Epilepsy Article 1: Epilepsy Overview and Revised Classification Of

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321. – s level of awareness, ’ s and epilepsies, including epilepsy incidence. pMinn).April2019;25(2Epilepsy):306 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Copyright © American Academy of Neurology. Unauthorized reproduction of this article is © 2019 American Academy of Neurology. SUMMARY: The recent ILAE seizure and epilepsy classificationclassify system seizures aims and to the create a epilepsies. Universal framework adoption toenable and patients, better their implementation of families, this clinicians, and system researchersepilepsies. will to Incidence studies better have define not and generally treat classifiedof the seizures this and classification the system, epilepsies, which and emphasizes etiology, use epilepsy will incidence. lead to a better understanding of The 2017 ILAE classification system buildsepilepsy. on Seizure newly classification formulated begins definitions by of determining seizures whetherseizure and the are initial focal manifestations or of generalized. the If theunknown onset onset. of Focal the seizures seizure are is classified missed according or to unclear, the the individual seizure is of RECENT FINDINGS: the most prominent motor or nonmotorevolves features to of a the bilateral seizure, tonic-clonic and seizure. whetheraccording Similarly, to the generalized seizures motor focal are or seizure classified nonmotor manifestations. Motormotor seizures seizures. are Nonmotor either generalized tonic-clonic seizures or primarily other referseizure to classification, the absence epilepsies seizures. can Similar to benew classified as classification system focal recognizes or two generalized. new Inepilepsy categories: addition, combined and the generalized unknown and epilepsy. focal The conceptunder of the an new epilepsy classification syndrome system has and beentypes, refers introduced EEG, to imaging, a and cluster other of features featuresemphasizes including the incorporating genetics. seizure etiology The of new seizures classification system and epilepsies. Alison M. Pack, MD, MPH. Continuum (Minnea ABSTRACT PURPOSE OF REVIEW: The classification of seizures, epilepsies, and epilepsyclinicians, researchers, syndromes and creates a patients and framework their for families.years, This and classification in has 2017 evolved the over International the classification League of Against seizures Epilepsy and (ILAE) epilepsies. published Understanding an thisdiagnosis, operational classification treatment, is and important in understanding the of seizure Article 1: Epilepsy Overview andClassification Revised of Seizures and Epilepsies Epilepsy

Downloaded from https://journals.lww.com/continuum by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3ctdU4DsFBzTgASp4Nhk0mjkaE175OyXcfQYSYIN3YAkpQ/bGQIr5oA== on 04/03/2019 Downloaded from https://journals.lww.com/continuum by BhDMf5ePHKav1zEoum1tQfN4a+kJLhEZgbsIHo4XMi0hCywCX1AWnYQp/IlQrHD3ctdU4DsFBzTgASp4Nhk0mjkaE175OyXcfQYSYIN3YAkpQ/bGQIr5oA== on 04/03/2019 KEY POINTS • In 2014 the International League Against Epilepsy redefined epilepsy as a disease and not a disorder to emphasize the importance and impact of epilepsy. Epilepsy occurs when an individual has an epileptic seizure and his or her “brain demonstrates a pathologic and enduring tendency to have recurrent seizures.” • Prior and current classification systems aim to group seizures according to clinical presentation and brain region onset and epilepsies according to seizure type, age of onset, probability of remission, EEG findings, radiologic findings, and genetics. • The 2017 International League Against Epilepsy seizure classification addresses limitations of the 1981 seizure classification, which include the following: (1) some seizure types can have either focal or generalized onset, (2) lack of knowledge about seizure onset makes a seizure unclassifiable and difficult to place within the 1981 system, (3) retrospective seizure descriptions often do not include a level of consciousness, (4) terms used in the 1981 seizure classification such as complex partial or simple partial are difficult to understand, and (5) some seizure types are not included in the 1981 classification. • Focal seizures originate within a neuronal network limited to one hemisphere that may be discretely localized or more widely distributed, whereas generalized seizures originate at some point within the brain and rapidly engage bilateral distributed networks. • Focal seizures are classified according to the patient’s level of awareness and the first most prominent motor or nonmotor features of the seizure. These early prominent features are important to consider when localizing the seizure onset or epileptogenic zone. The final feature used in classification is whether the focal seizure evolves to a bilateral tonic-clonic seizure. • Generalized seizures are classified according to motor or nonmotor manifestations. Broadly, motor seizures are either tonic-clonic or other motor seizures. Nonmotor generalized seizures primarily refer to absence seizures. • Seizures of unknown onset can be classified by motor (tonic-clonic, epileptic spasms) or nonmotor (behavior arrest) presentation. If information is inadequate or if the seizure cannot be categorized, then the seizure is considered unclassified. • Similar to seizure classification, the epilepsies are classified as generalized or focal. The new classification system additionally recognizes two new categories: combined generalized and focal epilepsy and unknown epilepsy. • Patients with generalized epilepsy have one or more of the generalized seizure types, and their EEGs typically display generalized spike-wave activity. For individuals who have generalized seizure types and a normal EEG, other data are needed to determine whether the epilepsy is generalized. • Patients with one or more focal seizure types have focal epilepsy. These epilepsies can be either unifocal or multifocal. • Designation of combined generalized and focal epilepsy is for patients with both focal and generalized seizures. EEG may reveal both focal and generalized electrographic findings. Examples of combined generalized and focal epilepsy include Dravet syndrome and Lennox-Gastaut syndrome. • When the patient has epilepsy as defined by the International League Against Epilepsy, but it remains undetermined whether the patient has focal or generalized epilepsy, the classification of unknown epilepsy type is used. • The epilepsy syndrome is a new addition to the current classification system and is defined as “a cluster of features incorporating seizure types, EEG, and imaging features that tend to occur together.” • Idiopathic generalized epilepsies include childhood absence epilepsy, juvenile absence epilepsy, juvenile myoclonic epilepsy, and generalized tonic-clonic seizures alone. • Reflex epilepsy syndromes are epilepsies in which seizures are provoked by a specific stimulus. • Well-described focal epilepsy syndromes include childhood epilepsy with centrotemporal spikes and Panayiotopoulos syndrome. • The etiology of seizures and epilepsies is emphasized in the 2017 International League Against Epilepsy classification system.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. • A structural etiology is determined when a structural abnormality is seen on neuroimaging and when the signs and symptoms of seizures, in combination with EEG data, suggest this abnormality is the probable cause of the seizures. • Genetic etiologies are determined if there is a known or presumed genetic mutation in which seizures are a core symptom of the disorder. • Infectious etiologies are the most common worldwide etiology of epilepsy. • Epilepsies with a metabolic etiology occur secondary to a known or presumed metabolic disorder in which seizures are a core symptom of the disorder. • Immune etiologies are increasingly recognized as potential causes of epilepsy. Article 2: Evaluation of Seizure Etiology From Routine Testing to Genetic Evaluation

Stephan U. Schuele, MD, MPH, FAAN. Continuum (Minneap Minn). April 2019; 25 (2 Epilepsy):322–342.

ABSTRACT

PURPOSE OF REVIEW: Recognizing the cause of a first seizure and identifying the etiology of epilepsy are essential for management. A systematic approach to patients who present with a first seizure helps distinguish between an acute symptomatic seizure, a provoked or unprovoked seizure, and potential mimickers. Routine testing with EEG and MRI may reveal a predisposition for further seizures and help to establish the underlying epilepsy syndrome. An acquired etiology can be identified in 30% of patients with established epilepsy. The remaining 70% of patients have a presumably genetic etiology. Particularly in patients with specific epilepsy syndromes or suspicion for an autosomal dominant inheritance, genetic testing and counseling should be considered.

RECENT FINDINGS: Neuroimaging, autoimmune antibodies, and genetic testing have revolutionized our ability to investigate the etiology of many epilepsies. The new epilepsy classification distinguishes structural, metabolic, genetic, infectious, and immune-mediated etiologies, which often help determine prognosis and treatment.

SUMMARY: There is growing acceptance and demystification of the term epilepsy as the most common cause for recurrent seizures. The new classification of epilepsy does not stop with the recognition of particular epilepsy syndromes but aims to determine the underlying etiology. This can lead to earlier recognition of surgical candidates, a better understanding of many of the genetic epilepsies, and medical treatments aimed at the underlying mechanism causing the disease.

KEY POINTS • Syncope is the most common mimicker of a new-onset seizure. A situational trigger, an aura of “going to faint,” and a quick recovery often support a diagnosis of vasovagal syncope. • Laboratory testing after a first seizure should include a complete blood cell count; blood chemistry, including calcium, magnesium, and phosphate; thyroid-stimulating hormone; and urine toxicology. A 12-lead ECG should also be considered.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. • Acute brain insults can have a risk of leading to late seizures in up to 20% of patients and do not warrant prolonged seizure prophylaxis, even if the injury was associated with early seizures or status. Exceptions are possibly a penetrating head trauma and herpes encephalitis, which are associated with a 50% risk of developing epilepsy. • Typical MRI lesions associated with surgically amenable epilepsy, such as glioneuronal tumors, low-grade gliomas, hippocampal sclerosis, small cavernous malformations, and subtle malformations of cortical development (eg, cortical dysplasia or isolated periventricular nodular heterotopia), are not seen on brain CT scans and often missed on standard MRIs. • An epilepsy-protocol brain MRI differs from a typical MRI in that it includes thin 1- to 3-mm slices without interslice gap and coronal fluid–attenuated inversion recovery sequences, which offer additional sensitivity over standard-protocol MRIs. • A brain CT and an EEG should be considered even in the presence of an alternative etiology for a provoked seizure. • According to national guidelines, patients who continue to have seizures after 1 year on medical therapy should be referred to an epilepsy center. • Genetic testing should be considered in all patients with an autosomal dominant familial epilepsy, epileptic encephalopathies, and progressive myoclonic epilepsy and patients with clinical findings suggestive of a genetic etiology. • Whole exome sequencing and whole genome sequencing are usually performed within the setting of a genetic clinic and research program with access to genetic counseling and the ability to interpret variants of unknown significance. • It is worthwhile to be familiar with glucose transporter type 1 (GLUT1) deficiency syndromes associated with SLC2A1 gene mutation given the excellent response to dietary treatment and the recent discovery of milder, later-onset variants. • Genetic counseling for a specific epilepsy syndrome can be straightforward in patients with a 100% penetrant syndrome but complicated in situations of incomplete penetrance and de novo mutations (eg, Dravet syndrome) and should be performed with the help of a genetic counselor. • The high prevalence of comorbidities associated with epilepsy is best addressed within a comprehensive care setting including a social worker, psychologist, psychiatrist, neuropsychologist, dietician, and genetic counselor. Article 3: Optimizing Management of Medically Responsive Epilepsy

Derek Bauer, MD; Mark Quigg, MD, MSc, FANA, FAES. Continuum (Minneap Minn). April 2019; 25 (2 Epilepsy):343–361.

ABSTRACT

PURPOSE OF REVIEW: This article reviews the management of patients with medically responsive epilepsy, including discussion of factors that may lead to transient breakthrough seizures and patient and physician strategies to maintain freedom from seizures.

RECENT FINDINGS: Imperfect adherence, unanticipated changes in ongoing medical therapy, inadvertent use of proconvulsants or concurrent medications that alter epilepsy medication kinetics, and a variety of seizure precipitants such as stress or sleep deprivation may alter long-term seizure control.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. SUMMARY: The majority of patients with epilepsy are medically responsive. Many potential factors may lead to breakthrough seizures in these patients. Identification of these factors, patient education, and use of self-management techniques including mindfulness therapy and cognitive-behavioral therapy may play a role in protecting patients with epilepsy against breakthrough seizures.

KEY POINTS • Approximately two-thirds of patients with epilepsy will become seizure free with pharmacotherapy. • Comparatively little evidence exists for evaluating risk factors for breakthrough seizures. The available data suggest that nonadherence is the most important factor leading to breakthrough seizures. • Antiseizure medication nonadherence is common and should be screened for when a patient’sseizuresare uncontrolled. • Increasing complexity of the antiseizure medication regimen, including increased dosing frequency or increased numbers of medications, is associated with an increased risk of medication nonadherence. • Many demographic factors may convey an increased risk of nonadherence, including socioeconomic status and race, although other factors such as gender and age are not clearly associated with increased risk. • Current data suggest that adherence may be improved by increasing patient education and providing feedback to address concerns that may be obstacles to adherence. • Medications and supplements may cause seizures, either through interactions with antiseizure medication or through proconvulsant properties. • Switching antiseizure medications may result in seizure recurrence, even in the setting of prolonged seizure freedom. • Current data from large population studies suggest that generic antiepileptic drugs are bioequivalent to name brand medication. • Stress and sleep deprivation are the most common seizure precipitants in patients with epilepsy. • Insomnia is common in patients with epilepsy and is correlated with poor seizure control. • Mood disorders are common in patients with epilepsy. Screening should be performed to address both inherent mood concerns but also to potentially improve seizure control. • Self-management techniques may improve psychiatric comorbidities associated with epilepsy, and some evidence suggests this may translate into improved seizure frequency. • The first-line treatment for insomnia is cognitive-behavioral therapy; sedative-hypnotic use should be avoided as much as possible in patients with epilepsy because of risks of polypharmacy and the fluctuation of seizure thresholds, such as in the withdrawal from and habituation to benzodiazepines. Article 4: Identification and Treatment of Drug-Resistant Epilepsy

Ji Yeoun Yoo, MD; Fedor Panov, MD. Continuum (Minneap Minn). April 2019; 25 (2 Epilepsy):362–380.

ABSTRACT

PURPOSE OF REVIEW: Drug-resistant epilepsy is a potentially life-threatening condition affecting one-third of people living with epilepsy. Despite existing evidence of improved outcomes in patients who received surgical treatment compared to continued medical treatment, epilepsy surgery remains underused in patients with drug-resistant epilepsy. This article discusses the gap between

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. evidence and practice and common misconceptions about epilepsy surgery and reviews the current diagnostic and therapeutic surgical options.

RECENT FINDINGS: Three randomized controlled trials comparing the medical versus surgical treatment for patients with drug-resistant epilepsy have shown the superiority of surgery in controlling seizures and improving patients’ quality of life. In addition to resective surgery, neuromodulation through devices such as responsive neurostimulation and vagal nerve stimulation have also shown efficacy in seizure control that increases over time. Diagnostic and therapeutic surgical tools are tailored to the needs of each patient.

SUMMARY: Appropriate patients with drug-resistant epilepsy benefit more from epilepsy surgery than from continuing medical treatment. These patients should be referred to comprehensive epilepsy centers where a thorough presurgical workup and surgical options can be provided. The gap between evidence and practice can be bridged by education, community outreach, and providers’ earnest efforts to improve the quality of life of patients with epilepsy.

KEY POINTS • Drug-resistant epilepsy is defined as the “failure of adequate trials of two tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in combination) to achieve sustained seizure freedom.” • Drug-resistant epilepsy affects about one-third of people living with epilepsy. • Currently, three randomized controlled trials have shown superiority of surgery compared to continued medical treatment in patients with drug-resistant epilepsy, not only for seizure control but also for quality of life. • A formal practice guideline by the American Academy of Neurology, American Epilepsy Society, and American Association of Neurological Surgeons recommends that the patients for whom appropriate trials of first-line antiepileptic drugs have failed should be considered for referral to an epilepsy surgery center. • A gap between evidence and practice exists in regard to treatment for patients with drug-resistant epilepsy. Although evidence clearly dictates referral of patients with drug-resistant epilepsy to a comprehensive epilepsy center, such referrals are still not completed due to a variety of reasons. • Epilepsy surgery is generally safe; most complications are minor and transient. • Cognition and memory deficits are not contraindications to epilepsy surgery. • The risk of cognitive and memory decline is less when an abnormality is seen in imaging such as mesial temporal sclerosis, or with earlier age of seizure onset, or with preexisting memory and language deficits. • After failure (having recurrent seizures despite adequate trials) of two antiepileptic drugs, the chance of a third antiepileptic drug effectively controlling a patient’s seizures is very low. • “Normal” brain MRIs are not always normal. A careful review by dedicated neuroradiologists, with attention to the patient’s seizure symptomatology, and correlation with EEG findings, can help identity subtle findings. • A focal lesion is not always the culprit for the patient’s seizures, and careful review through multiple modalities is still necessary. • Involvement of eloquent cortex is not a contraindication to epilepsy surgery. When the resection of the epileptogenic zone is not possible, a device can be an effective treatment option. • A treatment-viable seizure onset zone can still be identified even if multiple or diffuse lesions are seen on MRI or if multifocal spikes are seen on EEG. • What seems to be generalized epilepsy or bilateral spikes on EEG may still have a unilateral seizure onset zone, and in cases of truly generalized epilepsy, a device can be an effective option. • A referral to an epilepsy center is not only for possible epilepsy surgery but is also to identify a “pseudoresistance” and to adjust treatments accordingly.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. • Invasive diagnostic tools are used for delineating the intracranial seizure onset zone and for functional brain mapping. The diagnostic tools include grids, strips, depth electrodes, or stereo-EEG, and these tools can be used as dictated by the needs of the specific patient. • Different surgical options are available, including resection, laser ablation, and neuromodulatory devices, with therapeutic surgery tailored to the specific patient. • The efficacy of vagal nerve stimulation improves over time, with 60% of patients experiencing a significant response (>50% seizure reduction), but the goal of seizure freedom is unlikely to be attained with this therapy (8% seizure freedom after 2 years).

Article 5: Antiepileptic Drug Treatment of Epilepsy in Children

Ahsan N. V. Moosa, MD. Continuum (Minneap Minn). April 2019; 25 (2 Epilepsy):381–407.

ABSTRACT

PURPOSE OF REVIEW: The treatment of epilepsy in children is highly individualized at each and every major step in the management. This review examines various factors that modify the treatment from the point of initiation of therapy to the decision to stop an antiepileptic drug (AED).

RECENT FINDINGS: AED therapy leads to seizure freedom in about 70% of all children with epilepsy. AED initiation could be delayed until a second seizure in most children and may be avoided altogether in many children with self-limited childhood focal epilepsies. Three key factors influence the choice of AED: seizure type(s), efficacy of the drug for the seizure type, and the side effect profile of the drug(s). For epileptic spasms, steroids and vigabatrin are the most effective treatment options. For absence seizures, ethosuximide and valproic acid are superior to lamotrigine. For focal seizures, many newer AEDs have favorable side effect profiles with efficacy comparable to older-generation drugs. For generalized epilepsies, valproic acid remains the most effective drug for a broad range of seizure types. Genetic and metabolic etiologies may guide unique treatment choices in some children. After 2 years or more of seizure freedom, if the recurrence risk after AED withdrawal is acceptable, slow weaning of AEDs should be done over the span of 6 weeks or longer. After discontinuation, about 70% of patients remain seizure free, and of those with recurrence, the majority achieve seizure control with restarting an AED. When treatment with two or more AEDs fails, other treatment opportunities for drug-resistant epilepsy, including epilepsy surgery, vagal nerve stimulation, and dietary therapies should be considered.

SUMMARY: Carefully selected medical therapy guided by seizure type and AED characteristics is effective in more than two-thirds of children with epilepsy.

KEY POINTS • A clinical diagnosis of epilepsy is met when a child has two or more unprovoked seizures or if the predicted risk of recurrence of seizure is 60% or more after the first seizure. • In selected children with self-limited childhood focal epilepsies (with centrotemporal or occipital spikes), long-term daily antiepileptic drug treatment may not be needed because children invariably outgrow their tendency to have seizures.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. • The single most important determinant of treatment choice is the type of seizure that is being targeted. • Drugs with low risk of drowsiness and cognitive dulling are preferred. • A higher risk of Stevens-Johnson syndrome in patients of Asian ancestry with the HLA-B*1502 allele and a risk of liver failure with valproic acid in patients with a POLG1 mutation are two noteworthy situations in which pharmacogenomics factors influence antiepileptic drug selection. • The results of a network meta-analysis showed that, for focal seizures, lamotrigine and levetiracetam were significantly better than carbamazepine, which was better than phenytoin and phenobarbital. • The results of a network meta-analysis showed that, for generalized seizures, valproic acid was superior to phenobarbital, topiramate, and carbamazepine. • The American Academy of Neurology quality committee recommends initiation of therapy within 7 days of the onset of epileptic spasms to improve developmental outcome. • Steroids (oral prednisone or IM adrenocorticotropic hormone) and vigabatrin are the mainstays of therapy for epileptic spasms. • Reversible hyperintense signal abnormalities in white matter, basal ganglia, thalamus, and brainstem have been reported in as many as 30% of infants treated with vigabatrin. • Both valproate and ethosuximide produce comparable rates of seizure control for absence seizures, but ethosuximide has a favorable side effect profile, particularly in the behavioral domain. • The focus of management in Lennox-Gastaut syndrome should be on the overall quality of life and not seizure count per se. • Valproic acid is frequently used as a first-line medication for children with Lennox-Gastaut syndrome because of its broad spectrum of action against various seizure types. • Two commonly used treatment options for electrical status epilepticus in slow-wave sleep include high-dose nightly benzodiazepines and steroids. • Examples of antiepileptic drugs known to worsen epilepsy in certain diseases include phenytoin, carbamazepine, and lamotrigine in Dravet syndrome due to SCNA1 mutation. • A pooled analysis of five trials in children provided evidence to support a minimum 2-year seizure-free period before considering the need for continued treatment. • The majority of children with epilepsy belong in the “uncertain” group for whom the long-term chances for seizure remission without antiepileptic drugs are not very predictable. • Pooled analyses of studies in children who had achieved sustained seizure freedom show that 70% remained seizure free after discontinuation of antiepileptic drugs, and 30% had one or more recurrences. • Risk factors for increased recurrence include epileptiform abnormalities on EEG, epilepsy onset before 2 years of age and after 10 years of age, intellectual disability (IQ <70), history of status epilepticus, and higher seizure burden before and during treatment. • A comparison of slow weaning over 9 months versus relatively faster weaning over 6 weeks showed no significant difference in seizure recurrence risk. Article 6: Treatment of Women With Epilepsy

Mona Sazgar, MD, FAES. Continuum (Minneap Minn). April 2019; 25 (2 Epilepsy):408–430.

ABSTRACT

PURPOSE OF REVIEW: This article provides the latest information to guide practitioners in counseling and treating women with epilepsy.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. RECENT FINDINGS: There is an increasing body of literature on the multidirectional effects of sex hormones on seizure frequency and severity and of seizures altering areas of the brain involved in neuroendocrine function. Ongoing pregnancy outcome data from pregnancy registries and meta-analysis of observational studies have provided key information on the safety of using antiseizure medications during pregnancy and the risk to the fetus.

SUMMARY: In treating and counseling women with epilepsy from puberty to menopause, it is important to understand the complex interactions of sex hormones, seizures, and antiseizure medications on reproductive health and pregnancy outcomes.

KEY POINTS • Nearly 1.5 million women of childbearing age in the United States live with epilepsy. • Catamenial epilepsy is reported in at least one-third of women with epilepsy. • Women with catamenial epilepsy have a cyclic exacerbation of their seizures with the fluctuation of their hormones. • As a rule, estrogens are proconvulsant and progesterone is anticonvulsant. • Menstrual disorders are estimated to occur in one-third of women with epilepsy as compared with 12% to 14% of women in the general population. • Theoralcontraceptivefailurerateis1%inhealthywomenbut3%to6%inthepopulationofwomenwithepilepsy. • Neurologists should be aware of the complex and at times bidirectional interactions between antiepileptic drugs and hormonal contraception. • Intrauterine devices are a safe and effective method of contraception in women with epilepsy. • In most women with epilepsy, pregnancy has no effect or a protective effect on their seizure frequency. • Having a seizure disorder that was active in the year before pregnancy appears to be the best predictor of seizure recurrence during pregnancy. • There is evidence for better seizure control during pregnancy in women with catamenial epilepsy compared with women with epilepsy in general. • The most common cause of seizure recurrence in pregnancy is likely a reduced plasma concentration of antiepileptic drugs and changes in antiepileptic drug metabolism. • American Academy of Neurology guidelines recommend checking antiepileptic drug levels at baseline before conception and monthly thereafter. • In counseling women with epilepsy who plan to become pregnant, the practitioners should discuss the need for staying on antiseizure medication, simplifying the medication regimen, attempting monotherapy, and selecting medications with a more favorable side effect profile. • Exposure to valproate in utero may adversely affect child IQ and contribute to autistic traits. • In the Neurodevelopmental Effects of Antiepileptic Drugs study, breast-fed children exposed to antiepileptic drugs in utero and through breast milk exhibited higher IQs and enhanced verbal abilities compared with children exposed to antiepileptic drugs in utero who were not breast-fed. • At perimenopause, seizures may worsen because of a temporary increased estrogen-to-progesterone ratio. After menopause is established, women with catamenial epilepsy may experience improvement in seizures. • Antiepileptic drugs used to treat epilepsy can adversely affect bone health and calcium metabolism. Article 7: Electroencephalography in Epilepsy Evaluation

Hai Chen, MD, PhD; Mohamad Z. Koubeissi, MD, FAAN. Continuum (Minneap Minn). April 2019; 25 (2 Epilepsy):431–453.

PURPOSE OF REVIEW: Epilepsy is a heterogeneous disorder that is often associated with abnormal electroencephalogram (EEG) findings. This article provides an overview of common EEG findings in epileptic disorders. The physiologic basis of EEG and intracranial EEG studies is also discussed.

RECENT FINDINGS: EEG is widely used in clinical practice. Because of the paroxysmal nature of seizure disorders, interictal epileptiform discharges, such as spikes and sharp waves, are often used to support the diagnosis of epilepsy when a habitual seizure is not captured by EEG. Interictal and ictal EEG findings also underlie the classification of seizures and epilepsy. Continuous critical care EEG monitoring has become an invaluable study in the diagnosis and treatment of subclinical seizures and nonconvulsive status epilepticus. Intracranial EEG with subdural or intraparenchymal electrodes is warranted when localization of the seizure focus and mapping of eloquent brain areas are required to plan epilepsy surgery.

SUMMARY: The EEG is a key tool in the diagnosis of epilepsy. Interictal and ictal EEG findings are crucial for the confirmation and classification of seizure disorders. Intracranial EEG monitoring is also indispensable for planning surgery for some patients.

KEY POINTS • The EEG signal is generated by the summation of extracellular postsynaptic potentials. • Paroxysmal depolarizing shifts are considered the intracellular correlate of the interictal epileptiform discharge on EEG recordings. • The finding of interictal epileptiform discharges may aid in the diagnosis of epilepsy. • Ictal discharges seen on EEG in patients with epilepsy vary in morphology, frequency, and distribution and often show pattern evolutions. • Seizures are classified as focal-onset or generalized-onset seizures. • Periodic discharges can be considered as ictal or interictal phenomena in various clinical settings. • Continuous EEG monitoring is important in the diagnosis and treatment of nonconvulsive status epilepticus. • Intracranial electrodes allow for earlier seizure detection and spatial resolution than do scalp recordings. • Intracranial monitoring is an invaluable tool in surgical planning. Article 8: Epilepsy Emergencies: Status Epilepticus, Acute Repetitive Seizures, and Autoimmune Encephalitis

Stephen VanHaerents, MD; Elizabeth E. Gerard, MD. Continuum (Minneap Minn). April 2019; 25 (2 Epilepsy):454–476.

ABSTRACT

PURPOSE OF REVIEW: This article reviews epilepsy emergencies, including status epilepticus, acute repetitive seizures, autoimmune encephalitis, and the current perspective on their diagnosis and treatment.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. RECENT FINDINGS: Recent guidelines on the treatment of status epilepticus from the Neurocritical Care Society in 2012 and the American Epilepsy Society in 2016 highlight areas of consensus in the treatment of status epilepticus as well as areas of uncertainty. The TRENdS (Treatment of Recurrent Electrographic Nonconvulsive Seizures) trial is the first prospective randomized clinical trial to evaluate the efficacy of IV antiseizure medications in controlling nonconvulsive seizures on continuous EEG. It demonstrated that IV lacosamide is noninferior to fosphenytoin in this setting. Autoimmune encephalitis is an increasingly recognized cause of new-onset seizures or status epilepticus. Recently described scoring systems, the Antibody Prevalence in Epilepsy score and the Response to Immunotherapy in Epilepsy score, can help in the assessment of autoimmune encephalitis.

SUMMARY: Status epilepticus, acute repetitive seizures, and autoimmune encephalitis are neurologic emergencies. For all these conditions, rapid and appropriate treatment may influence patient prognosis and mitigate neuronal injury. For convulsive status epilepticus, there is reasonable consensus on the initial steps that need to be taken. There is less agreement about the management of acute repetitive seizures and nonconvulsive status epilepticus. An increasingly recognized etiology of status epilepticus is autoimmune encephalitis, which may not be as rare as previously thought.

KEY POINTS • Currently, the most commonly accepted definition for convulsive status epilepticus is either 5 minutes or more of continuous seizure activity or two or more discrete seizures between which there is incomplete recovery of consciousness. • Refractory status epilepticus refers to either clinical or electrographic seizures that persist after adequate doses of an initial benzodiazepine and an acceptable second-line antiseizure drug. • Super-refractory status epilepticus is defined as status epilepticus that continues or recurs 24 hours or more after the initiation of anesthetic therapy. • Benzodiazepine therapy has been well established as the first-line treatment for convulsive status epilepticus. • Both guidelines (from the Neurocritical Care Society and American Epilepsy Society) state that phenytoin, fosphenytoin, valproate sodium, levetiracetam, and phenobarbital are reasonable choices for second-line antiseizure drugs with little evidence to guide the choice between them. • One proposed clinical definition of acute repetitive seizures is three or more seizures within 24 hours for patients whose habitual seizure frequency is fewer than three seizures per day. • In a patient who is critically ill, his or her mental status may be affected by the underlying cause of seizures, so it can be difficult to determine if the patient would return to baseline between seizures. • In a recent randomized controlled trial, lacosamide was noninferior to fosphenytoin in the treatment of nonconvulsive seizures. • No clinical consensus exists for how aggressively to treat nonconvulsive status epilepticus, but in clinical practice, the determination is often based on the patient’s mental status and clinical course. • New-onset refractory status epilepticus (NORSE) is a recently described clinical presentation that can affect all ages and occurs in patients without active epilepsy or other preexisting neurologic disorders and has no clear acute or active structural, toxic, or metabolic cause. • Febrile infection–related epilepsy syndrome (FIRES) is thought to be a subcategory of new-onset refractory status epilepticus that requires a preceding febrile infection, with fever starting between 2 weeks and 24 hours before the onset of refractory status epilepticus. • In one study, an Antibody Prevalence in Epilepsy score of 4 or greater had a sensitivity of 82.6% and a specificity of 82.0% for detecting a positive antibody.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. • In one study, a Response to Immunotherapy in Epilepsy score of 7 or greater predicted favorable seizure outcome and had a sensitivity of 87.5% and specificity of 83.8%. • When choosing a treatment strategy for any antibody-associated central nervous system disorder, it is key to choose objective markers to monitor treatment response. Article 9: Counseling and Management of the Risks of Living With Epilepsy

Katherine Noe, MD, PhD, FAAN. Continuum (Minneap Minn). April 2019; 25 (2 Epilepsy): 477–491.

ABSTRACT

PURPOSE OF REVIEW: For patients living with epilepsy, quality of life is determined not only by seizure control but by mood, antiepileptic drug adverse effects, relationships, and access to education, employment, and transportation. This article reviews some of the most commonly encountered concerns associated with epilepsy, including mood disorders, driving, injuries, mortality, bone health, genetic burden, and impact on relationships.

RECENT FINDINGS: People with epilepsy are at increased risk for anxiety, depression, and suicide. Depression is underrecognized in patients with epilepsy, but effective validated screening tools are available for use. Mortality rates for people with epilepsy are 2 times higher than those of the general population, but much of this is attributable to underlying conditions rather than seizures. Sudden unexpected death in epilepsy (SUDEP) occurs in an estimated 1:1000 adults with epilepsy per year, and the risk can be reduced by improved observation and seizure control. An increased risk of injury, including fractures, is also present in patients with epilepsy. Reduced bone health leading to increased fracture risk is an important negative consequence of long-term use of antiepileptic medication. Seizures while driving can also cause accidents and injury. Despite the importance of driving for people with epilepsy, physicians are underperforming in providing counsel about driving.

SUMMARY: Optimal care of the patient with epilepsy includes addressing risks to emotional health, physical health including fractures and SUDEP, social health, and an independent lifestyle. Identification of and treatments to reduce these risks can do more to improve quality of life than a narrow clinical focus on seizure control alone.

KEY POINTS • Depression risk is increased 2 to 3 times in people with epilepsy. People with epilepsy are twice as likely to report suicidal thoughts and up to 3 times more likely to die of suicide compared to the general population. • Depression in patients with epilepsy is underrecognized and undertreated. • The often-cited fear that a selective serotonin reuptake inhibitor will worsen seizure control is not supported by evidence and should not be a barrier to treatment of depression in the patient with epilepsy. • People living with epilepsy rated their ability to drive as the most important factor determining quality of life. • Physicians are underperforming in counseling patients with epilepsy about driving. • Fracture risk is 2 to 6 times higher in people with epilepsy than in the general population, and fracture risk increases with duration of antiepileptic drug therapy.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. • Evidence-based or expert consensus recommendations on prevention, screening, and treatment of bone disease and fractures in people with epilepsy are lacking. Medical providers must rely on common sense or strategies used in the general population. • Mortality in patients with epilepsy is primarily attributable to underlying medical disorders, rather than to seizure-related injury or sudden unexpected death in epilepsy. • Uncontrolled generalized tonic-clonic seizures are an important risk factor for sudden unexpected death in epilepsy. • The majority of people with epilepsy want to be informed by their physician about sudden unexpected death in epilepsy. • People with epilepsy tend to overestimate the risk of passing on epilepsy to a child, which may falsely influence decisions about having children. Article 10: Nonepileptic Episodic Events

Jennifer L. Hopp, MD, FAAN. Continuum (Minneap Minn). April 2019; 25 (2 Epilepsy): 492–507.

ABSTRACT

PURPOSE OF REVIEW: This review addresses the scope, evaluation, treatments, and outcomes of patients with nonepileptic episodic events with a focus on psychogenic nonepileptic seizures. Differentiation of the types of events, including a review of terminology, is included, as well as a brief review of special patient populations with these disorders.

RECENT FINDINGS: There are continued efforts to develop tools to improve the diagnosis of these disorders. A thorough evaluation with trained personnel and physicians knowledgeable in the assessment and treatment of these disorders is important. Although inpatient video-EEG monitoring in an epilepsy monitoring unit remains the gold standard for diagnosis, the assessment of clinical and historical factors is critical and can be useful in expediting the process and improving diagnostic certainty. International efforts have recently assisted in providing guidelines for the evaluation of the psychogenic disorders and may help target educational and other resources to underserved areas.

SUMMARY: The prompt and accurate diagnosis of nonepileptic episodic events and psychogenic nonepileptic seizures is possible with current technology, and the appropriate and targeted use of evidence-based treatments may help improve patient quality of life and avoid unnecessary disability in patients with these disorders.

KEY POINTS • The term nonepileptic episodic events is broad and includes disorders of both physiologic and psychogenic origin. Nonepileptic events of a psychogenic origin are often referred to as psychogenic nonepileptic seizures. • Syncope may be mistaken for an epileptic seizure when followed by tonic-clonic movements (convulsive syncope), and a thorough evaluation should be performed to exclude physiologic causes of loss of consciousness. • No single sign can differentiate between types of physiologic or psychogenic nonepileptic episodic events or between nonepileptic episodic events and epilepsy.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. • Patients with psychogenic nonepileptic seizures may account for 20% of those seen in an outpatient setting and up to one-third of patients in an epilepsy monitoring unit. • Psychiatric disorders, such as depression and anxiety, are common in patients with nonepileptic episodic events and epileptic seizures, and their presence should not be used to discriminate between the two disorders when making a diagnosis. • Common clinical signs in patients with psychogenic nonepileptic seizures include waxing and waning movements or a fluctuating course, a long duration of events, eye closure, ictal crying, gradual onset, asynchronous movements, pelvic thrusting, recall during the period of apparent unresponsiveness, and hyperventilation. • Although a psychogenic nonepileptic seizure was traditionally considered a manifestation of a conversion, somatization, or dissociative disorder, it is now considered to have a multifactorial etiology that also comprises biological and social factors. • The diagnosis of nonepileptic episodic events, including psychogenic nonepileptic seizures, should be a stepwise process that includes clinical and historical assessment and video and EEG monitoring capturing typical events for the patient. • Inpatient video-EEG monitoring will demonstrate wakefulness during events for patients with psychogenic nonepileptic seizures compared with some events in patients with physiologic nonepileptic episodic events or epileptic seizures. • Prolactin levels may help distinguish epileptic seizures from psychogenic nonepileptic seizures by demonstrating a twofold rise from baseline in the 10 to 20 minutes after a seizure but should be interpreted with caution. • The diagnosis of psychogenic nonepileptic seizures should be presented to the patient in an honest, positive manner with an outline of plans for further evaluation and treatment. • Barriers to the treatment of psychogenic nonepileptic seizures include a lack of consistent follow-up with neurologists, shortage of trained treatment providers, and stigma related to psychological and psychiatric care. • Cognitive-behavioral therapy is an evidence-based treatment shown to reduce seizure frequency and improve the quality of life in patients with psychogenic nonepileptic seizures. • Although up to 70% of patients with psychogenic nonepileptic seizures may continue to have seizures after diagnosis, higher education, shorter time to diagnosis, and lower somatoform and dissociative scores may predict better outcomes. • Up to 10% of patients with psychogenic nonepileptic seizures may also have epileptic seizures, and careful attention is needed during evaluation and treatment to identify and manage both disorders. • Physiologic causes of nonepileptic episodic events in children that may mimic epilepsy include reflux, sleep disorders, and breath-holding spells. Article 11: Update on Antiepileptic Drugs 2019

Bassel W. Abou-Khalil, MD, FAAN. Continuum (Minneap Minn). April 2019; 25 (2 Epilepsy):508–536.

ABSTRACT

PURPOSE OF REVIEW: This article is an update from the article on antiepileptic drug (AED) therapy published in the last Continuum issue on epilepsy and is intended to cover the vast majority of agents currently available to the neurologist in the management of patients with epilepsy. Treatment of epilepsy starts with AED monotherapy. Knowledge of the spectrum of efficacy, clinical pharmacology,

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. and modes of use for individual AEDs is essential for optimal treatment for epilepsy. This article addresses AEDs individually, focusing on key pharmacokinetic characteristics, indications, and modes of use.

RECENT FINDINGS: Since the previous version of this article was published, three new AEDs, brivaracetam, cannabidiol, and stiripentol, have been approved by the US Food and Drug Administration (FDA), and ezogabine was removed from the market because of decreased use as a result of bluish skin pigmentation and concern over potential retinal toxicity. Older AEDs are effective but have tolerability and pharmacokinetic disadvantages. Several newer AEDs have undergone comparative trials demonstrating efficacy equal to and tolerability at least equal to or better than older AEDs as first-line therapy. The list includes lamotrigine, oxcarbazepine, levetiracetam, topiramate, zonisamide, and lacosamide. Pregabalin was found to be less effective than lamotrigine. Lacosamide, pregabalin, and eslicarbazepine have undergone successful trials of conversion to monotherapy. Other newer AEDs with a variety of mechanisms of action are suitable for adjunctive therapy. Most recently, the FDA adopted a policy that a drug’s efficacy as adjunctive therapy in adults can be extrapolated to efficacy in monotherapy. In addition, efficacy in adults can be extrapolated for efficacy in children 4 years of age and older. Both extrapolations require data demonstrating that an AED has equivalent pharmacokinetics between its original approved use and its extrapolated use. In addition, the safety of the drug in pediatric patients has to be demonstrated in clinical studies that can be open label. Rational AED combinations should avoid AEDs with unfavorable pharmacokinetic interactions or pharmacodynamic interactions related to mechanism of action.

SUMMARY: Knowledge of AED pharmacokinetics, efficacy, and tolerability profiles facilitates the choice of appropriate AED therapy for patients with epilepsy.

KEY POINTS • Phenobarbital, primidone, phenytoin, and carbamazepine are potent inducers of liver enzymes, reducing the efficacy of drugs metabolized by the cytochrome P450 enzyme system. • Long-term phenobarbital use is associated with decreased bone density, Dupuytren contractures, plantar fibromatosis, and frozen shoulder. • In addition to sedation and other adverse effects of phenobarbital, primidone use is associated with an acute toxic reaction unrelated to phenobarbital, with potentially debilitating drowsiness, dizziness, ataxia, nausea, and vomiting. • Phenytoin has saturable nonlinear kinetics. Beyond a certain serum concentration, usually within the accepted therapeutic range, phenytoin concentration increases disproportionately with an increase in the dose. Small increments are necessary when increasing the dose at a serum concentration in the therapeutic range. • The traditional sodium channel blockers phenytoin, carbamazepine, and oxcarbazepine may exacerbate generalized absence and myoclonic seizures and should be avoided in idiopathic generalized epilepsy. Other antiepileptic drugs that have similar potential are gabapentin, pregabalin, tiagabine, and vigabatrin. • Unlike phenytoin, the phenytoin prodrug fosphenytoin may be administered intramuscularly, with reliable absorption, in the absence of IV access. • Carbamazepine induces its own metabolism, so it has to be titrated gradually to the target dose. • The HLA-B1502 allele is predictive of a carbamazepine-induced severe rash in individuals of Asian descent. • Oxcarbazepine is more likely to cause hyponatremia than carbamazepine. Older individuals taking a diuretic are at particularly high risk. • Eslicarbazepine has a long half-life in CSF, justifying once-daily oral dosing. • Valproate has a broad spectrum of efficacy against all focal and generalized seizure types.

Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. • Valproate has the highest rate of teratogenicity among antiepileptic drugs and should be avoided in women of childbearing potential. • Ethosuximide is the drug of choice for pure absence seizures. While valproate is equally effective, it is associated with more cognitive adverse effects. • Tolerance may develop to the therapeutic effect of benzodiazepines; this appears less likely with clobazam than clonazepam. • Felbamate-related aplastic anemia and liver failure are unlikely to start after 1 year of treatment. • Gabapentin bioavailability is low and decreases with increasing doses. • Like gabapentin, pregabalin has a narrow spectrum of efficacy against focal seizures and may exacerbate generalized myoclonic and absence seizures. • Lamotrigine clearance is decreased by valproate and increased by estrogen and pregnancy as well as by enzyme inducers. • Tiagabine may be associated with dose-related episodes of nonconvulsive status epilepticus or encephalopathy, even in subjects who do not have epilepsy. • Levetiracetam is the only antiepileptic drug with Class I evidence of efficacy against generalized myoclonic seizures. • Brivaracetam may have fewer behavioral side effects than levetiracetam. • Zonisamide’s long half-life of about 60 hours may be an advantage in reducing the impact of a missed dose. • Lacosamide may produce a dose-dependent prolongation in PR interval, which could be clinically significant in patients with known conduction problems, or if it is combined with other drugs that have a similar effect. • Long-term vigabatrin use may be associated with irreversible visual field constriction; hence, it should only be continued if it produces a remarkable improvement in seizure control. • Valproate reduces rufinamide clearance; as a result, rufinamide has to be started at a lower dose and titrated more slowly in the presence of valproate. • Perampanel has a very long half-life, justifying once-daily dosing. • Antiepileptic drug combinations with different mechanisms of action may have a greater probability of success.