Posts Tagged AEDs

[WEB PAGE] Seizures and epilepsy

Author(s): Rani Haley Lindberg, Devin Wells MDOriginally published: August 7, 2012 Last updated: April 5, 2016

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disease/disorder:

Definition

Seizure is the transient onset of paroxysmal events due to abnormal electrical activity within the brain as a result of excessive or synchronous neuronal activity.1

  • Acute symptomatic seizures: seizures resulting from acute central nervous system (CNS) insult including but not limited to metabolic, toxic, structural, infectious, or inflammatory insults.2
  • Unprovoked seizures: seizures that occur in the absence of active CNS insult or beyond the time interval estimated for acute seizures.2
  • Seizures can be focal (with or without dyscognitive features) or generalized. Generalized seizures include absence, tonic-clonic, atonic, and myotonic seizures.
  • Status epilepticus denotes that the seizure is prolonged or immediately recurrent without return of consciousness.

Epilepsy is a brain disorder in which there is a chronic underlying CNS disorder resulting in unprovoked, recurring seizures

Etiology

Seizure precipitants include but are not limited to the following:

  • Traumatic brain injury
  • Hypoxic-ischemic events in the brain
  • Intracranial hemorrhage
  • Infection of the central nervous system
  • Metabolic disorder
  • Congenital abnormalities of the brain
  • Neurodegenerative disorders
  • Drug withdrawal or intoxication
  • Brain tumors/mass lesions
  • Fever
  • Primary or idiopathic epilepsy (unknown cause)

While seizures can be unprovoked, in some cases they may be triggered by factors such as fatigue, sleep deprivation, or flickering lights.

Epidemiology including risk factors and primary prevention

According to the World Health Organization 2015 update, there are approximately 50 million people world-wide who are living with epilepsy: a prevalence of 4 to 10 per 1000 people. Around 5% of the population will have at least 1 seizure within their lifespan.3 Incidence of neonatal seizures is 1-1.2% of live births. Younger children are at a higher risk if they have congenital, genetic, or developmental conditions; in adults, neoplastic, vascular, and degenerative etiologies are more common. The highest incidence of epilepsy occurs at the extremes of life. Men are at higher risk than women for epilepsy.

Focal seizures are the most common seizure type, yet generalized seizures are more common in children. Seizures developing 1 week post-TBI occurs in 14-53% of the moderate to severe TBI survivors. 50% of TBI survivors with penetrating brain injuries develop epilepsy. In individuals aged 15 to 24, TBI is the leading cause of epilepsy.

Patho-anatomy/physiology

An impairment of the biochemical processes at the neurotransmitter and ion channel level causes hyperexcitability and neuronal hypersynchrony. Seizures are a result of this abnormal and excessive neuronal activity because of an imbalance between excitatory and inhibitory forces within the brain.

The primary excitatory neurotransmitter in the brain is glutamate, and the primary inhibitory neurotransmitter is gamma-aminobutyric acid (GABA). Antiepileptic drugs (AEDs) facilitate neuronal inhibition and/or reduce excitation.

Disease progression including natural history, disease phases or stages, disease trajectory (clinical features and presentation over time)

Individuals in whom the sole cause of a seizure is a correctable condition, for example a metabolic disturbance without an underlying structural lesion, are rarely at risk for future epilepsy or recurrent seizures in the absence of recurrence of the condition.

The risk of seizure recurrence in someone with an unprovoked or idiopathic initial seizure is estimated to be 30-70% in the first 12 months, depending on seizure type and etiology. Abnormal neurologic exam, postictal paralysis, abnormal electroencephalogram (EEG), and strong family history of seizures increase the risk of seizure recurrence.

Approximately 60-70% of individuals whose seizures are completely controlled can eventually discontinue antiepileptic therapy.

Specific secondary or associated conditions and complications

Consequences and complications associated with seizures and epilepsy include but are not limited to:

  • Impairment of consciousness
  • Physical injuries during the event
  • Anoxic injury to the brain
  • Learning disabilities
  • Memory loss
  • Language deficits
  • Impaired self-esteem
  • Fatigue
  • Mood disorders (e.g., anxiety, depression, adjustment disorders)
  • Loss of independence and limitations in participation, including specific work activities and driving.

Side effects of AEDs are common and include osteoporosis, weight gain, negative cognitive impairments, nausea, sedation, and/or ataxia.

2. essentials of assessment

History

A comprehensive history is necessary to confirm seizure activity, to characterize the seizure, and to identify risk factors for seizure. An accurate description of surrounding events, including witness interview, helps identify sources that elicit seizures, the presence of any aura, and ictal and postictal behaviors.

  • Aura may include abnormal smell or taste, deja vu feeling, or an intense feeling that a seizure is imminent.
  • Patients or witnesses may report: generalized convulsions, repetitive movements, staring spells, visual or auditory disturbances, or dysesthesias

History should also include a comprehensive review of medications, alcohol or drug use/abuse, family history, and thorough medical history, including history of head trauma, stroke, neurodegenerative diseases, and intracranial infections. In patients with confirmed epilepsy, history should assess seizure control and the functional/social impact of seizures.

Differential diagnosis includes but is not limited to transient ischemic attacks, vaso-vagal/syncopal episodes, delirium, migraine headaches, movement disorders, and psychological factors.

Physical examination

A careful neurologic examination in the interictal period, including assessment of cortical function and mental status, is essential. Presence of TBI or other premorbid neurological disorder can mask signs and symptoms of seizure.  Thus, observation for subtle clues and symptoms is essential to seizure diagnosis.

The physical manifestation of a seizure is dependent on its classification:

  • Generalized tonic-clonic seizures: Abrupt onset with loss of consciousness; generalized muscle rigidity, followed by jerking/twitching movements. Often followed by a postictal phase characterized by deep sleep with deep respirations and gradual awakening accompanied by a headache.
  • Focal seizures with dyscognitive features (complex partial seizures): altered consciousness without loss of consciousness often associated with repetitive behaviors or automatisms (lip smacking, snapping fingers, facial grimacing). The postictal phase includes confusion, somnolence, and headaches.
  • Absence seizures (typically occurs during childhood): staring spell with impaired consciousness; during is typically 5-10 seconds.
  • Subclinical seizures: abnormal electroencephalographic activity without physically symptoms or signs.

The physical exam should be comprehensive to assist in searching for an underlying cause of seizure, such as infection or a systemic disorder.

Functional assessment

Depending on the cause and duration of the seizure, there can be subsequent impairments in mobility, self-care, behavior, cognition, mood, self-esteem, learning abilities, and speech/language. In mesial temporal sclerosis, the most commonly diagnosed focal structural abnormality in patients with epilepsy, associated neuropsychiatric impairments may include decreased memory, cognition, depression, anxiety, and psychiatric comorbidities.

Laboratory studies

Laboratory tests include:

  • Comprehensive metabolic panel including sodium, glucose, calcium, magnesium, renal and liver function levels
  • Hematology studies
  • Toxicology screens
  • Serum prolactin level (elevated post seizure, must be drawn within 1 hour of the event)
  • Lumbar puncture is indicated if there is suspicion of a central neurologic infectious process

Imaging

Neuroimaging studies are typically indicated for evaluation of the brain structure. Magnetic resonance imaging (MRI) is preferred over computerized tomography (CT)11, given that it facilitates better identification of structural causes of epilepsy, such as mesial temporal sclerosis, cortical dysplasia, brain tumors, vascular malformations, TBI, cerebral infarction/hemorrhages, and infectious process.

An epilepsy protocol for the MRI should be performed, which would ideally include the following:

  • Standard T1-weighted images.
  • T2-weighted fast spin-echo sequences.
  • Gradient echo (T2) sequences.
  • Fluid-attenuated inversion recovery sequences.
  • Three-dimensional (3D) volume acquisition sequences with high definition of the gray-white junction; 3D fast spoiled gradient recalled echo acquisition at the steady state.

Functional imaging techniques such as positron emission tomography (PET), single-photon emission computerized tomography (SPECT), functional magnetic resonance imaging (fMRI), and magnetic resonance spectroscopy (MRS) are helpful in localizing/mapping epileptic foci and can aide in surgical management of epilepsy.

Supplemental assessment tools

EEG is an essential diagnostic tool when evaluating seizures. Epileptiform abnormalities usually increase the likelihood that the patient will experience another seizure over the next 2 years. EEG abnormalities can be nonspecific and a normal EEG does not rule out epilepsy. Long-term video EEGs are helpful in recording multiple seizures. Epileptiform discharges are associated with epilepsy, while nonepileptiform abnormalities are nonspecific EEG abnormalities that do not support the diagnosis of epilepsy.

Neuropsychological testing can be used in nonoperative or postoperative epilepsy patients to assess level of cognitive functioning. Results can assist with recommendations for vocational and cognitive rehabilitation.

Early predictions of outcomes

In individuals with TBI resulting in loss of consciousness or amnesia lasting less than thirty minutes (mild injury), there is a 0.5% cumulative five-year probability of seizures. In moderate injury, or loss of consciousness for 30 minutes to 24 hours or skull fracture, there is a 1.2% probability and for severe injuries (loss of consciousness or amnesia >24hours, cerebral contusion, SDH) there is a 10% probability.13

In hospitalized TBI patients with initial GCS of 13 to 15, the 2 year incidence of epilepsy is 8%. For GCS 3 to 8, the 2 year incidence is 16.8%.12

Refractory epilepsy requiring multiple medications is more likely in those with focal seizures due to underlying structural abnormalities, multiple seizure types, or comorbid developmental delays.

Environmental

Seizures can be triggered by environmental factors such as loud noises and flashing lights.

Environmental safety considerations include avoiding heights/climbing activities, scuba diving, and swimming alone.

Social role and social support system

Seizures and epilepsy can significantly impact functional independence, learning abilities, employability, insurability/financial resources, self-esteem, mood, ability to drive or operate heavy equipment, and vocational skills.

Support systems should provide resources within the home and the community to provide these patients, families, and support network with education, and counseling about seizure triggers, physical and psychosocial consequences of seizures, and coping with seizure/epilepsy diagnosis.

Professional Issues

States differ in their requirements for reporting seizure/epilepsy diagnoses to the Office of Driver Services. Physicians should be knowledgeable of their local state law and regulations regarding drivers with an active history of epilepsy.4

3. rehabilitation management and treatments

Available or current treatment guidelines

The following are recommendations for seizure prophylaxis with antiepileptic drugs (AEDs) in patients with TBI:5

  • Immediate seizures (within first 24 hours) post-TBI do not require any additional prophylaxis after 7 days.
  • Early seizures (between days 1 and 7) post-TBI should be treated for at least 24 months with AEDs, unless there was a casual time-limited intracranial abnormality (hydrocephalus, active hemorrhage, or infectious process). Early seizures are associated with a higher incidence of intracranial bleeding. Incidence of early seizures post-TBI decreases significantly with seizure prophylaxis the first 7 days post-TBI.
  • Late seizures (after 7 days) post TBI should be treated for at least 24 months.
  • Any seizure post-TBI that is considered status epilepticus, requires treatment with AEDs for at least 12-24 months.6
  • Individuals with frequent seizures during the first year post-trauma are less likely to have seizure remission.7

Recommendations for seizure prophylaxis for newly diagnosed brain tumors:8

  • Anticonvulsant medications are not proven effective in preventing initial seizures. Because of a lack of efficacy and potential side effects, prophylactic anticonvulsants should not be routinely used in patients with newly diagnosed brain tumors.
  • In patients with brain tumors who have not had a seizure, tapering and discontinuing anticonvulsants after the first postoperative week is appropriate, particularly in those patients who are medically stable and who are experiencing anticonvulsant-related side effects.

At different disease stages

New onset/acute:

  • Initial seizure: Treat acute underlying cause (metabolic derangements, alcohol and drug withdrawal, intracranial hemorrhages, infectious process, hypoxic events, drug toxicity). If there is strong evidence of an epileptogenic focus, then AED treatment should be initiated.
  • Initiate an AED after 2 or more unprovoked seizures.
  • Choice of AED should take into consideration drug effectiveness for the seizure type, potential adverse effects including neurological/cognitive impairments, medication interactions, comorbid medical conditions, age and sex (pregnancy risk), lifestyle, cost, and patient preferences.
  • Monotherapy is preferred. 10-15%of people need two AEDs to control seizure activity. Up to 80% of patients can become seizure free on AED treatment.
  • First-line antiepileptic drugs include:
    • Generalized tonic-clonic seizures: valproic acid or lamotrigine
    • Focal seizures: carbamazepine, lamotrigine, or phenytoin
    • Absence seizures: valproic acid or ethosuximide for absence seizures
  • Routine follow up of patients on AEDs should include AED serum level, blood counts, albumin level (for phenytoin), and hepatic and renal function monitoring.
  • After a seizure-free period of 2-4 years, it is reasonable to consider discontinuation of AEDs. Tapering should be performed slowly; there is no well-defined accepted tapering schedule. It should be done over a 2-3 month period at minimum.
  • Treatment for seizures resistant to AEDs include: Vagal nerve stimulators or surgical procedures9 such as anteromedial temporal resection, corpus callosotomy, functional hemispherectomy (hemispherotomy), and multiple subpial transection.
  • Status epilepticus: Benzodiazepines are the first line of treatment followed by phenytoin, barbiturates, and propofol.

Coordination of care

Medical care should be coordinated with measures to address psychosocial consequences. Treatment team should include primary care physician, neurologist, physiatrist, neurosurgeon, psychiatry/psychology, physical therapy, occupation therapy, speech therapy, and vocational therapist.

Emerging/unique Interventions

Emerging and unique interventions include transcranial magnetic stimulation and deep brain stimulation and are discussed below.

4. cutting edge/emerging and unique concepts and practice

Cutting edge concepts and practice

Up to one third of patients do not have a response to current AED’s and therapies. 19

Clobazam is a benzodiazepine which is used for treatment of various types of epilepsy, though only approved for Lennox-Gastuat syndrome in the United States. It has less sedating effects that other benzodiazepines and has high safety profile and efficacy in refractory epilepsy. 17

Deep brain stimulation (DBS) is a newer area of study that is useful in treating pharmacologically refractory epilepsy.10 Stimulation of the anterior nuclei of the thalamus (ANT) has been shown to be useful in adjunctive treatment of refractory epilepsy; the FDA approved DBS in the ANT as treatment for severe and refractory partial-onset seizures. Other deep brain areas, such as the subthalamic nucleus, caudate nucleus, cerebellum, are being studies as it relates to DBS. More well-controlled, larger studies are needed for other deep brain structures.

Transcranial magnetic stimulation (TMS) is another area being studies for improvement in refractory cases of epilepsy. Low-frequency high intensity repetitive TMS has a significant antiepileptic effect when delivered to epileptogenic areas of the brain and can also reduce interictal epileptic discharge improving psychological conditions in patients.15

Responsive neurostimulator (RNS) is a device that when implanted in the cortical or subcortical epileptogenic areas of the brain detects abnormal activity and delivers electrical stimulation to inhibit seizures prior to the onset of symptoms. Clinical trials are ongoing currently, but data supports the RNS device as a therapy option for refractory partial seizures.16

Other treatment options that are being explored include Synchrotron radiation and lactate dehydrogenase inhibition.18,19

5. gaps in the evidence-based knowledge

Gaps in the evidence-based knowledge

Although there are multiple resources providing recommendations regarding prophylaxis for seizures/epilepsy in high risk populations such as patients with CNS pathology, there are limited references providing a consensus to develop evidence-based guidelines for prevention and treatment.

references

  1. Fisher RS, van Emde Boas W, Blume W, et al. Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia. 2005 Apr. 46(4):470-2.
  2. Beghi E, Carpio A, Forsgren L, et al. Recommendation for a definition of acute symptomatic seizure. Epilepsia. 2010;51:671-675.
  3. Moran NF, Poole K, Bell G, et al. Epilepsy in the United Kingdom: seizure frequency and severity, anti-epileptic drug utilization and impact on life in 1652 people with epilepsy. Seizure. 2004;13:425-433.
  4. Shareef YS, McKinnon JH, Gauthier SM, Noe KH, Sirven JI, Drazkowski JF. Counseling for driving restrictions in epilepsy and other causes of temporary impairment of consciousness: how are we doing? Epilepsy Behav. 2009;14:550-552.
  5. Temkin NR. Risk factors for posttraumatic seizures in adults. Epilepsia. 2003;44 Suppl 10:18-20.
  6. Christensen J, Pedersen MG, Pedersen CB, Sidenius P, Olsen J, Vestergaard M. Long-term risk of epilepsy after traumatic brain injury in children and young adults: a population-based cohort study. Lancet. 2009;373:1105-1110.
  7. Emanuelson I, Uvebrant P. Occurence of epilepsy during first 10 years after traumatic brain injury acquired in childhood up to the age of 18 years in the south western Swedish population-based series. Brain Inj. 2009;23:612-616.1. 64p.
  8. Kerrigan S, Grant R. Antiepileptic drugs for treating seizures in adults with brain tumors. Cochrane Database Syst Rev. 2011 Aug 10;(8):CD008586.
  9. Wyllie E, Comair YG, Kotagal P, Bulacio J, Bingaman W, Ruggieri P. Seizure outcome after epilepsy surgery in children and adolescents. Ann Neurol. 1998;44:740-748.
  10. Wakerley B, Schweder P, Green A, Aziz T. Possible seizure suppression via deep brain stimulation of the thalamic ventralis oralis posterior nucleus. J Clin Neurosci. 2011;18:972-973.
  11. Salmenpera TM, Duncan JS. Imaging in epilepsy. Journal of Neurol Neurosurg Psychiatry. 2005(76): iii2-iii10.
  12. EnglanderJ, Bushnik T, et al. Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation. Arch Phys Med Rehabil. 2003; 84 (3): 365
  13. Annegers JF, Hauser WA, et al. A population-based study of seizures after traumatic brain injuries. N Engl J Med. 1998;338 (1): 20
  14. SANTE Trial of Deep Brain Stimulation in Epilepsy Published; FDA Panel Recommends Approval in Close Vote. Medscape. Mar 19, 2010
  15. Sun W, Mao W, et al. Low-frequency repetitive transcranial magnetic stimulation for the treatment of refractory partial epilepsy: A controlled clinical Study. Epilepsia 2012; 53: 1782-1789
  16. Bergey G, Morrell M, et al. Long-term treatment with responsive brain stimulation in adults with refractory partial seizures. Neurology. 2015; 84: 810-817
  17. Gauthier A, Mattson R. Clobazan: A safe, efficacious, and newly rediscovered therapeutic for epilepsy. CNS Neuroscience & Therapeutics; 2015; 21: 543-548.
  18. Romanelli P, Bravin A, et al. New radiosurgical paradigms to treat epilepsy using synchrotron radiation. Epilepsy Toward the Next Decade. 2014; 231-236
  19. Rho J, Inhibition of Lactate Dehydrogenase to Treat Epilepsy. N Engl J Med. 2015; 373:187-189
  20. Sada N, Lee S, Katsu T, Otsuki T, Inoue T. Epilepsy treatment: targeting LDH enzymes with a stiripentol analog to treat epilepsy. Science 2015;347:1362-1367

Source: https://now.aapmr.org/seizures-and-epilepsy/

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[NEWS] Funding boost for AI-based epilepsy monitoring

September 8th, 2020

Funding boost for AI-based epilepsy monitoring
Routinely recorded EEG is used to build a personalised model of the brain Credit: monsitj

University spinout company Neuronostics has received funding to develop its BioEP platform, an AI-based system for faster, more accurate diagnosis of epilepsy and to monitor response to treatment with anti-epileptic drugs (AEDs).

BioEP works by creating mathematical models of the brain using short segments of electroencephalogram (EEG) recordings. Computer simulations rapidly reveal the ease with which seizures can emerge and form the basis of the BioEP seizure risk score.

Neuronostics is developing BioEP in partnership with the University of Birmingham, where mathematician Professor John Terry, co-founder of the company, is Director of Centre for Systems Modelling & Quantitative Biomedicine.

Professor Terry’s research aims to improve diagnosis and treatment for people with epilepsy. He explains: “We build personalised models of the brain using EEG that is routinely collected when seeking to diagnose epilepsy. From these models the risk of epilepsy can be quickly determined. In contrast, multiple EEG recordings are often required to reach a clinical diagnosis at present. This is expensive, time-consuming, and exposes people with suspected epilepsy to risk.”

The funding, from the National Institute for Health Research (NIHR), will enable the research partnership to progress a prototype clinical platform that can provide a risk score showing the individual’s susceptibility to seizures. This measurement can be used in diagnosis, and as an objective assessment of response to treatment with AEDs, resulting in faster seizure control for people with epilepsy.

The clinical utility of the BioEP seizure risk score has already been demonstrated in a cohort of people with idiopathic generalized epilepsy.1 Using just 20 seconds of an EEG recording that would be considered inconclusive in the current clinical pathway, BioEP achieved 72% diagnostic accuracy. This matches the accuracy achieved in the current diagnostic pathway, which typically takes a year, and involves multiple follow-ups.2

The company is interested to hear from commercial partners in EEG hardware manufacturing, digital EEG analysis, and companion diagnostics or prognostics, and research and clinical partners with interests in epilepsy, traumatic brain injury and dementia. For collaboration enquiries please email: info@neuronostics.com.

The NIHR funding was delivered through the AI in Health and Care Award, part of the NHS AI Lab, which was launched by the UK Government earlier this year to accelerate the adoption of Artificial Intelligence in health and care.


More information:
References
1. H Schmidt et al. A computational biomarker of idiopathic generalized epilepsy from resting state EEG Epilepsia 57: e200-e204 (2016).
2. S Smith. EEG in the diagnosis, classification, and management of patients with epilepsy Journal of Neurology, Neurosurgery & Psychiatry 76: ii2-ii7 (2005).

For further media information please contact: Ruth Ashton, Reputation & Communications Development Manager, University of Birmingham Enterprise, email: r.c.ashton@bham.ac.uk.

About Neuronostics

Neuronostics was established in 2018 and is focussed on developing clinical decision support tools and at home monitoring devices for people with suspected neurological conditions. Neuronostics is currently Medilink SW Start up of the Year and has been supported by grant funding in excess of £1M. Neuronostics’ first product—BioEP—is a revolutionary, patented, biomarker of the susceptibility to seizures in the human brain, informed by clinical EEG recordings.

About the University of Birmingham

The University of Birmingham is ranked amongst the world’s top 100 institutions. Its work brings people from across the world to Birmingham, including researchers, teachers and more than 6,500 international students from over 150 countries.

About NIHR

The National Institute for Health Research (NIHR) is the nation’s largest funder of health and care research. The NIHR:
● Funds, supports and delivers high quality research that benefits the NHS, public health and social care
● Engages and involves patients, carers and the public in order to improve the reach, quality and impact of research
● Attracts, trains and supports the best researchers to tackle the complex health and care challenges of the future
● Invests in world-class infrastructure and a skilled delivery workforce to translate discoveries into improved treatments and services
● Partners with other public funders, charities and industry to maximise the value of research to patients and the economy

The NIHR was established in 2006 to improve the health and wealth of the nation through research, and is funded by the Department of Health and Social Care. In addition to its national role, the NIHR supports applied health research for the direct and primary benefit of people in low- and middle-income countries, using UK aid from the UK government.

Provided by University of Birmingham

Source: https://sciencex.com/wire-news/361008258/funding-boost-for-ai-based-epilepsy-monitoring.html

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[BOOK Chapter] Medication: Epilepsy – Abstract References Resources

Abstract

This chapter covers the use of medication in epilepsy, specific information about antiepileptic medication and what to do if there are issues or concerns about an individual’s medication.

References

  1. Berg A (2008) Risk of recurrence after a first unprovoked seizure. Epilepsia 49(Suppl 1):13–18CrossRefGoogle Scholar
  2. Brodie M, Barry S, Bamagous G, Norrie J, Kwan P (2012) Patterns of treatment response in newly diagnosed epilepsy. Neurology. 15:78(20)1548–1554Google Scholar
  3. Epilepsy Action (2019) Travel advice for people with epilepsy. https://www.epilepsy.org.uk/info/daily-life/travelling-abroad. Accessed 03 Jan 2019
  4. Epilepsy Society (2019) Generic and branded anti-epileptic drugs. https://www.epilepsysociety.org.uk/generic-and-branded-anti-epileptic-drugs. Accessed 03 Jan 2019
  5. House of Commons and Social Care Committee (2019) Drugs policy: medicinal cannabis. https://publications.parliament.uk/pa/cm201719/cmselect/cmhealth/1821/1821.pdf. Accessed 03 Jan 2019
  6. Medicines and Healthcare Products Regulatory Agency (2018) Valproate use by women and girls. Updated 2019. https://www.gov.uk/guidance/valproate-use-by-women-and-girls. Accessed 02 Jan 2020
  7. Medicines for Children (2017) Frequently asked questions (FAQs). https://www.medicinesforchildren.org.uk/frequently-asked-questions-faqs. Accessed 03 Jan 2019
  8. Mohanraj R, Brodie M (2006) Diagnosing refractory epilepsy: response to sequential treatment schedules. Eur J Neurol 13(3):277–282CrossRefGoogle Scholar
  9. National Institute for Health and Care Excellence (NICE) (2012) Epilepsies: diagnosis and management. Clinical Guideline CG137. Updated 2019. https://www.nice.org.uk/guidance/cg137. Accessed 02 Jan 2020
  10. National Institute for Clinical Excellence (NICE) (2016) Controlled drugs: safe use and management. NICE Guidance NG46. https://www.nice.org.uk/guidance/ng46. Accessed 02 Jan 2020
  11. Shakespeare J, Sisodiya S (2019) Guidance document on valproate use in women and girls of childbearing years. https://www.rcog.org.uk/globalassets/documents/guidelines/valproate-guidance-march-2019.pdf. Accessed 02 Jan 2020

Resources

  1. British National Formulary (BNF); Children’s British National Formulary (BNFC). https://bnf.nice.org.uk/
  2. Epilepsy Society (2016) Contraception and Epilepsy. https://www.epilepsysociety.org.uk/contraception-and-epilepsy#.XiwkV2j7TIU. Accessed 25 Jan 2020
  3. Medicines for Children (2017) Helping your child to swallow tablets. https://www.medicinesforchildren.org.uk/sites/default/files/contenttype/leaflet/pdf/Guide%20to%20swallowing%20tablets%2030.11.17.pdf. Accessed 25 Jan 2020
  4. Medicines Healthcare products Regulatory Authority (MHRA) (2017) Branded anti-seizure medication information. https://www.gov.uk/drug-safety-update/antiepileptic-drugs-updated-advice-on-switching-between-different-manufacturers-products
  5. NHS (2018) What is a controlled medicine (drug)? https://www.nhs.uk/common-health-questions/medicines/what-is-a-controlled-medicine-drug/. Accessed 02 Jan 2020

via Medication: Epilepsy | SpringerLink

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[ARTICLE] Levetiracetam and brivaracetam: a review of evidence from clinical trials and clinical experience – Full Text

Until the early 1990s, a limited number of antiepileptic drugs (AEDs) were available. Since then, a large variety of new AEDs have been developed and introduced, several of them offering new modes of action. One of these new AED families is described and reviewed in this article. Levetiracetam (LEV) and brivaracetam (BRV) are pyrrolidone derivate compounds binding at the presynaptic SV2A receptor site and are thus representative of AEDs with a unique mode of action. LEV was extensively investigated in randomized controlled trials and has a very promising efficacy both in focal and generalized epilepsies. Its pharmacokinetic profile is favorable and LEV does not undergo clinically relevant interactions. Adverse reactions comprise mainly asthenia, somnolence, and behavioral symptoms. It has now been established as a first-line antiepileptic drug. BRV has been recently introduced as an adjunct antiepileptic drug in focal epilepsy with a similarly promising pharmacokinetic profile and possibly increased tolerability concerning psychiatric adverse events. This review summarizes the essential preclinical and clinical data of LEV and BRV that is currently available and includes the experiences at a large tertiary referral epilepsy center.

Since the introduction of bromides as the first effective antiepileptic drugs (AEDs),1 chronic AED treatment that consisted of the sustained prevention of epileptic seizures has remained the standard of epilepsy therapy.2 Before to the introduction of the newer generation of AEDs, a limited number of drugs were available that addressed the blockade of sodium channels, acting on gamma-aminobutyric acid (GABA) type A receptors, or interacting with calcium channels as the leading modes of action.3 With the introduction of the newer AEDs a heterogeneous group of drugs appeared, some of them offering new mechanisms of action2 including the blockade of GABA aminotransferase (vigabatrin [VGB]), GABA re-uptake from the synaptic cleft (tiagabine [TGB]), the modulation of calcium channels (gabapentin [GBP], pregabalin [PGB]), the selective non-competitive α-amino-3-hydroxy-5-methyl-4-isoxazolproprionic acid (AMPA) receptor antagonism (perampanel [PER]), and the binding to the presynaptic SV2A receptor site which is the unique mode of action of levetiracetam (LEV) and brivaracetam (BRV), the AEDs this review will cover. The authors will summarize the development of both compounds as derivatives of piracetam, review the currently available preclinical and clinical data, and discuss the question of whether BRV has the potential to be recognized as being superior to LEV and if it can replace it as the standard AED with the main mode of action both AEDs reflect.[…]

 

Continue —-> Levetiracetam and brivaracetam: a review of evidence from clinical trials and clinical experience – Bernhard J. Steinhoff, Anke M. Staack, 2019

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[Abstract] Pharmacology and epilepsy : update on the new antiepileptic drugs

New antiepileptic drugs are regularly approved for treatment and offer large therapeutic opportunities. Efficacy of these drugs is relatively similar on-label with different mechanisms to be combined for a synergic effect. Treatments such as cannabidiol have benefitted from large media coverage despite limited clinical evidence so far. The objective of antiepileptic drugs is to stop the recurrence of epileptic seizures with as few adverse events as possible. When confronted to a difficult-to-treat epilepsy, referral to a specialised centre is strongly advised. The aim is to confirm that the diagnosis is correct, that the treatment is well adapted (indication, pharmacokinetic and compliance) and to evaluate the indication for non-pharmacological treatments such as epilepsy surgery.

 

via [Pharmacology and epilepsy : update on the new antiepileptic drugs]. – Abstract – Europe PMC

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[BLOG POST] Which are the safest epilepsy drugs in pregnancy? – Neurochecklists Updates

Maternal use of antiepileptic agents during pregnancy and major congenital malformations in children

Bromley RL, Weston J, Marson AG.

JAMA 2017; 318:1700-1701.

Abstract

CLINICAL QUESTION:

Is maternal use of antiepileptic drugs during pregnancy associated with major congenital malformations in children?

BOTTOM LINE:

Certain antiepileptic drugs were associated with increased rates of congenital malformations (eg, spina bifida, cardiac anomalies). Lamotrigine (2.31% in 4195 pregnancies) and levetiracetam (1.77% in 817 pregnancies) were associated with the lowest risk and valproate was associated with the highest risk (10.93% in 2565 pregnancies) compared with the offspring of women without epilepsy (2.51% in 2154 pregnancies).

Also see

Weston J, Bromley R, Jackson CF, et al. Monotherapy treatment of epilepsy in pregnancy: congenital malformation outcomes in the child. Cochrane Database Syst Rev 2016; 11:CD010224.

Both references are cited in the neurochecklist:

Antiepileptic drugs (AEDs): teratogenicity

Abstract link 1

Abstract link 2

Drugs firms ‘creating ills for every pill’. Publik15 on Flickr. https://www.flickr.com/photos/publik15/3415531899

via Which are the safest epilepsy drugs in pregnancy? – Neurochecklists Updates

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[BLOG POST] The 29 proven anti-epilepsy drugs…and their practical checklists

Neurochecklists Blog

Epilepsy is a big problem for Neurology. It is a common, and often life-long, disease. Epilepsy is like the mythical hydra in its diverse manifestations, and in its duplicitous evasion of treatment.

By http://wellcomeimages.org/indexplus/obf_images/5c/4e/30eb7506272a7b448f0f1f22ae63.jpgGallery: http://wellcomeimages.org/indexplus/image/L0011685.html, CC BY 4.0, Link By http://wellcomeimages.org/indexplus/obf_images/5c/4e/30eb7506272a7b448f0f1f22ae63.jpgGallery: http://wellcomeimages.org/indexplus/image/L0011685.html, CC BY 4.0, Link

The pillars of epilepsy treatment are the anti-epileptic drugs (AEDs). It is however a very tricky business to wield these very powerful tools. For example, one epilepsy medication may work wonders for one form of the epilepsy, and make another type much worse.

Cocktail of drugs. Phillppa Willitts on Flikr. https://www.flickr.com/photos/hippie/2563571511 Cocktail of drugs. Phillppa Willitts on Flikr. https://www.flickr.com/photos/hippie/2563571511

Any successful anti-epilepsy regime must therefore be carefully thought through, requiring a strategy that keeps the following key issues in mind all the time:

Mode of action

Indications

Dosing

Side effects

Interaction with other drugs

Teratogencity

With these in mind, neurochecklists explored the difficult terrain, and came up with comprehensive, but concise, checklists for the 29 essential anti-epilepsy drugs. What better way…

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[Abstract] Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy

Abstract

Objective To characterize the magnitude and time course of pregnancy-related clearance changes for different antiepileptic drugs (AEDs): levetiracetam, oxcarbazepine, topiramate, phenytoin, and valproate. A secondary aim was to determine if a decreased AED serum concentration was associated with increased seizure frequency.

 

Methods Women with epilepsy were enrolled preconception or early in pregnancy and prospectively followed throughout pregnancy and the first postpartum year with daily diaries of AED doses, adherence, and seizures. Study visits with AED concentration measurements occurred every 1–3 months. AED clearances in each trimester were compared to nonpregnant baseline using a mixed linear regression model, with adjustments for age, race, and hours postdose. In women on monotherapy, 2-sample t test was used to compare the ratio to target concentrations (RTC) between women with seizure worsening each trimester and those without.

 

Results AED clearances were calculated for levetiracetam (n = 18 pregnancies), oxcarbazepine (n = 4), topiramate (n = 10), valproate (n = 5), and phenytoin (n = 7). Mean maximal clearances were reached for (1) levetiracetam in first trimester (1.71-fold baseline clearance) (p = 0.0001), (2) oxcarbazepine in second trimester (1.63-fold) (p = 0.0001), and (3) topiramate in second trimester (1.39-fold) (p = 0.025). In 15 women on AED monotherapy, increased seizure frequency in the first, second, and all trimesters was associated with a lower RTC (p < 0.05).

 

Conclusion AED clearance significantly changes by the first trimester for levetiracetam and by the second trimester for oxcarbazepine and topiramate. Lower RTC was associated with seizure worsening. Early therapeutic drug monitoring and dose adjustment may be helpful to avoid increased seizure frequency.

 

via Antiepileptic drug clearances during pregnancy and clinical implications for women with epilepsy | Neurology

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[Abstract] The use of antidepressant drugs in pregnant women with epilepsy: A study from the Australian Pregnancy Register

Summary

Objective

To study interactions between first‐trimester exposure to antidepressant drugs (ADDs) and antiepileptic drugs (AEDs), and a history of clinical depression and/or anxiety, on pregnancy outcomes and seizure control in pregnant women with epilepsy (WWE).

Methods

We examined data from the Australian Pregnancy Register of Antiepileptic Drugs in Pregnancy, collected from 1999 to 2016. The register is an observational, prospective database, from which this study retrospectively analyzed a cohort. Among the AED‐exposed outcomes, comparisons were made among 3 exposure groups: (1) pregnancy outcomes with first‐trimester exposure to ADDs; (2) outcomes with mothers diagnosed with depression and/or anxiety but who were not medicated with an ADD; and (3) those with mothers who were not diagnosed with depression and/or anxiety and were not medicating with ADD. Prevalence data was analyzed using Fisher’s exact test.

Results

A total of 2124 pregnancy outcomes were included in the analysis; 1954 outcomes were exposed to AEDs in utero, whereas 170 were unexposed. Within the group of WWE taking AEDs, there was no significant difference in the prevalence of malformations in infants who were additionally exposed to ADDs (10.2%, 95% confidence interval [CI] 3.9‐16.6), compared to individuals in the non–ADD‐medicated depression and/or anxiety group (7.7%, 95% CI 1.2‐14.2), or those without depression or anxiety (6.9%, 95% CI 5.7‐8.1; = 0.45). The malformation rates in pregnancy outcomes unexposed to AEDs were also similar in the above groups (= 0.27). In WWE medicated with AEDs and ADDs, the frequency of convulsive seizures (= 0.78), or nonconvulsive seizures (= 0.45) throughout pregnancy, did not differ across comparative groups.

Significance

Co‐medicating with ADDs in WWE taking AEDs does not appear to confer a significant added teratogenic risk, and it does not affect seizure control.

 

via The use of antidepressant drugs in pregnant women with epilepsy: A study from the Australian Pregnancy Register – Sivathamboo – – Epilepsia – Wiley Online Library

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[Abstract] Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update

Abstract

Backgrounds:

Antiepileptic drugs (AEDs) are the mainstay of epilepsy treatment. Since 1989, 18 new AEDs have been licensed for clinical use and there are now 27 licensed AEDs in total for the treatment of patients with epilepsy. Furthermore, several AEDs are also used for the management of other medical conditions, e.g., pain and bipolar disorder. This has led to an increasingly widespread application of therapeutic drug monitoring (TDM) of AEDs, making AEDs among the most common medications for which TDM is performed. The aim of this review is to provide an overview of the indications for AED TDM, to provide key information for each individual AED in terms of the drug’s prescribing indications, key pharmacokinetic characteristics, associated drug-drug pharmacokinetic interactions and the value and the intricacies of TDM for each AED. The concept of the reference range is discussed as well as practical issues such as choice of sample types (total vs free concentrations in blood vs saliva) and sample collection and processing.

Methods:

The present review is based on published articles and searches in PubMed and Google Scholar, last searched March in 2018, in addition to references from relevant papers.

Results:

In total, 171 relevant references were identified and used to prepare this review.

Conclusions:

TDM provides a pragmatic approach to epilepsy care in that bespoke dose adjustments are undertaken based on drug concentrations so as to optimize clinical outcome. For the older first generation AEDs (carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone and valproic acid), much data has accumulated in this regard. However, this is occurring increasingly for the new AEDs (brivaracetam, eslicarbazepine acetate, felbamate, gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, perampanel, piracetam, pregabalin, rufinamide, stiripentol, sulthiame, tiagabine, topiramate, vigabatrin and zonisamide).

via Therapeutic Drug Monitoring of Antiepileptic Drugs in Epilepsy: A 2018 Update

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