays critical healthcare decisions for epilepsy management. Roughly 70% of epilepsy cases can be controlled with medication, and medication adherence is a key factor for keeping seizures at bay. Epileptologists often adjust their prescriptions using the patient’s self-reported experience of their seizure counts and side-effects. Therefore, precise seizure counts and side-effect data are critical to inform healthcare decisions.

However, current options for tracking seizures and medication are antiquated & inaccurate, fractured, lacking and episodic.

1) Antiquated & inaccurate: Patients often rely on pen-and-paper journals, or single-function seizure tracking apps, to log their seizures, which easily leads to forgetting and inaccuracies.
2) Fractured: Separate alarms and apps are needed for medication reminders, activity and mood tracking, promoting frustration and confusion.
3) Lacking: Patients who are aware of an impending seizure cannot easily notify family for help. During sleep, 1 in every 150 patients with uncontrolled seizures may experience SUDEP (Sudden Unexpected Death in Epilepsy), a devastating condition that is preventable — if provided with adequate monitoring or intervention methods, which are currently lacking.
4) Episodic: with a 3+ month gap between physician visits, patients experience a lag in critical healthcare to keep their seizures under optimal control.

The nEureka® for Epilepsy system combines everyday consumer devices, a cloud data platform and real-time alerts into a powerful all-in-one Epilepsy Remote Care Solution that resolves current pain points. Wearables embedded with seizure-related biomarker sensors will allow continuous recording of biomarkers, and simplified one-button tracking of seizure events to increase the accuracy of seizure counts. Built under the guidance of epileptologists and people with epilepsy, nEureka® also includes SOS alerts to caregivers—day and night—providing patients with independence, and caregivers with peace-of-mind. All data are seamlessly transferred to the patients’ physician portal, and organized as a dashboard into clean and informative charts for easy 24/7 review and follow-ups.

As certified by Impactable, nEureka® delivers significant healthcare impact including $2B+ reduction in cost to reach optimal treatment in the next 5 years in the US alone, with a 40% improvement in medication adherence.

“Altogether, nEureka® for Epilepsy transforms antiquated Epilepsy Care from single snapshots in time to a continuous, data-rich movie. Long gone are the days of intermittent, guess-based healthcare. nEureka® paves the way for patients to launch remote visits with their physicians—anytime, anywhere,” says Ray Iskander, CEO of Novela Neurotech.


About nEureka®
nEureka® by Novela Neurotech is a telehealth Data-as-a-Service platform transforming current costly episodic care to personalized, efficient, and accessible remote care for epilepsy & other chronic neurological conditions. nEureka® leverages everyday consumer technology and wearables to connect patients with their clinicians and caregivers resulting in continuous care and significantly reducing risk of premature death and care costs. For more information, contact shelly.fan@novelaneuro.com.

About CapCon
The CapCon mission is to change the world by promoting forward-thinking life science companies through finance and media. Lack of efficiencies in healthcare need to be addressed to save people and their families, and CapCon aspires to make a dent in the current state of medical problems. Companies that register for CapCon receive exposure to the exact investors they want to meet — including those who have a fundamental interest in the growth of their company. Companies will also receive educational content in finance, legal affairs, regulatory affairs, and business. More at CapCon 2020.

Source: https://www.einnews.com/pr_news/526886922/novela-neurotech-to-present-neureka-for-epilepsy-platform-at-capcon-2020-venture-conference

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[Abstract + References] Evaluation of an Activity Tracker to Detect Seizures Using Machine Learning

Abstract

Currently, the tracking of seizures is highly subjective, dependent on qualitative information provided by the patient and family instead of quantifiable seizure data. Usage of a seizure detection device to potentially detect seizure events in a population of epilepsy patients has been previously done. Therefore, we chose the Fitbit Charge 2 smart watch to determine if it could detect seizure events in patients when compared to continuous electroencephalographic (EEG) monitoring for those admitted to an epilepsy monitoring unit. A total of 40 patients were enrolled in the study that met the criteria between 2015 and 2016. All seizure types were recorded. Twelve patients had a total of 53 epileptic seizures. The patient-aggregated receiver operating characteristic curve had an area under the curve of 0.58 [0.56, 0.60], indicating that the neural network models were generally able to detect seizure events at an above-chance level. However, the overall low specificity implied a false alarm rate that would likely make the model unsuitable in practice. Overall, the use of the Fitbit Charge 2 activity tracker does not appear well suited in its current form to detect epileptic seizures in patients with seizure activity when compared to data recorded from the continuous EEG.

References

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3.Beniczky, S, Jeppesen, J. Non-electroencephalography-based seizure detection. Curr Opin Neurol. 2019;32(2):198–204.
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4.Ryvlin, P, Ciumas, C, Wisniewski, I, Beniczky, S. Wearable devices for sudden unexpected death in epilepsy prevention. Epilepsia. 2018;59(suppl 1):61–66.
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9.Scheffer, IE, Berkovic, S, Capovilla, G, et al. ILAE classification of the epilepsies: position paper of the ILAE Commission for Classification and Terminology. Epilepsia. 2017;58(4):512–521.
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12.Moreno-Pino, F, Porras-Segovia, A, Lopez-Esteban, P, Artes, A, Baca-Garcia, E. Validation of Fitbit charge 2 and Fitbit alta HR against polysomnography for assessing sleep in adults with obstructive sleep apnea. J Clin Sleep Med. 2019;15(11):1645–1653.
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13.Regalia, G, Onorati, F, Lai, M, Caborni, C, Picard, RW. Multimodal wrist-worn devices for seizure detection and advancing research: focus on the Empatica wristbands. Epilepsy Res. 2019;153:79–82.
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14.Van Ness, PC . Are seizure detection devices ready for prime time? Epilepsy Curr. 2019;19(1):36–37.
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19.Patel, AD, Moss, R, Rust, SW, et al. Patient-centered design criteria for wearable seizure detection devices. Epilepsy Behav. 2016;64(pt A):116–121.
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20.Kurada, AV, Srinivasan, T, Hammond, S, Ulate-Campos, A, Bidwell, J. Seizure detection devices for use in antiseizure medication clinical trials: a systematic review. Seizure. 2019;66:61–69.
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21.Benedetto, S, Caldato, C, Bazzan, E, Greenwood, DC, Pensabene, V, Actis, P. Assessment of the Fitbit charge 2 for monitoring heart rate. PLoS One. 2018;13(2):e0192691.
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22.Gutierrez, EG, Crone, NE, Kang, JY, Carmenate, YI, Krauss, GL. Strategies for non-EEG seizure detection and timing for alerting and interventions with tonic-clonic seizures. Epilepsia. 2018;59(suppl 1):36–41.
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[WEB SITE] Scientists: Mozart’s music helps with epilepsy

Scientists from Italy conducted a study, during which they established the beneficial effects of Mozart’s piano music on people’s mental health. They proved that the works of the composer help with epilepsy.

Scientists: Mozart's music helps with epilepsy
Image via: pikist.com

The “Mozart effect” has been known since the end of the last century. However, until recently, no research has provided convincing evidence of its existence, and therefore doctors are skeptical about it. Scientists from the University of Pisa carried out scientific work, during which they carried out a detailed analysis of 147 published articles devoted to this phenomenon. After reviewing all the materials, Dr. Federico Sicca and Gianluca Sesso chose the 12 most accurate. They compared the results obtained by experts working independently of each other, revealing patterns. In their opinion, listening to classical works of Mozart daily can have a significant impact on health. The number of seizures with epilepsy among fans of such music decreases from 31% to 66%. Even a one-time listening has a positive impact. Probably, the effect is due to special rhythmic structures, but the therapeutic effect can be revealed when listening to compositions by other authors.

Their colleague from the Lithuanian University of Medical Sciences Vesta Steiblienė agrees with them. In her opinion, interest in non-invasive methods of brain stimulation is growing and is increasingly being practiced by doctors, but for widespread use and acceptance of recommendations, such neurostimulation should be studied more carefully and accurately. Since it is already obvious now that Mozart’s music really has an effect, but it is not clear at the expense of what exactly.

Source: https://thetimeshub.in/scientists-mozarts-music-helps-with-epilepsy/2050/

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[Review] Diet in the Treatment of Epilepsy: What We Know So Far – Full Text

Abstract

Epilepsy is a chronic and debilitating neurological disorder, with a worldwide prevalence of
0.5–1% and a lifetime incidence of 1–3%. An estimated 30% of epileptic patients continue to experience
seizures throughout life, despite adequate drug therapy or surgery, with a major impact on society
and global health. In recent decades, dietary regimens have been used effectively in the treatment of
drug-resistant epilepsy, following the path of a non-pharmacological approach. The ketogenic diet
and its variants (e.g., the modified Atkins diet) have an established role in contrasting epileptogenesis
through the production of a series of cascading events induced by physiological ketosis. Other dietary
regimens, such as caloric restriction and a gluten free diet, can also exert beneficial effects on
neuroprotection and, therefore, on refractory epilepsy. The purpose of this review was to analyze
the evidence from the literature about the possible efficacy of different dietary regimens on epilepsy,
focusing on the underlying pathophysiological mechanisms, safety, and tolerability both in pediatric
and adult population. We believe that a better knowledge of the cellular and molecular biochemical
processes behind the anticonvulsant effects of alimentary therapies may lead to the development of
personalized dietary intervention protocols.
[…]

Full Text PDF

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[ARTICLE] Medication use in poststroke epilepsy: A descriptive study on switching of antiepileptic drug treatment – Full Text

Highlights

  • It is unknown why patients switch their antiepileptic drugs in poststroke epilepsy.
  • We found that 40% of patients needed to switch.
  • 13% of patients switched because of ineffectivity of the first prescribed AED.
  • Dosages at the time of switching were higher in case of ineffectivity than in case of side effects.

Abstract

Objective

Currently, as evidence-based guidelines are lacking, in patients with poststroke epilepsy (PSE), the choice of the first antiepileptic drug (AED) is left over to shared decision by the treating physician and patient. Although, it is not uncommon that patients with PSE subsequently switch their first prescribed AED to another AED, reasons for those switches are not reported yet. In the present study, we therefore assessed the reasons for switching the first prescribed AED in patients with PSE.

Method

We gathered a hospital-based case series of 53 adult patients with poststroke epilepsy and assessed the use of AEDs, comedication, and the reasons for switches between AEDs during treatment. We also determined the daily drug dose (DDD) at the switching moment.

Results

During a median follow-up of 62 months (Interquartile range [IQR] 69 months), 21 patients (40%) switched their first prescribed AED. Seven patients switched AED at least once because of ineffectivity only or a combination of ineffectivity and side effects, whereas 14 patients switched AED at least once because of side effects only. The DDD was significantly (p < 0.001) higher in case of medication switches due to ineffectivity (median 1.20, IQR 0.33) compared to switching due to side effects (median 0.67, IQR 0.07). There was no difference in the use of comedication between the group that switched because of ineffectivity compared to the group that switched because of side effects.

Conclusion

In our case series, up to 40% of patients with epilepsy after stroke needed to switch their first prescribed AED, mostly because of side effects in lower dosage ranges.

1. Introduction

Stroke is the cause of about 10% of all epilepsy and 55% of newly diagnosed seizures among the elderly [1]. Nevertheless, there are no specific evidence-based guidelines regarding treatment of patients with poststroke epilepsy (PSE). Therefore, the choice of antiepileptic drug (AED) is left over to shared decision by the treating physician and patient. From the 2013 International League Against Epilepsy (ILAE) report on initial monotherapy for epileptic seizures and syndromes, it appears that carbamazepine, levetiracetam, phenytoin, and zonisamide have ‘level A’ evidence for treating focal epilepsy in adults [2345]. This may already guide the choice of the AED by mainly effectivity arguments. On the other hand, according to a recent study by Larsson et al., in patients with PSE, retention rates are highest for levetiracetam and lamotrigine, and lowest for carbamazepine and phenytoin [6], meaning that carbamazepine and phenytoin are more often switched to another drug or discontinued. A 2018 review of randomized controlled trials on AED for the treatment of PSE found that levetiracetam and lamotrigine were better tolerated than carbamazepine [7]. However, reasons for discontinuation or switching of AEDs in patients with PSE are not reported. We therefore aimed to study the reasons for switching the first prescribed AED in patients with epilepsy after stroke.[…]

Continue —-> https://www.epilepsybehavior.com/article/S1525-5050(19)30593-1/fulltext

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[Ebook] Epilepsy Complementary And Alternative Treatments – PDF


Ebook Title : Epilepsy Complementary And Alternative Treatments

Read Epilepsy Complementary And Alternative Treatments PDF on your Android, iPhone, iPad or PC directly.

The following PDF file is submitted in 19 Jan 2020

Ebook ID PDF-12ECAAT11.

Download full version PDF for Epilepsy Complementary And Alternative Treatments using the link below:

Download: EPILEPSY COMPLEMENTARY AND ALTERNATIVE
TREATMENTS PDF

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[WEB PAGE] Epilepsy: A Neurological Disorder

Image

Epilepsy is a group of neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures are episodes that can vary from brief and nearly undetectable periods to long periods of vigorous shaking. These episodes can result in physical injuries, including occasionally broken bones. In epilepsy, seizures have a tendency to recur and, as a rule, have no immediate underlying cause.

Isolated seizures that are provoked by a specific cause such as poisoning are not deemed to represent epilepsy. People with epilepsy may be treated differently in various areas of the world and experience varying degrees of social stigma due to their condition.

The underlying mechanism of epileptic seizures is excessive and abnormal neuronal activity in the cortex of the brain. The reason this occurs in most cases of epilepsy is unknown. Some cases occur as the result of brain injury, stroke, brain tumors, infections of the brain, or birth defects through a process known as epileptogenesis. Known genetic mutations are directly linked to a small proportion of cases. The diagnosis involves ruling out other conditions that might cause similar symptoms, such as fainting, and determining if another cause of seizures is present, such as alcohol withdrawal or electrolyte problems. This may be partly done by imaging the brain and performing blood tests. Epilepsy can often be confirmed with an electroencephalogram (EEG), but a normal test does not rule out the condition. Epilepsy that occurs as a result of other issues may be preventable.

Seizures are controllable with medication in about 70% of cases; inexpensive anti-seizure medications are often available. In those whose seizures do not respond to medication, surgery, neurostimulation or dietary changes may then be considered. Not all cases of epilepsy are lifelong, and many people improve to the point that treatment is no longer needed. As of 2015, about 39 million people have epilepsy.

Nearly 80% of cases occur in the developing world. In 2015, it resulted in 125,000 deaths, an increase from 112,000 in 1990. Epilepsy is more common in older people. In the developed world, onset of new cases occurs most frequently in babies and the elderly. In the developing world, onset is more common in older children and young adults due to differences in the frequency of the underlying causes. About 5–10% of people will have an unprovoked seizure by the age of 80, and the chance of experiencing a second seizure is between 40 and 50%. In many areas of the world, those with epilepsy either have restrictions placed on their ability to drive or are not permitted to drive until they are free of seizures for a specific length of time.

The word epilepsy is from Ancient Greek ἐπιλαμβάνειν, ‘to seize, possess, or afflict’. Seizures Main article: Epileptic seizure The most common type (60%) of seizures are convulsive. Of these, one-third begin as generalized seizures from the start, affecting both hemispheres of the brain. Two-thirds begin as focal seizures (which affect one hemisphere of the brain) which may then progress to generalized seizures. The remaining 40% of seizures are non-convulsive. An example of this type is the absence seizure, which presents as a decreased level of consciousness and usually lasts about 10 seconds.

Focal seizures are often preceded by certain experiences, known as auras. They include sensory (visual, hearing, or smell), psychic, autonomic, and motor phenomena. Jerking activity may start in a specific muscle group and spread to surrounding muscle groups in which case it is known as a Jacksonian march. Automatisms may occur, which are non-consciously-generated activities and mostly simple repetitive movements like smacking of the lips or more complex activities such as attempts to pick up something. There are six main types of generalized seizures: tonic-clonic, tonic, clonic, myoclonic, absence and atonic seizures. They all involve loss of consciousness and typically happen without warning.

Regards,

Leza

Source: http://www.jopenaccess.com/blog/epilepsy-a-neurological-disorder-7531.html

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[ARTICLE] Early postoperative seizures (EPS) in patients undergoing brain tumour surgery – Full Text

Abstract

Early postoperative seizures (EPS) are a common complication of brain tumour surgery. This paper investigates risk factors, management and clinical relevance of EPS. We retrospectively analysed the occurrence of EPS, clinical and laboratory parameters, imaging and histopathological findings in a cohort of 679 consecutive patients who underwent craniotomies for intracranial tumours between 2015 and 2017. EPS were observed in 34/679 cases (5.1%), with 14 suffering at least one generalized seizure. Patients with EPS had a worse postoperative Karnofsky performance index (KPI; with EPS, KPI < 70 vs. 70–100: 11/108, 10.2% vs. 23/571, 4.0%; p = 0.007). Preoperative seizure history was a predictor for EPS (none vs. 1 vs. ≥ 2 seizures: p = 0.037). Meningioma patients had the highest EPS incidence (10.1%, p < 0.001). Cranial imaging identified a plausible cause in most cases (78.8%). In 20.6%, EPS were associated with a persisting new neurological deficit that could not otherwise be explained. 34.6% of the EPS patients had recurrent seizures within one year. EPS require an emergency work-up. Multiple EPS and recurrent seizures are frequent, which indicates that EPS may also reflect a more chronic condition i.e. epilepsy. EPS are often associated with persisting neurological worsening.

Introduction

Early postoperative seizures (EPS) are a common complication of brain tumour surgery. EPS are often categorized as acute symptomatic seizures1,2. They are usually felt to reflect acute medical or surgical conditions that may require emergency treatment. This includes haemorrhages, infectious complications and electrolyte disturbances, but also systemic infections and cardiopulmonary disorders resulting in hypotension and hypoxia. Hence, EPS may have potentially severe consequences. They may result in significant and often persisting (neurological) morbidity and reduced quality of life. Furthermore, they usually prolong the patient’s hospital stay. Potential negative consequences include a delayed transfer for rehabilitation therapy, an overall prolonged rehabilitation and, importantly, delayed adjuvant therapy. This latter aspect is of considerable importance e.g. in patients with gliomas and metastasis who will often not realize the benefits of surgery if adjuvant therapy is withhold. In addition, many patients with brain metastases require more or less urgent treatment for their systemic disease.

There is also the issue of distinguishing between incidental or acute symptomatic seizures with no or a very low risk of recurrent seizures and true postoperative chronic epilepsy1,2,3. The latter condition requires chronic treatment with antiepileptic drugs and comes with relevant socioeconomic sequelae such as restriction of driving privileges. This may be a particularly important issue for patients with benign tumours such as many meningiomas who have a good chance of a surgical cure of their tumour. In such cases, the risk of recurrent seizures may well be their only (neurological) health concern4,5.

There is a growing interest in tumour-associated epilepsy6,7. However, relatively few investigators have focused specifically on EPS8,9. Consequently, questions regarding the necessary diagnostic work-up and the use of antiepileptic drugs in cases with EPS are difficult to answer. For the present study, we have therefore reviewed our recent institutional experience with EPS after brain tumour surgery between 2015 and 2017. […]

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[WEB PAGE] Why Did Terms for Seizures Change?

Article written by Mary K. Talbot

In 2017, the International League Against Epilepsy (ILAE) released updated classifications for epilepsy. The new classifications better reflect current scientific understanding of seizures. The classifications were last updated in 1989.

Before this new update, seizures were divided into two broad categories — partial-onset seizures and generalized seizures. Partial-onset seizures originate in one area or side of the brain and generalized seizures start in both sides of the brain.

The new classification considers three main factors when defining seizures:

  1. Point of origin
  2. Awareness level
  3. Behaviors

For example, simple partial seizures have been renamed focal onset aware seizures, and complex partial seizures have been reclassified as focal onset impaired awareness seizures.

Why the changes? Ingrid Scheffer, who led the ILAE effort to reclassify seizures, said the group was focused on creating “transparent language” for seizure types. “We wanted language that patients could understand, not just doctors.”

Current Classification of Types of Seizures

Seizure type is now identified by point of origin, awareness level, and accompanying behaviors.

Point of Origin

The point of origin for each type of seizure is now classified into one of four categories:

  • Focal Onset — Formerly known as a “simple partial seizure,” focal onset seizures originate within networks limited to one hemisphere of the brain. They may be localized to one small area of the brain or more widely distributed.
  • Generalized Onset — These originate within and rapidly engage areas in both sides of the brain at once.
  • Unknown Onset — As the name suggests, the origin of these seizures is unknown.
  • Focal to Bilateral Seizure — These seizures start on one side of the brain and spread to both sides.

Awareness Level

Awareness levels during seizures have four distinguishing features:

  • Focal Aware — During focal aware seizures, a person is aware, but may be unable to talk or respond during a seizure.
  • Focal Impaired Awareness — Formerly known as a “complex partial seizure,” a focal impaired awareness seizure occurs when a person’s awareness is impacted at some point during a seizure.
  • Awareness Unknown — This classification is used when a seizure takes place with no witness to observe awareness levels.
  • Generalized Seizures — Generalized seizures, which affect both halves of the brain, usually always affect a person’s awareness or level of consciousness in some way.

Behaviors

Behaviors that accompany focal onset seizures also have classifications:

  • Focal Motor Seizure — This term describes a seizure accompanied by movement, such as stiffening, thrashing, jerking, or automatic movements like walking or running.
  • Focal Nonmotor Seizure — This is a seizure with other symptoms that precede it, such as changes in thinking, emotions, or sensation.

These behaviors accompany generalized onset seizures:

  • Generalized Motor Seizure — “Tonic-clonic seizures,” with their characteristic stiffening and jerking motions, is still an accurate term. However, the term “grand mal seizure” that often accompanied that description is no longer relevant.
  • Generalized Nonmotor Seizure — “Absence seizures,” with brief changes in awareness that include staring and some repeated movements, is the new classification. This has replaced “petit mal seizures.”

Read more about types of focal seizures and their symptoms.

Read about treatments for focal seizures.

Scientific Progress in Understanding Epilepsy

Understanding the history of epilepsy research can shed light on how and why terminology has changed, and why the current set of terms is the most accurate so far. The ancient Greeks coined the term epilepsy (meaning “to seize”) and attributed the condition to an attack by a demon or a god. Babylonians documented seizures on clay tablets. Ancient Persians believed the source was mental illness, while Chinese physicians more than 2,500 years ago believed epilepsy was caused by an excess of secretions in the brain.

By the 1860s, British neurologist John Hughlings Jackson had determined that seizures were due to activity in the brain. For the first time, he hypothesized that seizures present differently depending upon the part of the brain from which they originated. In the 1930s, this groundbreaking theory inspired Canadian-American neurosurgeon Wilder Graves Penfield to use electrostimulation to simulate the seizure behavior and locate the area of the brain where the onset occurred.

Henri Jean Pascal Gastaut took that research one step further, working with his wife, Yvette, to define five major human electroencephalogram (EEG) patterns. He also discovered Gastaut syndrome (photosensitive epilepsy) and Lennox-Gastaut syndrome (severe childhood encephalopathy). Diagnostic imaging helped Gestaut better understand seizures.

Significant advances in diagnostic imaging have been made in the last 50 years. New imaging tools include computerized tomography (CT scan), magnetic resonance imaging (MRI), single photon emission computerized tomography (SPECT) and positron-emission tomography (PET), magnetic resonance spectroscopy, and magnetoencephalography (MEG). With each new tool, scientists have become better able to understand brain activity.

Collaboration and Education

As scientists gained a deeper understanding of the brain and epilepsy, formal organizations were established to study epilepsy, share knowledge, and improve care. The International Bureau for Epilepsy (IBE) was established in 1961 to study the medical and nonmedical aspects of epilepsy. In 1966, the surgeon general of the United States created the General Public Health Service Advisory Committee on the Epilepsies.

The International League Against Epilepsy took a leadership role in 1969 when it accepted the first “Clinical and electroencephalographic classification of epileptic seizures” at its General Assembly in New York. The new standards created common terminology for epilepsy. A shared set of terminology facilitated improved communication and information-sharing among researchers. Those original classifications were updated in 1981 and 1989 before the most recent update in 2017.

References

  1. Epilepsy: from the early civilizations to modern days — Hektoen International
  2. Brief History of Epilepsy & Seizures — University Health Network
  3. Highlights in the History of Epilepsy: The Last 200 Years — Hindawi
  4. International Bureau for Epilepsy
  5. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology — International League Against Epilepsy
  6. 2017 Revised Classification of Seizures — Epilepsy Foundation
  7. The ILAE seizure and epilepsy classifications: Critique, response and the way forward — International League Against Epilepsy

via Why Did Terms for Seizures Change? | MyEpilepsyTeam

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[ARTICLE] Epileptic Disorders – Epilepsy and cannabidiol: a guide to treatment – Full Text

The therapeutic potential of cannabis-related products has been suggested for many years (Perucca, 2017), and interest in the subject in recent decades has fluctuated in parallel with perceptions of cannabis and changes in legislation. With the realisation that (-)-trans-Δ-9-tetrahydrocannabinol (THC) is a component with prominent psychoactive properties, attention shifted to the potential therapeutic value of cannabidiol (CBD). In recent decades, interest in the therapeutic value of CBD-containing products, as anti-inflammatory, anti-emetic, anti-psychotic, and anti-epileptic treatments, has emerged for a wide range of conditions. However, the supporting data is principally based on anecdotal or in vitro experiments with supraphysiological concentrations. In addition, other compounds that may be present in artisanal CBD preparations may have independent physiological effects, leading to inevitable confusion regarding the effectiveness and safety of the preparations.

It is only within the last two years that Class I evidence has become available for a pure form of CBD, based on placebo-controlled RCTs. In the light of this recent evidence, this review aims to provide information on the current status of what is known about CBD as a therapeutic option for epilepsy, which will likely be of value to neurologists and epileptologists. This paper contributes to the following competencies of the ILAE curriculum (Blümcke et al., 2019): “Demonstrate up-to-date knowledge about the range of pharmacological treatments for epilepsy ; Recommend appropriate therapy based on epilepsy presentation ; Demonstrate up-to-date knowledge about special aspects of pharmacological treatment ”.

LEGISLATION

Laws regarding the use of raw herbal cannabis, cannabis extracts and cannabinoid-based medicines differ between countries (Abuhasira et al., 2018; Specchio et al., 2020). Recreational use of cannabis has been legalised in Canada and Uruguay, as well as 11 states and the District of Columbia in the US. More restricted recreational use has been adopted in Georgia, South Africa, Spain, and The Netherlands. The use of herbal cannabis for medicinal purposes is now authorised in a number of countries, including Argentina, Australia, Canada, Chile, Colombia, Croatia, Ecuador, Cyprus, Germany, Greece, Israel, Italy, Jamaica, Lithuania, Luxembourg, North Macedonia, Norway, the Netherlands, New Zealand, Peru, Poland, Switzerland, and Thailand, as well as a number of states in the US.

Cannabis and cannabis extracts have not been approved by the FDA or the European Medicines Agency (EMA), although cannabinoid-based products have been approved by the FDA as well as by 23 European countries and Canada. In some cases, authorisation is specific to certain indications, while in others the choice of indication may be dictated by the physician (Abuhasira et al., 2018).

In the European Union, CBD, in contrast to THC, is not a controlled substance and according to EU law, CBD products must not contain more than 0.2% THC. Several companies within the EU produce and distribute CBD-based products obtained from inflorescences of industrial hemp varieties. No analytical controls are mandatory and no legal protection or guarantees regarding the composition and quality is required. An obligatory testing and basic regulatory framework to determine the indication area, daily dosage, route of administration, maximum recommended daily dose, packaging, shelf life, and stability is also not required. Much of the ongoing confusion results from whether such products should be regulated as a food, a supplement, or medicine.

It is beyond the scope of this review to provide details for individual countries. However, physicians considering prescribing cannabis related products should be fully aware of the relevant legislation in relation to the heath care service for their specific geographical location. Since the situation can be complex, provision and use of guidelines from recognised national professional associations and or governmental bodies can be extremely helpful. For example, in the UK, such guidelines have been provided by the British Paediatric Neurology Association (BPNA, 2018) and the National Institute for Health and Care Excellence (NICE, 2019). In both, to prescribe a cannabis related product for medicinal use for epilepsy, the prescriber must be on the Specialist Register (Reference: Section 34D of the Medical Act 1983) and the prescription should be made by a consultant paediatric neurologist. Within the UK, responsibility for the prescribing and potential adverse effects of a cannabis related product remain with the prescribing clinician. Thus, clinicians are advised to be aware of the General Medical Council (GMC) guidance on prescribing unlicensed medication (GMC, 2019), and to investigate whether medical protection insurance and hospital indemnity will cover them for prescription of unlicensed cannabis related products. Should a doctor feel under pressure to prescribe a medication that they believe is not in the patient’s interests, then paragraph 5d of the GMC guidance “Consent: patients and doctors making decisions together” is relevant (GMC, 2008). It states: “If the patient asks for a treatment that the doctor considers would not be of overall benefit to them, the doctor should discuss the issues with the patient and explore the reasons for their request. If, after discussion, the doctor still considers that the treatment would not be of overall benefit to the patient, they do not have to provide the treatment. But they should explain their reasons to the patient, and explain any other options that are available, including the option to seek a second opinion”.

ARTISANAL PRODUCTS ADVERTISED WITH CBD CONTENT

The known physiologically active components of cannabis include cannabinoids, terpenoids, and flavonoids. Plant or phyto cannabinoids are unique to the cannabis plant. Over a hundred different cannabinoid compounds have been isolated from the cannabis plant, for which various chemovars exist (Cannabis indicaruderalis, and particularly sativa being the most common). Of these compounds, only 16 exist in meaningful concentrations; these include THC, CBD, cannabichromene (CBC), and cannabigerol (CBG) (as both acid and varin forms). The majority of animal and in vitro studies have focussed on THC and CBD, and whereas the effect of THC is less clear and appears to exhibit both proconvulsant and anticonvulsant properties under different conditions, CBD demonstrates clear anti-convulsant properties, making it a focus as a potential treatment for epilepsy.

An abundance of CBD-related products is currently commercially available, ranging extensively in purity, content of effective compounds and price. The global market for these products is considerable and according to the Centre for Medicinal Cannabis (2019) in the UK, at the current rate, the market will be worth one billion pounds/year in 2025.

Importantly, the content of CBD-related products is dependent on the type of cannabis plant as well as the different parts of the plant and growing conditions. Hemp and marijuana may be considered as different varieties of the same cannabis plant; whereas hemp is low in all cannabinoids including THC (≤0.3%), marijuana has a higher THC content (>0.3%).

Hemp seed oils (from seeds) contain minimal cannabinoids (i.e. THC); this depends principally on the extent of washing prior to subsequent processing, as cannabinoids in the flowers and leaves appear to transfer to the outer coating or husk of the seed during harvesting and preparation. Cannabis oils (from flowers and leaves of marijuana) contain variable levels of CBD and THC, depending on the chemovars. CBD-enriched oils (from flowers and leaves of hemp) contain high levels of CBD and some THC. The maximum ratio of CBD to THC that can be achieved without subsequent purification, irrespective of the chemovar, is 20:1, however, it should be noted that THC is significantly more potent (50-100-fold) than CBD. Moreover, for CBD-enriched oils advertised as “high CBD/low THC” content, in order to obtain CBD at similar doses to those used in randomised controlled trials (see below), the meaningful amount of THC may be higher than expected. For a child of 18 kg taking 300 mg CBD/day, this equates to 15 mg THC/day, based on a 20:1 CBD:THC ratio in preparations, which is similar to the maximum daily dosage of marinol or dronabinol, a synthetic Δ-9-THC (prescribed for chemotherapy-induced nausea and vomiting as well as weight loss in cancer or AIDS/HIV patients).

Galenic products are available in the form of cannabis decoction filter bags and cannabis extracts as oils, creams, and supplement capsules. Supplements appear to be the most common form, often referred to as “CBD dietary supplements” or “CBD-enriched oils”, obtained from extraction of different Cannabis sativa L. chemovars with high CBD content. Of the CBD-enriched oils, there are six main varieties available on the market in Europe: Bedrocan, Bedrobinol, Bediol, Bedica, Bedrolite and Bedropuur (table 1).

It is important to emphasise that these products demonstrate significant variation with regards to content, which is dependent not only on the initial source of the plant (e.g. the use of fertilisers and pesticides) but also the method by which they are prepared (Carcieri et al., 2018; Pegoraro et al., 2019; Bettiol et al., 2019). There are a number of different methods to prepare such oils, the most common being “supercritical CO2 extraction”. This leads to an extract rich in lipophilic cannabis components plus waxes, however, different biologically active compounds can be isolated during subsequent procedures, including omega-3 fatty acids, vitamins, terpenes, flavonoids, and other phytocannabinoids such as CBC, CBG, cannabidivarin (CBDV), and cannabinol (CBN) as a degradant (according to how the fresh the materials is) (Calvi et al., 2018). Terpenes represent the largest group (with more than 100 different molecules) of cannabis phytochemicals; these can easily cross cell membranes and the blood-brain barrier. Moreover, a synergistic effect between cannabinoids and terpenes has been hypothesised, but not proven (Russo, 2011; Aizpurua-Olaizola et al., 2016; Santiago et al., 2019).

It is also worth mentioning that an adequate dose of CBD based on commercially available CBD-enriched oils (up to 10-20 mg/kg/day), similar to doses used in randomised controlled trials (see below), comes at considerable financial cost to the family; in excess of 500 euros per month.

PRODUCT LABELLING

When it comes to CBD-enriched oils, there are major concerns regarding THC, CBD and terpene concentration, as well as appropriate preparation methods and storage conditions. These may vary significantly (Carcieri et al., 2018; Pavlovic et al., 2018), leading to insufficient quality control. Moreover, laboratory analyses have shown that the cannabinoid content is often not reflected on the marketing label (Vandrey et al., 2015).

Based on a report by the Centre for Medicinal Cannabis (2019) in the UK, there is an urgent need for a move towards accurate labelling regarding CBD content, as many products are sold with quantities of CBD which are well below those used in clinical trials. In the study by Bonn-Miller et al. (2017), the label accuracy of 84 products was analysed. Overall, CBD concentration ranged from 0.10 to 655.27 mg/mL (median: 9.45 mg/mL; median labelled concentration: 15.00 mg/mL). Of the products tested, 42.85% (n = 36) products were under-labelled, 26.19% (n = 22) were over-labelled, and 30.95% (n = 26) were accurately labelled. The level of CBD in the over-labelled products in the study is similar in magnitude to levels that triggered a warning from the US Food and Drug Administration (FDA) to 14 businesses in 2015-2016, indicating that there is a continued need for federal and state regulatory agencies to take steps to ensure accurate labelling of these consumer products.

Under-labelling is of less concern, as CBD itself does not appear to be susceptible to abuse and there have been no reported serious adverse effects (AEs) at high doses, however, the THC content observed may be sufficient to produce intoxication or impairment, especially among children. Clear labelling regarding the exact concentration of CBD is not yet mandatory, and there is clearly a need to introduce stricter legislation regarding accurate content labelling.

EFFECTIVENESS AS A TREATMENT FOR EPILEPSY

Anecdotal reports have fuelled public interest and, understandably, have inspired families to seek CBD-related products for the treatment of drug-resistant epilepsy (Filloux, 2015). The most well-known report is that of Charlotte, a five-year-old girl in the US who was diagnosed in 2013 with SCN1A-confirmed Dravet syndrome, with up to 50 generalised tonic-clonic seizures per day. Following three months of treatment with high-CBD-strain cannabis extract (later marketed as “Charlotte’s Web”), her seizures were reported to have reduced by more than 90% (Maa and Figi, 2014). Other anecdotal reports suggesting that CBD may improve seizure control as well as alertness, mood and sleep have also been documented (Porter and Jacobson, 2013; Hussain et al., 2015; Schonhofen et al., 2018).

A number of studies have investigated the effect of oral cannabis extracts on intractable epilepsy, based on parental reporting. These include the study by Press et al. (2015) of 75 patients (23% with Dravet syndrome and 89% with Lennox-Gastaut syndrome) in the US and Tzadok et al. (2016) of 74 patients in Israel over an average of six months; 50% seizure reduction was reported in 33%, and 50-75% seizure reduction in 34% in the two studies, respectively. In a retrospective study by Porcari et al. (2018) of 108 children with epilepsy in the US, the addition of CBD oil over an average of six months resulted in >50% seizure reduction in 29% patients, with 10% becoming seizure-free.

Based on a meta-analysis (n=670), Pamplona et al. (2018) provide evidence in support of the therapeutic value of high-content CBD treatments (CBD-rich cannabis extract or purified CBD). The results indicated a favourable effect for both patients with CBD-rich extracts (6.1 mg/kg/day CBD) and purified CBD (27.1 mg/kg/day), which was in fact more pronounced in patients taking the CBD-rich extracts. This may provide evidence in favour of the inclusion of other components within CBD-rich extracts offering beneficial entourage effects.

Overall, the studies on CBD-enriched oils indicate a 50% reduction in seizures in roughly 30-40% patients. However, it should be emphasised that these are uncontrolled studies with heterogeneous CBD preparations, the CBD content of which varied significantly (estimated at Press et al. (2015), the effect of cannabis extracts was investigated in a cohort of paediatric patients with epilepsy in a single tertiary epilepsy centre in Colorado, where the law on cannabis-related products is more relaxed. Interestingly, the overall responder rate (47%) for patients who had moved to Colorado for treatment was greater than that (22%) of those who were already living in Colorado, indicating a possible positive reporting bias and the need for appropriately controlled studies.

ADVERSE EVENTS

The studies described above reported AEs in 40-50% patients, including increased seizure frequency, gastrointestinal disturbances/diarrhoea, appetite alteration, weight changes, nausea, liver dysfunction, pancreatitis and, particularly, somnolence and fatigue. More serious effects included developmental regression, abnormal movements and status epilepticus.

More long-term effects regarding cannabis-derived products have generally been gathered based on indirect evidence, however, no hard conclusions can be drawn, mainly due to methodological limitations (dosage of THC and other cannabis-derived products, duration of exposure, concordant addiction to other drugs, genetic factors, psychiatric comorbidity, etc.). Long-term data from studies on prenatal and adolescent exposure to cannabis products indicate, however, a possible negative and lasting effect on cognitive and, particularly, behavioural functions (Lagae, 2020). Moreover, the externalisation of behavioural problems and a decrease in IQ have been reported as a result of chronic cannabis use. Clearly, long-term studies using large childhood epilepsy cohorts are needed on the chronic use of CBD and cannabis-related products.

PURIFIED CBD (EPIDIOLEX/EPIDYOLEX®)

A purified preparation of CBD is available from GW Pharmaceuticals plc, under the name of Epidiolex/Epidyolex® (>98% CBD). Interest has so far largely focussed on Epidiolex as an add-on drug for cases of epilepsy. Another product, Sativex® (also known as Nabiximol) (51% THC, 49% CBD), made by the same company as a refined extract, has been approved for cases of neuropathic pain, spasticity, overactive bladder and other symptoms of multiple sclerosis in some countries.

Purified CBD has been shown to demonstrate positive effects against a wide spectrum of seizures and epilepsy based on animal models (Rosenburg et al., 2017a). While the precise mechanism of action of CBD in the control of epileptic seizures in humans remains unknown, recent evidence suggests a role in modulating intracellular Ca2+ (including effects on neuronal Ca2+ mobilisation via GPR55 and TRPV1) and modulating adenosine-mediated signalling (Gray and Whalley, 2020).

In 2017 and 2018, the first randomised controlled trials for pharmaceutically prepared Epidiolex were published for Dravet syndrome and Lennox-Gastaut syndrome, respectively (Devinsky et al., 2017; Thiele et al., 2018), and in June 2018, the FDA approved CBD as an add-on antiepileptic drug for patients with Lennox-Gastaut syndrome or Dravet syndrome over the age of two. Epidiolex was also later approved by the EMA in September 2019 for patients over two years of age with Dravet syndrome and Lennox-Gastaut syndrome, in conjunction with clobazam. However, accessibility to Epidiolex outside of Europe and the US remains variable (e.g. only patients involved in RCTs may be eligible), due to a lack of approval and legal reform by central agencies. While such reform is clearly welcomed, it cannot come fast enough for those who may benefit.

PHARMACOLOGY AND DRUG INTERACTIONS

As a therapeutic drug, the pharmacokinetic profile of CBD exhibits low bioavailability, significant protein binding (99% protein binding capability), and interactions with various metabolic pathways in the liver, including CYPs that are susceptible to pharmacogenetic variability and drug interactions. However, as CBD interacts with many enzymes, it is cleared quickly and is therefore less susceptible to modulation by drugs that affect metabolising enzymes. Moreover, the pharmacokinetic profile of CBD seems relatively unaffected by inhibitors and inducers or genetic background. The bioavailability of oral oil formulations is limited (<6%) due to extensive first pass metabolism in the liver (Bialer et al., 2017, 2018).

CBD may exhibit numerous interactions with AEDs (Johannessen Landmark and Patsalos, 2010; Johannessen and Johannessen Landmark, 2010; Johannessen Landmark et al., 2012, 2016; Patsalos, 2013a, 2013b) including both potent enzyme inducers (such as carbamazepine and phenytoin) and inhibitors (such as stiripentol, felbamate and valproate) (table 2), however, the clinical significance of these interactions may not be meaningful. The most obvious and clinically significant interaction between CBD and other concomitantly used drugs, based on clinical trials, is that with clobazam. CBD, via enzyme inhibition (CYP2C19), may lead to an increase (up to five-fold) in its less potent metabolite, N-desmethylclobazam (Geffrey et al., 2015; Devinsky et al., 2018a), leading to toxicity (principally manifesting as sedation [Gaston et al., 2017]), which may occur at even low levels (1 mg/kg/day) (unpublished observations; Johannessen Landmark). In addition, concurrent clobazam may lead to increased 7-hydroxy-cannabidiol (an active metabolite of CBD) (Morrison et al., 2019), which arguably may lead to better seizure control by boosting the effect of CBD, however, studies with and without clobazam are needed to confirm this. Other AEDs with a similarly increased effect, concomitant with CBD, may include topiramate, rufinamide, zonisamide and eslicarbazepine (Gaston et al., 2017; Franco and Perucca, 2019). There are therefore still a number of unanswered questions regarding the pharmacology of CBD (Johannessen Landmark and Brandl, 2020; Brodie and Ben-Menachem, 2018).

The clinical impact of such interactions in the individual patient is difficult to predict. Patients should be systematically questioned about efficacy, tolerability and adherence, and serum concentrations should be measured if possible and dosages adjusted accordingly to optimise each patient’s treatment.

EFFICACY AS A TREATMENT FOR EPILEPSY

The first trials for purified CBD (Epidiolex) were launched as an expanded access programme in 2014 for patients with significant medically refractory epilepsy in the form of an open-label, non-controlled trial for compassionate use (Devinsky et al., 2016). Patients (n=214) with intractable seizures (at least four weekly) were monitored over a 12-week period (relative to a four-week baseline) with initial CBD doses of 2.5-5 mg/kg/day, increasing weekly to 25 or 50 mg/kg/day. Overall, a 36.5% median reduction of motor seizures was reported (49.8% for Dravet syndrome patients), and five patients were free of all motor seizures (of the patients with motor and atonic seizures, 39% and 56% showed a >50% reduction of seizures, respectively). This programme was continued and interim data on >600 patients over a 96-week period were published in 2018 by Szaflarski et al., revealing a reduction of median monthly convulsive seizures by 51% (52% with ≥50% seizure reduction) and total seizures by 48% at 12 weeks, with similar results over the 96-week period.

With these very encouraging results, shortly after the initial launch of this programme, controlled trials for Epidiolex were established for Dravet syndrome (Devinsky et al., 2017) and Lennox-Gastaut syndrome (Thiele et al., 2018; Devinsky et al., 2018b). For further details regarding these trials, refer to Nabbout and Thiele (2020).

Lennox Gastaut syndrome

In the two Lennox-Gastaut syndrome double-blind placebo-controlled trials, patients (n=171 and 225) were administered CBD at 20 mg/kg/day (GWPCARE4; Thiele et al., 2018) or 10 or 20 mg/kg/day (GWPCARE3; Devinsky et al., 2018b) over a 14-week treatment period (including a titration phase of two weeks starting with a dose of 2.5 mg/kg/day, titrated to 10 or 20 mg/kg/day), and data were compared relative to a four-week baseline observation period. CBD in an oral solution or placebo was administered as add-on to current AEDs. For CBD at 20 mg/kg/day, the median percentage reduction in total seizure frequency was 41% (vs 13.7% placebo) and 38.4% (vs 18.5% placebo), and monthly median decrease in drop seizures was reported to be 44% (vs 22% placebo) and 42% (vs 17% placebo) in the two trials, respectively. At 10 mg/kg/day, the median percentage reduction in total seizure frequency was similar at 36.4% (vs 18.5% placebo), and monthly median decrease in drop seizures was 37% (vs 17% placebo).

Lennox-Gastaut syndrome patients who enrolled in these RCTs were also invited to enter an open-label study (GWPCARE5; Thiele et al., 2019a). The interim data after 48 weeks of treatment revealed a 48-60% median decrease in drop seizure frequency and a 48-57% median decrease in monthly total seizure frequency relative to baseline (figure 1).

Based on the patient or caregiver Clinical Global Impression (CGI) scale, overall improvements were reported in patients of each trial: 58% patients (compared to 34% in the placebo group) in the study of Thiele et al. (2018), 57% and 66% in the 20 mg/kg/day and 10 mg/kg/day group, respectively (compared to 44% in the placebo group) in the study of Devinsky et al. (2018b), and 88% at 24 weeks (also similar at 38 and 48 weeks) in the open-label study of Thiele et al. (2019a).

Dravet syndrome

For Dravet syndrome, two trials involved an initial double-blind placebo-controlled trial (n=120) (GWPCARE1B; Devinsky et al., 2017) and a later open-label extension programme (GWPCARE5; Devinsky et al., 2019). An additional trial has also recently been completed (GWPCARE2; Miller et al., 2019). For the former, similar to the Lennox-Gastaut syndrome trials, patients were administered 20 mg/kg/day CBD over a 14-week treatment period, and data were compared relative to a four-week baseline period. For the open-label extension programme, a subset of these patients together with participants from the recently completed GWPCARE2 trial were enlisted (n=189) and followed over 48 weeks. For the controlled trial, during the treatment period, the median percent reduction of convulsive seizures and total seizures was 39% and 29% in the CBD arm relative to 13% and 9% in the placebo arm, respectively. The difference in median percent reduction in non-convulsive seizures was not significant. During the open-label extension programme, the median percent reduction of total seizures continued at between 39% and 51% over a 48-week period (figure 2).

As part of the expanded access programme mentioned above, the long-term effect of add-on CBD at up to 25-50 mg/kg/day over a period of 144 weeks was reported for Dravet syndrome and Lennox-Gastaut syndrome patients (Laux et al., 2019). Monthly major motor seizures were reduced by 50% and total seizures by 44%, with consistent reductions in both seizure types across the treatment period, thus supporting CBD as a long-term treatment option.

Based on the patient or caregiver CGI scale, overall improvements were reported for both trials: 62% patients (compared to 34% in the placebo arm) in the study of Devinsky et al. (2017), and 85% at 48 weeks in the open-label study of Devinsky et al. (2019).

Tuberous sclerosis complex

A clinical trial (GWPCARE6) for Epidiolex as add-on treatment in patients with tuberous sclerosis complex (TSC) was completed earlier this year and has also revealed promising results (Thiele et al., 2019b). Patients were randomised into two groups with Epidiolex (25 or 50 mg/kg/day) or placebo. Of the 201 patients who completed the study, total seizure frequency was decreased by 48% (p=0.0013), 48% (p=0.0018) and 27%, and 50% seizure reduction in 36% (p=0.0692), 40% (p=0.0245), and 22% in the 20 mg/kg/day, 50 mg/kg/day and placebo groups, respectively. An overall improvement, based on the caregiver CGI scale, was reported for 69% (p=0.0074), 62% (p=0.580) and 40% in the three groups, respectively. In conclusion, Epidiolex significantly reduced seizures in TSC patients. The therapeutic effect of the lower 25 mg/kg/day concentration was similar to that of the higher 50 mg/kg/day dose, and since the latter was associated with more AEs (see below), the 25 mg/kg/day dose would therefore be indicated for these patients.

Other syndromes

Based on an open-label trial for compassionate use, CBD was tested as a treatment for CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes over a 12-week period (n=55) (Devinsky et al., 2018c). The mean decrease in convulsive seizure frequency was 51.4% (n=35). Studies are underway to evaluate CBD efficacy for a broader range of epilepsy syndromes and more than 20 trials are currently listed at ClinicalTrials.gov.

Overall, evidence from open-label studies suggests a favourable effect of CBD as an add-on treatment for a number of severe epileptic conditions and the controlled trials for Lennox-Gastaut syndrome, Dravet syndrome and TSC provide a clearer picture of the positive effect of CBD, in some cases even correlating with seizure freedom. A general positive trend for quality of life (particularly in Lennox-Gastaut syndrome patients), sleep behaviour (particularly in Dravet syndrome patients) and adaptive behaviour was reported. There were also particular improvements in the socialisation domain and communication domain for Dravet syndrome and Lennox-Gastaut syndrome patients, respectively. In the prospective, open-label clinical study by Rosenberg et al. (2017b), in which caregiver-reported quality of life (n=48) was evaluated for a subset of patients treated with CBD for 12 weeks, improvements (in energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behaviour and global QOL) were not related to changes in seizure frequency or AEs, suggesting that CBD may have beneficial effects on patient QOL, distinct from anti-seizure effects, however, this should be confirmed in controlled studies.

ADVERSE EFFECTS

In contrast to artisanal CBD-related products, the AEs associated with purified CBD have been more clearly demonstrated based on the open-label trials and, particularly, the randomised, double-blind placebo-controlled trials (Anciones and Gil-Nagel, 2020).

Based on the collective data from the controlled trials, AEs were frequently reported (86% in CBD groups and 76% in placebo groups), however, the vast majority of AEs were mild and moderate. These included somnolence, decreased appetite, pyrexia and diarrhoea, followed by other less frequent AEs such as vomiting, fatigue and upper respiratory infections (table 3). Most AEs appeared within the first two weeks of treatment. Serious AEs were far less common (affecting 19% of CBD groups and 9% of placebo groups). These included, in particular, somnolence, pyrexia, convulsion, rash, lethargy and elevated transaminases (>three times the normal upper limit). The latter occurred in 16% patients in the CBD groups and 1% in the placebo groups. Moreover, in >79-100% of the cases with elevated transaminases, patients were concomitantly taking valproate.

No seizure worsening, suicidal ideation or deaths related to the treatment were reported. It should be emphasised, however, given the novelty of Epidiolex, that long-term AEs are currently unknown.

In the recent TSC trial with the higher dose of 50 mg/kg/day CBD (Thiele et al., 2019b), AEs were common but similarly overall reported as mild and moderate (93%, 100% and 95% in the 25 mg/kg/day; 50 mg/kg/day and placebo groups, respectively). The most common AEs were diarrhoea, decreased appetite, and somnolence, and treatment discontinuation due to AEs occurred in 11%, 14% and 3%, respectively. Elevated liver enzymes were reported in 12% (n=9) and 25% (n=18) in the 25 mg/kg/day and 50 mg/kg/day, respectively (of those, 81% were also taking valproate).

RECOMMENDATIONS FOR USE

CBD is administered orally as an oil solution. In open-label studies, doses mostly up to 25 mg/kg/day were used, and in the controlled studies, higher doses up to 50 mg/kg/day were used. The studies on Lennox-Gastaut syndrome, however, show that a significant proportion of children respond to doses of as little as 10 mg/kg/day. Therefore a “start slow” and “increase on a case-by-case basis” strategy is recommended. A starting dose of 5 mg/kg/day, divided in two doses, would appear to be adequate. This dose should be increased to 10 mg/kg/day after two weeks of treatment. Thereafter, the individual’s response should be carefully observed. The required observation time strictly depends on baseline seizure frequency before the administration of CBD. If the drug is well tolerated but not sufficiently effective, the dose should be slowly increased in increments of 5 mg/kg/day, as long as it is tolerated, up to a maximum of 20-25 mg/kg/day (table 4).

As mentioned above, special care should be taken if both CBD and clobazam are administered, since the addition of CBD may lead to an increase (up to five-fold) in its less potent metabolite, N-desmethylclobazam. A toxic benzodiazepine level may manifest as fatigue, somnolence, ataxia, a decrease in cognitive function or behavioural changes. Clinically, these are difficult to distinguish from the possible AEs of CBD itself and monitoring of clobazam/N-desmethylclobazam levels is therefore recommended. Baseline therapeutic drug monitoring should be performed before administration of CBD and subsequently after each increase. If a significant increase in benzodiazepine level is observed, the dose of clobazam should be reduced (and then checked), according to an estimate based on linear kinetics. Like CBD, however, stiripentol inhibits the same P450 subtype 2C19 (CYP2C19), and an increase in benzodiazepine level may not, therefore, occur if the patient is already on stiripentol (Devinsky et al., 2018b). It is highly recommended to follow serum concentrations of all drugs when initiating CBD as a basis for appropriate dosage adjustment. This includes psychotropic drugs (mood stabilisers, antidepressants, and antipsychotics) in order to reveal possible pharmacokinetic interactions or reasons for poor clinical effects or observed AEs.

Pharmacogenetic testing for CYP2C19 could be performed if a poor metabolizer genotype is suspected based on unexpectedly high levels of CBD relative to the dose.

Finally, biochemical markers of toxicity should be measured, particularly regarding liver enzymes in conjunction with valproate (Gaston et al., 2017; Devinsky et al., 2018a). In the controlled studies, increased liver enzymes led to withdrawal of CBD if levels were more than three times the upper normal limit in the presence of any symptoms (fever, rash, nausea, abdominal pain or increased bilirubin) or eight times higher in the absence of such symptoms. In rare cases, an increase in enzymes was observed with 20 mg/kg/day CBD without concomitant use of valproate, but not with lower doses of CBD. Overall, the increase in liver enzymes was reversible in about half the cases, without taking any action; in the remaining cases, CBD was withdrawn, leading to normalisation of levels (Devinsky et al., 2018b). A mild increase in enzyme levels may be observed over a few weeks before taking any action, however, as levels become too high, CBD or valproate should be withdrawn or reduced, according to the benefit of each.

CONCLUSIONS

Given the range of, and easy access to CBD-enriched oils on the market, alongside the fallacious perception that “natural” products may be safer with fewer AEs than conventional AEDs, it is clear to see why such products are popular. However, analytical controls for CBD-enriched products are not mandatory, leaving consumers with no legal protection or guarantees about the composition and quality of the product they are acquiring. Currently, CBD-enriched products are not subject to any obligatory testing or basic regulatory framework to determine the indication area, daily dosage, route of administration, maximum recommended daily dose, packaging, shelf life or stability. The content of these products is therefore highly variable and although components other than CBD are present which may even be beneficial, there is currently no way this can be ascertained or controlled.

In contrast, purified CBD, in the form of Epidiolex/Epidyolex, is a standardised pharmaceutical preparation that is subject to minimal variability. Based on controlled trials, Epidiolex appears to be an effective treatment option for patients with Dravet syndrome, Lennox-Gastaut syndrome and TSC and has a relatively good safety profile, although it should be emphasised that, at least from the controlled trials, CBD does not outperform other drugs and will by no means represent a silver bullet for everyone. It does, however, add to the arsenal of available add-on drugs against these severe forms of epilepsy, in some cases offering substantial benefits.

Given the range of different seizure types associated with Dravet syndrome, Lennox-Gastaut syndrome and TSC, CBD would appear to have a favourable effect on a large spectrum of convulsive (consistent with preclinical data), rather than non-convulsive seizures (Devinsky et al., 2017), namely clonic, myoclonic, myoclonic-astatic, and generalised tonic-clonic seizures. It should be noted, however, that the effect of CBD on specific types of seizures was not described in detail in the controlled trials and further studies will therefore be required to address this. Other forms of intractable epilepsy cases have been investigated in open-label trials (CDKL5 deficiency disorder and Aicardi, Dup15q and Doose syndromes; Devinsky et al., [2018c]), and more than 20 trials are currently listed at ClinicalTrials.gov (including Rett syndrome and other forms of intractable epilepsy). Although these syndromes collectively represent a small fraction of the epilepsy population, clinical trials in the future may lead to CBD or indeed other cannabinoids being indicated more broadly across the spectrum of epilepsy syndromes.

DISCLOSURES

A. Arzimanoglou receives salary support from the University Hospitals of Lyon (HCL). His work is also partly supported by the European Union grant for the coordination of the EpiCARE European Reference Network. He has a mission of Editor-in-Chief for the ILAE educational journal Epileptic Disorders and of Associate Editor for the European Journal of Paediatric Neurology. He is an investigator on research grants awarded to HCL, France and Sant Joan de Deu Hospital Barcelona from the Caixa Foundation, GW Pharma and UCB; he has received travel expenses or consulting fees from Advicenne Pharma, Amzell, Arvelle, Biomarin, Eisai, GW Pharma, Lündbeck, Sanofi, Shire, Takeda, UCB Pharma, Zogenix. R. Nabbout receives salary from APHP and university Paris Descartes. She reports grants from EU (EJP-RD, Horizons 2020, and FP7), research grants from Shire, Livanova, Eisai and UCB, consulting and lecturer fees from Eisai, Advicenne Pharma, Takeda, Biomarin, Lundbeck, Zogenix, novartis, and GW pharma, outside the submitted work. Antonio Gil-Nagel has received support from Zogenix, Bilal, Stoke Therapeutics, GW, UCB, Arvelle Therapeutics, Sanofi, Marinus Pharma. Nicola Specchio has received grant support and fees for advisory board participation from GW Pharma. J. Helen Cross has acted as an investigator for studies with GW Pharma, Zogenix, Vitaflo and Marinius. She has been a speaker and on advisory boards for GW Pharma, Zogenix, and Nutricia; all remuneration has been paid to her department. Her work is supported by the NIHR Biomedical Research Centre at Great Ormond Street Hospital & University College London. U. Brandl, Lieven Lagae, Cecilie Johannessen Landmark, Oliver Gubbay, and EA. Thiele have no disclosures. The workshop was supported by an educational grant from the Fundació Sant Joan de Déu (Barcelona, Spain) and the Association ESEFNP (Lyon, France).

a Collaborators, Members of The Cannabinoids International Experts Panel: Stéphane Auvin (France), Mar Carreno (Spain), Richard Chin (UK), Roberta Cilio (Belgium), Vincenzo Di Marzo (Italy), Maria Del Carmen Fons (Spain), Elaine Hughes (USA), Floor Janssen (The Netehrlands), Reetta Kalvilainen (Finland), Tally Lerman-Sagie (Israel), Maria Mazurkiewicz-Bełdzińska (Poland), Nicola Pietrafusa (Italy), Georgia Ramantani (Switzerland), Sylvain Rheims (France), Rocio Sánchez-Carpintero (Spain), Pasquale Striano (Italy), Ben Whalley (UK).

via John Libbey Eurotext – Epileptic Disorders – Epilepsy and cannabidiol: a guide to treatment

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