Types of Epilepsy

Abstract

Epilepsy, affecting at least 2% of the population, comprises a group of disorders of the brain characterized by the periodic and unpredictable occurrence of seizures. It is clear that epilepsy is a major public health problem in that those affected experience the periodic and unpredictable occurrence of seizures leading to impairment of consciousness. This handicap severely impairs the performance of many tasks and secondarily the procurement and maintenance of steady employment. In this chapter, we provide an overview of seizure types, epilepsy syndromes, animal models of epilepsy, and antiepileptic drugs (AEDs). Evidence indicates that astrocyte changes in epilepsy provide promising new targets for AED development.

Keywords

Seizure; epilepsy; anticonvulsant; antiepileptic; epileptogenesis; animal model; status epilepticus; surgery

Overview

It is estimated that one in 26 people will develop epilepsy in their lifetime, amounting to almost 12 million people in the United States alone [1]. Epilepsy is a group of conditions characterized by sporadic occurrence of seizures and unconsciousness. This severely limits the ability to perform everyday tasks and leads to increased difficulty with learning and memory, maintenance of steady employment, driving, and overall socioeconomic integration. Epilepsy is not a benign condition as it is associated with both increased mortality and decreased quality of life. A greater understanding of the cellular and molecular mechanisms underlying seizures and epilepsy is necessary, as it may lead to novel antiepileptic treatments.

In this chapter, we will provide a brief overview of seizure types, epilepsy classification, and common animal models of epilepsy.

Seizures and Epilepsy

A seizure is the clinical manifestation of abnormal excessive or synchronous neuronal activity in the brain. Epilepsy comprises a variety of syndromes characterized by recurrent seizures unprovoked by systemic or acute neurologic insults.

A summary of types of seizures is given in Table 4.1 [2]. Partial or focal seizures involve seizure onset from a focal area in one hemisphere. Simple partial seizures do not involve loss of consciousness whereas complex partial seizures involve some loss of consciousness or awareness.

Table 4.1

Overview of Seizure Types

Seizure Type	Brief Description	EEG Characteristic
Partial (or focal)	Seizure onset from one area of the brain and limited to one hemisphere. Divided into simple partial seizures (no loss of consciousness) and complex partial seizures (with loss of consciousness)	Start focally then may secondarily generalize
Neocortical	Seizure generation from the neocortex; manifestation depends on exact location of origin and pattern of spread	Focal onset from neocortex
Temporal lobe	Seizure generation from temporal lobe structures, such as the hippocampus; often consists of epigastric aura followed by automatisms, dystonia of contralateral hand, and postictal confusion	Focal onset from temporal lobe
Generalized	Seizure onset simultaneously from both hemispheres	Generalized
Absence	Brief loss of consciousness, eye blinking and staring, and/or facial movements with no postictal confusion	3-Hz generalized spike-and-slow-wave complexes
Myoclonic	Quick, repetitive, arrhythmic muscle twitching involving one or both sides of the body; consciousness remains intact	Generalized spike-and-wave discharge
Clonic	Seizures consist of rhythmic muscle jerks during impaired consciousness	Fast activity (≥10 Hz) and slow waves with occasional spike-wave patterns
Tonic	An increase in muscle tone causes flexion of head, trunk, and/or extremities for several seconds	Bilateral synchronous medium to high-voltage fast activity (10–25 Hz)
Tonic-clonic	Tonic extension of muscles followed by clonic rhythmic movements and postictal confusion	Tonic phase: Generalized rhythmic discharges decreasing in frequency and increasing in amplitude
Tonic-clonic		Clonic phase: Slow waves
Atonic	Brief loss of postural tone, which can result in falls and injuries	Slow rhythmic (1–2 Hz) spike-and-wave complexes or more rapid, irregular multifocal spike-and-wave activity

Modified with permission from Hubbard et al. Glial cell changes in epilepsy: overview of the clinical problem and therapeutic opportunities. Neurochem Int 2013; 63:638-651 (Table 1).

Simple partial seizures often have focal or localized signs related to the area of cortex involved. In addition they may be associated with auras. Auras (“breezes” in Greek) have been defined as “that portion of the seizure which occurs before consciousness is lost and for which memory is retained afterwards” [3]. Distinct epileptic auras have been categorized as: (1) epigastric; (2) fear and anxiety; (3) experiential (including déjà vu/jamais vu); (4) olfactory-gustatory (“uncinate fits”); (5) autonomous/vegetative; and (6) nonspecific [4]. The most common aura in temporal lobe epilepsy (TLE, the most common type of partial epilepsy) is rising epigastric aura [5]; interestingly, a single localized epileptogenic lesion can lead to multiple aura types [6].

Complex partial seizures by definition lead to some impairment of consciousness or awareness during the seizure. Clinical manifestations vary with site of origin and degree of spread. Complex partial seizures are often associated with auras, and also automatisms (eg, lip smacking, fumbling). Postictal confusion is very common. The duration of complex partial seizures is usually about 1–2 minutes.

Generalized seizures, by contrast, do not have focal onset. Generalized seizures are divided into absence, myoclonic, clonic, tonic, tonic-clonic, and atonic seizures. Absence seizures (petit mal) involve brief staring spells with impairment of awareness, usually lasting 3–20 seconds, with sudden onset and sudden resolution. Often provoked by hyperventilation, they have onset typically between 4 and 14 years of age, and often resolve by 18 years of age. They are usually associated with normal development and intelligence but episodes in school of “tuning out” have occasionally led to misdiagnosis as attention deficit-hyperactivity disorder (ADHD). Myoclonic seizures are characterized by brief, shock-like jerks of a muscle or group of muscles, typically bilateral, and so brief (seizures <1 second) that impairment of consciousness is difficult to assess. These must be differentiated from benign, nonepileptic myoclonus (eg, while falling asleep). Clonic seizures are similar to myoclonic but repetition rate is slower; tonic seizures involve rigid posturing of the limbs or torso often with deviation of the head or eyes toward one side; and tonic-clonic (grand mal) seizures involve both tonic and clonic phases. During the tonic phase, the patient may cry out, become rigid, and exhibit signs such as respiratory impairment, cyanosis, pupillary dilation, and increase in heart rate and blood pressure. During the clonic phase, the seizure evolves into clonic movement characterized by jerking of the extremities. Tonic-clonic seizures may extend for several minutes prior to termination or may evolve into status epilepticus (SE; continuous seizures). Atonic seizures involve sudden loss of postural tone which when severe results in falls (drop attacks), when milder may produce head nods or jaw drops. Consciousness is impaired but the duration is usually few seconds (<1 minute).

Seizure phases include preictal (period before seizure), ictal (period during the seizure), interictal (period between seizures), and postictal (period of transition from the ictal phase to the patient’s normal level of awareness and function—may be minutes to hours). Ictal and postictal assessment includes whether the patient can speak and follow commands, head or eye deviation, posturing of extremities, whether the patient sustained injuries (eg, falls, tongue biting), behavioral changes during and after seizure, incontinence, weakness (eg, Todd’s paralysis [7]), aphasia, and postictal confusion. Typical diagnostic evaluation of seizure will include a good history (family history, history of head trauma, febrile seizures, meningitis/encephalitis, medication history, illicit drug use) and other tests such as blood tests (complete blood count, electrolytes, glucose, calcium, magnesium, phosphate, hepatic, and renal function tests), lumbar puncture (limited to cases in which infectious etiology such as meningitis or encephalitis suspected), blood or urine screen for drugs, electrocephalogram (EEG), and brain MRI. The key goal is to diagnose the type of epilepsy if present, determine etiology and comorbid problems, establish prognosis, and decide treatment options. Definitive diagnosis is obtained often with the gold-standard test of video-EEG monitoring in an inpatient epilepsy monitoring unit. This is the cornerstone of diagnosing seizures (vs pseudoseizures or other syndromes) and epilepsies, to determine epileptogenic zone anatomy and to assess for candidacy for epilepsy surgery. Additional important tests employed may include: Wada test (intracarotid sodium amobarbital procedure, which anesthetizes one half of the brain temporarily to assess language and memory function localization), interictal PET (positron emission tomography), ictal or interictal SPECT (single photon emission computed tomography), MEG (magnetoencephalography), neuropsychological testing, and intracranial video-EEG monitoring.

International League Against Epilepsy Classification

All attempts at classification of seizures are hampered by our limited knowledge of the underlying pathological processes within the brain and that any classification must of necessity be a tentative one and will be subject to change with every advance in scientific understanding of epilepsy.

Source: Ref. [8].

The International League Against Epilepsy (ILAE) (www.ilae.org) has made many attempts over the years to standardize and refine a classification of epilepsies and epileptic syndromes. In 1981, they issued a classification for “epileptic seizures” and in 1989 for “epilepsies and epileptic syndromes.” Since 1997, the ILAE Task Force on Classification has made further significant efforts including the reports of 2001 and 2006 [9,10]. In 2010 [11] and 2014 [12], the ILAE issued other reports adding new terminology and concepts. For example, the previous etiologic categorization of epilepsies as “idiopathic,” “symptomatic,” or “cryptogenic” was replaced with “genetic,” “structural/metabolic,” or “unknown cause” [11]. However, these reports have generated significant controversy [13–16]. The complexity of classification of epilepsies, whether genetic, structural/metabolic, or of unknown cause is clear to see in Table 4.2. In a new, as yet unadopted classification, the ILAE commission (Scheffer et al. [12], www.ilae.org) proposes expanding the etiologic subtypes into six categories: genetic, structural, metabolic, immune, infectious, and unknown. Ultimately, as research progresses and understanding deepens, epilepsies will be increasingly categorized by etiology rather than (as traditionally done) by clinical semiology or electrographic (EEG) characteristics. Recently, the ILAE has published a new definition and classification scheme for SE as well, a topic omitted in many previous ILAE reports [17]. For updated detailed classification data and reports on the many types of epilepsy, the reader is encouraged to consult www.EpilepsyDiagnosis.org, an online diagnostic manual of the epilepsies published by the ILAE Commission on Classification and Terminology.

Table 4.2

Electroclinical Syndromes and Other Epilepsies

Electroclinical Syndromes Arranged by Age at Onset a

Neonatal period

Benign familial neonatal epilepsy (BFNE)

Early myoclonic encephalopathy (EME)

Ohtahara syndrome

Infancy

Epilepsy of infancy with migrating focal seizures

West syndrome

Myoclonic epilepsy in infancy (MEI)

Benign infantile epilepsy

Benign familial infantile epilepsy

Dravet syndrome

Myoclonic encephalopathy in nonprogressive disorders

Childhood

Febrile seizures plus (FS+) (can start in infancy)

Panayiotopoulos syndrome

Epilepsy with myoclonic atonic (previously astatic) seizures

Benign epilepsy with centrotemporal spikes (BECTS)

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE)

Late-onset childhood occipital epilepsy (Gastaut type)

Epilepsy with myoclonic absences

Lennox-Gastaut syndrome

Epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS)^b

Landau-Kleffner syndrome (LKS)

Childhood absence epilepsy (CAE)

Adolescence—Adult

Juvenile absence epilepsy (JAE)

Juvenile myoclonic epilepsy (JME)

Epilepsy with generalized tonic-clonic seizures alone

Progressive myoclonus epilepsies (PME)

Autosomal dominant epilepsy with auditory features (ADEAF)

Other familial temporal lobe epilepsies

Less specific age relationship

Familial focal epilepsy with variable foci (childhood to adult)

Reflex epilepsies

Distinctive constellations

Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE with HS)

Rasmussen syndrome

Gelastic seizures with hypothalamic hamartoma

Hemiconvulsion–hemiplegia–epilepsy

Epilepsies that do not fit into any of these diagnostic categories can be distinguished first on the basis of the presence or absence of a known structural or metabolic condition (presumed cause) and then on the basis of the primary mode of seizure onset (generalized vs focal)

Epilepsies attributed to and organized by structural–metabolic causes

Malformations of cortical development (hemimegalencephaly, heterotopias, etc.)

Neurocutaneous syndromes (tuberous sclerosis complex, Sturge-Weber, etc.)

Tumor

Infection

Trauma

Angioma

Perinatal insults

Stroke

Etc.

Epilepsies of unknown cause

Conditions with epileptic seizures that are traditionally not diagnosed as a form of epilepsy per se

Benign neonatal seizures (BNS)

Febrile seizures (FS)

^a The arrangement of electroclinical syndromes does not reflect etiology.

^b Sometimes referred to as Electrical Status Epilepticus during Slow Sleep (ESES).

Reproduced with permission from Berg et al. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 2010; 51:676–685 (Table 3).

Animal Models of Epilepsy

Critical to the neuroscientific researcher attempting to identify new concepts and targets for treatment of various forms of epilepsy are animal models. Comparison of various animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs has been previously extensively reviewed [18–20] and is itself the topic of many books and book chapters [20,21]. Some common (not an exhaustive list) animal models of epilepsy together with the types of human epilepsy they purport to model are listed in Table 4.3 [22]. The “perfect animal model” of a specific epileptic syndrome would recapitulate: (1) age of onset; (2) etiology; (3) seizure phenotype and EEG characteristics; and (4) comorbidities or other long-term consequences [18].

Table 4.3

Summary of Animal Models

Model	Induction	Manifestations	Human Relevance	Use	Limitations
CHEMOCONVULSANTS
KA-SE	Systemic or intrahippocampal injection	Limbic SE and chronic seizures	TLE with hippocampal sclerosis	AED screening, mechanisms of epileptogenesis	High mortality; variable frequency and severity of spontaneous seizures; not all neural damage comes from seizures
Pilo-SE	Systemic or intrahippocampal injection	Limbic SE and chronic seizures	TLE with hippocampal sclerosis	AED screening, mechanisms of epileptogenesis, and cognitive/psychiatric comorbidities	High mortality; variable frequency and severity of spontaneous seizures; neocortical lesions
Acute chemical models	Systemic or intrahippocampal injection	Nonconvulsive absence or generalized tonic-clonic seizures, depending on the drug and dose	Acute and repetitive seizures	Rapid screening of AED, effect of repetitive seizures	Lack of spontaneous recurrent seizures (SRS) and of neuronal loss or other neuropathological hallmarks
SE in immature rodents	Systemic injection of KA or Pilo	Tonic-clonic seizures	Prolonged seizures during development	Epileptogenesis and long-term consequences	KA and Pilo are not clinical causes of seizures; more extensive damage compared with other models
Repetitive seizures in immature rodents	Systemic injection of PTZ or flurothyl inhalation	Myoclonic and generalized tonic-clonic seizures	Repetitive brief seizures during development	AED screening and cognitive deficits	No spontaneous seizures in adulthood
ELECTRICAL STIMULATION
Electroshock-induced seizures	Corneal or auricular stimulation	Generalized tonic-clonic seizures	Tonic-clonic seizures	AED screening and molecular and physiological alternations related to epileptiform activities	Low-predictive validity for some AEDs
After discharges	Focal electrical stimulation	Complex partial seizures and myoclonic seizures	Focally generated seizure-like patterns that often spread to other regions	Electrophysiological and behavioral changes caused by focally generated seizure patterns	No specificity for groups of neurons; studying neuronal activity during stimulation is difficult
Kindling	Repeated afterdischarge induction	Partial seizures evolving into secondary generalization and, eventually, spontaneous seizures	Consequences of poorly controlled seizures and dynamics of epileptogenic processes	Prevention of epileptogenesis processes and treatment of pharmacoresistant epilepsies	Costly and time-consuming procedure
BRAIN PATHOLOGY
Hyperthermic seizures	Increase of body temperature in immature rodents through stream of heated air	Immobility, facial automatism, myoclonic jerks	Febrile seizure	Epileptogenesis mechanisms and cognitive consequences	Subtle behavioral seizures, necessity of EEG recording, possible morbidity from heat exposure
Hypoxia model	Exposure to air with low O₂ concentration in immature rodents	Brief and repetitive tonic-clonic seizures	Neonatal hypoxic encephalopathy	AED screening, long-term consequences, and epileptogenesis mechanisms	Susceptibility for seizures varies with the strain and age of rodents
Posttraumatic epilepsy	Rostral parasagittal fluid percussion injury	Generalized tonic-clonic seizures in the long term, with low frequency	Posttraumatic epilepsy	AED screening, mechanisms of epileptogenesis, and hippocampal sclerosis with dual pathology	Laborious induction, long latency periods, mild seizures during the first 4 months of posttrauma
GENETIC MODELS
Audiogenic models	Acoustic stimulation in genetically prone rats	Wild running and tonic-clonic seizures	Reflex epilepsy and TLE studies	Epileptogenesis mechanisms and comorbidities associated with epilepsies	Necessity of a trigger to evoke seizures; lack of SRS
GAERS, WAG/Rij, and mouse models of absence seizures	Spontaneous seizures	SWD generalization, behavioral arrest	Generalized idiopathic epilepsies	Electrographic and behavioral similarity to human absence seizures, response to AEDs	Diverse (and not fully known) genetic alterations