Epilepsies PDF

101 Epilepsies
Bassel W. Abou-Khalil, Martin J. Gallagher, Robert L. Macdonald
CHAPTER OUTLINE
OTHER THERAPIES
SEIZURES AND EPILEPSY DEFINITIONS Dietary Therapy
Vagus Nerve Stimulation
ICTAL PHENOMENOLOGY Other Stimulation Therapies
Glossary of Seizure Terminology and Other Definitions Radiosurgery
CLASSIFICATION OF SEIZURES QUALITY-OF-CARE STANDARDS IN THE MANAGEMENT
Other Seizure Terminology OF EPILEPSY
SEIZURE TYPES SEIZURE CLUSTERS AND STATUS EPILEPTICUS
Partial Seizures (Focal Seizures)
Generalized Seizures
CLASSIFICATION OF EPILEPSIES AND EPILEPTIC
SYNDROMES
SEIZURES AND EPILEPSY DEFINITIONS
Epileptic Syndromes and Constellations Seizures are transient events that include symptoms and/or
Causes and Risk Factors signs of abnormal excessive hypersynchronous activity in the
brain (Fisher et al., 2005). In 2005, the International League
SEIZURE PRECIPITANTS Against Epilepsy (ILAE) and International Bureau for Epilepsy
EPIDEMIOLOGY OF EPILEPSY AND SEIZURES (IBE) proposed a definition of epilepsy as a disorder of the
Descriptive Epidemiology brain characterized by an enduring predisposition to generate
Epidemiology of the First Unprovoked Seizure epileptic seizures and by the neurobiological, cognitive, psy-
chological, and social consequences of this condition (Fisher
MORBIDITY AND MORTALITY et al., 2005). Acute symptomatic seizures provoked by meta-
Morbidity and Comorbidity bolic or toxic derangements or occurring acutely in the setting
Mortality in Epilepsy of head trauma or stroke do not define epilepsy.
PATHOPHYSIOLOGY AND MECHANISMS The traditional definition of epilepsy requires at least two
Generalized Seizures unprovoked seizures. The definition proposed by the ILAE in
2005 suggested that one epileptic seizure is sufficient to diag-
Mesial Temporal Lobe Seizures
nose epilepsy if there is additional enduring alteration in the
Neocortical Focal Seizures (NFS) brain that increases the likelihood of future seizures, but the
DIFFERENTIAL DIAGNOSIS proposal did not specify what evidence is sufficient to define
Psychogenic Nonepileptic Seizures such an enduring alteration. The proposed definition has been
Syncope controversial and has not been widely accepted (Beghi et al.,
Migraine 2010). Most recently a practical clinical definition of epilepsy
Sleep Disorders was proposed by the ILAE (Fisher et al., 2014), addressing
some of the controversy. Epilepsy was defined as a disease of
Paroxysmal Movement Disorders
the brain defined by any of the following conditions: (1) at
EVALUATION AND DIAGNOSIS least two unprovoked (or reflex) seizures occurring >24 hours
Evaluation of Recent-Onset Seizures and Epilepsy apart, or (2) one unprovoked (or reflex) seizure and a prob-
Evaluation of Drug-Resistant Seizures and Epilepsy ability of further seizures similar to the general recurrence risk
Evaluation of Patients for Epilepsy Surgery (at least 60%) after two unprovoked seizures, occurring over
the next 10 years, or (3) diagnosis of an epilepsy syndrome.
MEDICAL THERAPY The definition of epilepsy used in this chapter requires at least
Initiating Therapy two unprovoked seizures that are >24 hours apart.
Antiepileptic Drug Considerations Based on Age and A variety of seizure types exist, and epilepsy is not a single
Gender entity but rather a collection of disorders that have in common
Pharmacoresistance, Tolerance, and Seizure the occurrence of seizures. Hence, a need exists for classifica-
Aggravation tion of seizures and of epilepsies and epileptic syndromes. The
Medication Adverse Effects classification is important for communication and diagnostic
Therapeutic Drug Monitoring purposes, but also for evaluating drug specificity and prescrib-
Discontinuation of Antiepileptic Drug Therapy ing the most appropriate therapy. The diagnosis of certain
seizure types can predict response to therapy and prognosis.
SURGICAL THERAPY In 2001, the ILAE proposed a diagnostic scheme for
Timing the classification of seizures and epilepsy (Engel, 2001). The
Presurgical Evaluation scheme recommended axes that are helpful concepts in the
Surgical Approaches evaluation of patients with epilepsy:
Surgical Results and Predictors of Surgical Freedom Axis 1: Ictal phenomenology—can be used to describe ictal
events with any degree of detail needed.
1563
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1564 PART III Neurological Diseases and Their Treatment
Axis 2: Seizure type. a truncal rotation. Dystonic posturing is a sustained contraction

Axis 3: Syndrome (understanding that a syndrome diagnosis that results in an abnormal posture with a rotator or twisting
may not always be possible). motion (Fig. 101.2). A myoclonic jerk or myoclonus refers to a
Axis 4: Etiology. very brief involuntary contraction usually lasting less than
Axis 5: Impairment (optional, but often useful, additional 100 msec. This can affect any distal or proximal body part and
diagnostic parameter). may also be generalized. Negative myoclonus refers to an inter-
ruption of tonic muscle activity for less than 500 msec without
Although this scheme is not widely used, it is a useful organi-
prior positive contraction. Negative myoclonus may produce
zational tool. This chapter will follow the ILAE scheme to
a jerk-like motion in association with a transitory loss of
describe seizure manifestations, seizure types, and epilepsies/
posture of that body part. Negative myoclonus would not be
epileptic syndromes.
visible if the affected body part were resting. Clonic activity
refers to a regularly repetitive jerking that is prolonged. Clonic
ICTAL PHENOMENOLOGY activity is further described as being without a march if it
remains confined to the same body part from beginning to
Glossary of Seizure Terminology and end. Clonic activity has a Jacksonian march if it spreads through
Other Definitions contiguous body parts on the same side, reflecting horizontal
The terms frequently used in the description of seizures follow. spread of seizure activity over the motor strip. Tonic-clonic
Whenever possible, the definition is derived from the glossary activity is a sequence of initial tonic posturing that evolves to
of descriptive terminology for ictal semiology, reported by the a clonic phase. Atonic activity refers to a sudden decrease or
ILAE task force on classification and terminology (Blume loss of muscle tone usually lasting more than 1 second. This
et al., 2001). The term ictal semiology means the signs and can affect the head, trunk, or limbs, usually bilaterally.
symptoms associated with seizures. However, focal atonic activity can also occur. Astatic refers to
Motor manifestations refer to involvement of the muscula- a loss of erect posture; an astatic seizure is synonymous with
ture, usually with an increase in muscle contraction that a drop attack.
produces a movement. A motor manifestation can also be Automatisms are repetitive motor activities that are more or
negative, associated with a decrease in muscle contraction. The less coordinated and resemble a voluntary movement but are
term positive motor can be used to specifically indicate an not purposeful. Automatisms usually occur in association
increase in muscle contraction. with altered sensorium, and the individual is usually amnestic
Several qualifiers for motor manifestation exist. Elementary to their occurrence. Automatisms may be an inappropriate
motor refers to the contraction of a muscle or group of muscles continuation of previously ongoing activity. This is referred to
that is usually stereotyped and does not include multiple as perseverative automatisms. Automatisms that start after seizure
phases. Elementary motor manifestations include tonic, which onset are called de novo automatisms. Automatisms may be
means a sustained increase in muscle contraction lasting up reactive—for example, fumbling with an object that was
to minutes. Tonic activity includes epileptic spasms that are a present or newly placed in the patient’s hand.
sudden flexion and/or extension which is more sustained than Automatisms can be described by the part of the body
a myoclonic jerk but yet very short in duration, affecting pre- affected. Some of the most common are oroalimentary autom-
dominantly proximal or truncal muscles. Postural manifestation atisms, which include lip smacking, chewing, swallowing, and
suggests tonic activity that results in a posture. This will usually other mouth movements. Ictal spitting and ictal drinking can
involve contraction of more than one muscle. Versive manifes- be considered forms of oroalimentary automatisms. Automa-
tation indicates a sustained or forced deviation of the eyes or tisms affecting the distal extremities are manual or pedal.
the head to one side (Fig. 101.1). This may be associated with Manual or pedal automatisms can be bilateral or unilateral.
Gestural automatisms include extremity movements such as
those used to enhance speech. More recently introduced cat-
egories for upper extremity automatisms are manipulative and
nonmanipulative (Kelemen et al., 2010). Manipulative automa-
tisms involve picking and fumbling motions, typically reflect-
ing interaction with the environment. Nonmanipulative upper
extremity automatisms tend to be rhythmic and do not involve
Fig. 101.1 Versive eye and head turning in transition to general-

ized tonic posturing in a subject with right frontal lobe seizures.
Note the associated neck extension. Fig. 101.2 Dystonic posturing of the right arm.
Epilepsies 1564.e1
101
eFig. 101.1 Versive eye and head turning in transition to generalized tonic posturing in a subject with right frontal lobe seizures. The images are
one second apart. Note the associated neck extension.
1564.e2 PART III Neurological Diseases and Their Treatment
eFig. 101.2 Dystonic posturing (DP): variable pattern demonstrated in four patients with temporal lobe epilepsy. Left to right: top, right arm DP,
left arm DP; bottom, right arm DP, right arm DP.
Epilepsies 1565
interaction with the environment. Distal nonmanipulative

upper-extremity automatisms have been described with the BOX 101.1 1981 International League Against Epilepsy 101
acronym RINCH (rhythmic ictal non-clonic hand) move- Classification of Epileptic Seizures
ments (Lee et al., 2006; Kuba et al., 2013). Hyperkinetic autom-
I. Partial (Focal, Local) Seizures
atisms imply an inappropriately rapid sequence of movements
A. Simple partial seizures (consciousness not impaired)
that predominantly involve axial and proximal limb muscles.
1. With motor symptoms
The resulting motion can be thrashing, rocking, pelvic thrust-
2. With somatosensory or special sensory symptoms
ing, kicking, or bicycling motions. Seizures with hyperkinetic
3. With autonomic symptoms
automatisms are often referred to as hypermotor. Gelastic refers
4. With psychic symptoms
to abrupt laughter or giggling, while dacrystic refers to abrupt
B. Complex partial seizures (with impairment of
crying, both inappropriate.
consciousness)
Seizures may include a variety of subjective or sensory phe-
1. With simple partial onset followed by impairment of
nomena. Sensory phenomena are described as elementary if they
consciousness
involve a single primary sensory modality with unformed phe-
2. With impairment of consciousness at onset
nomena. This is applied predominantly to visual or auditory
C. Partial seizures evolving to secondarily generalized seizures
hallucination. Elementary visual phenomena could consist of
1. Simple partial seizures evolving to generalized seizures
flickering or flashing lights and other simple patterns such as
2. Complex partial seizures evolving to generalized
spots, scotomata, or visual loss. Elementary auditory phenomena
seizures
include buzzing, ringing, or humming sounds or single tones,
3. Simple partial seizures evolving to complex partial
but may also be negative, with loss of hearing. Somatosensory
seizures evolving to generalized seizures
phenomena can include tingling and other paresthesias, shock-
II. Generalized Seizures (Convulsive or Nonconvulsive)
like sensations, numbness, pain, or a sense of movement or a
A. Absence seizures
desire to move a body part. Somatosensory phenomena can
1. Typical absence seizures
remain confined to the same body part or could also have a
2. Atypical absence seizures
Jacksonian march, in which case the sensation moves to adja-
B. Myoclonic seizures
cent body parts on the same side, reflecting spread of the
C. Clonic seizures
seizure discharge in the sensory cortex. Olfactory hallucinations
D. Tonic seizures
are most often disagreeable and usually difficult to character-
E. Tonic-clonic seizures
ize. A variety of gustatory hallucinations can occur, particularly
F. Atonic seizures
with a metallic taste. A cephalic sensation is a sensation in the
III. Unclassified Epileptic Seizures
head that can be described variably, including tingling, full-
ness, pressure, or lightheadedness. From Commission on Classification and Terminology of the International
The category of experiential phenomena is wide and includes League Against Epilepsy, 1981. Proposal for revised clinical and
affective experiences such as fear, sadness, elation, dysmnesic electroencephalographic classification of epileptic seizures. Epilepsia 22,
phenomena such as feelings of familiarity (déjà vu) or unfa- 489–501.
miliarity (jamais vu) and complex hallucination (such as
seeing people or hearing music), and illusions (alterations of
perception). Dyscognitive describes events in which the pre-
dominant feature is alteration of cognition including percep- BOX 101.2 1989 International League against
tion, attention, memory, or executive function. Epilepsy Classification of Epilepsies and
Autonomic phenomena are very common in seizures. They Epileptic Syndromes
may be subjective, including an epigastric sensation, a feeling
of palpitation, or a feeling of flushing, or can be objective, 1. Localization-related (focal, local, partial) epilepsies and
including pupillary dilation, piloerection, pallor or flushing, syndromes
nausea, vomiting, and even flatulence. 1.1. Idiopathic (with age-related onset)
1.2. Symptomatic
1.3. Cryptogenic
CLASSIFICATION OF SEIZURES 2. Generalized epilepsies and syndromes
Two classifications developed by the ILAE continue to be used 2.1. Idiopathic (with age-related onset, listed in order of age
widely: the Clinical and Electroencephalographic Classifica- appearance)
tion of Epileptic Seizures published in 1981 (Commission on 2.2. Cryptogenic or symptomatic (in order of age)
Classification and Terminology, 1981) (Box 101.1) and the 2.3. Symptomatic
Classification of Epilepsies and Epileptic Syndromes intro- 2.3.1. Nonspecific etiology
duced in 1989 (Commission on Classification and Terminol- 2.3.2. Specific syndromes
ogy, 1989) (Box 101.2). Revisions to these classifications have 3. Epilepsies and syndromes undetermined as to whether they
been recommended based on advances made in the last 3 are focal or generalized
decades (Berg et al., 2010; Engel, 2001, 2006). The major rec- 3.1. With both generalized and focal seizures
ommended revisions are outlined later in this section, but 3.2. Without unequivocal generalized or focal features
what follows will focus on the 1981 and 1989 classifications, 4. Special syndromes
because these classifications were used widely for clinical man- 4.1. Situation-related seizures (Gelegenheitsanfälle)
agement and research. 4.1.1. Febrile convulsions
The 1981 classification of seizures has a major dichotomy 4.1.2. Isolated seizures or isolated status epilepticus
based on whether seizures start in one part of one hemisphere 4.1.3. Seizures occurring only when there is an acute
or in both hemispheres simultaneously. Seizures that start in metabolic or toxic event
one part of one hemisphere are classified as partial (or partial-
From Commission on Classification and Terminology of the International
onset) seizures, whereas those that start in both hemispheres League Against Epilepsy, 1989. Proposal for revised classification of
simultaneously are classified as generalized (or generalized- epilepsies and epileptic syndromes. Epilepsia 30, 389–399.
onset) seizures. Partial-onset seizures are subclassified as simple
partial if there is no impairment of consciousness, complex the seizures being discretely localized or more widely distrib-
partial if there is impairment or loss of consciousness at any uted, and possibly originating in subcortical structures. Gener-
point in the seizure, and partial seizures evolving to generalized alized seizures were defined as “originating at some point
tonic-clonic convulsions. Simple partial seizures can have motor within, and rapidly engaging, bilaterally distributed net-
signs, somatosensory or special sensory symptoms, autonomic works,” which do not necessarily include the entire cortex
symptoms and signs, or psychic symptoms. Under the heading (Berg et al., 2010). The revised concepts acknowledge that gen-
of generalized seizures were included generalized absence eralized seizures can be asymmetrical and that individual sei-
(typical or atypical), myoclonic, clonic, tonic, tonic-clonic, and zures may appear to have a localized onset, but the location
atonic seizures. Acknowledging that some seizures cannot be and laterality of that onset will vary from seizure to seizure
classified into partial- or generalized-onset, the classification (Berg et al., 2010).
also includes a category of unclassified seizures.
One important criticism of the 1981 classification is that it
requires both clinical and electroencephalographic (EEG) Other Seizure Terminology
information, and assumptions on correlation of clinical and Convulsion is an old term typically used to denote a generalized
EEG features may be incorrect. A purely semiological classifi- tonic-clonic seizure. It may also be used to indicate a seizure
cation of epileptic seizures was proposed, based solely on with prominent motor activity. Convulsive is an adjective indi-
observed clinical features (Lüders et al., 1998). The semiologi- cating the presence of prominent motor activity such as tonic
cal seizure classification includes somatotopic modifiers to or clonic or both. Nonconvulsive refers to a seizure or status
define the somatotopic distribution of the manifestations and epilepticus without prominent clonic or tonic motor activity.
allows demonstration of evolution of ictal manifestations The term is most commonly used with status epilepticus to
using arrows to link sequential manifestations (Lüders et al., indicate that seizure activity is predominantly affecting con-
1998). Although this classification was not adopted by the sciousness or behavior, with minimal or no motor activity.
ILAE, it is considered an optional seizure classification system The term grand mal is also an old term that is usually synony-
that is useful for localization purposes in epilepsy surgery mous with generalized tonic-clonic seizure. The term is dis-
centers. couraged in scientific writing, because it does not specify
The latest revision of the seizure classification has main- whether the onset is focal or generalized. Patients may use the
tained the division of seizures based on generalized or focal term grand mal simply to indicate a big seizure, and the neu-
onset but has recommended replacing partial with focal. It also rologist has to convert this term into official terminology. The
recommended other changes in terminology (Table 101.1), term petit mal is an old synonym for childhood absence epilepsy
and added some seizure types. The current chapter will con- (CAE) but is also used to describe absence seizures. Again, the
tinue to use the established older terminology but will usually term is commonly used by patients to indicate a small seizure,
offer the corresponding newer terminology. The latest revision which may actually be a complex partial seizure. A primary
updated the definition of focal seizures as “originating within generalized seizure or primarily generalized seizure is a synonym
networks limited to one hemisphere,” with the possibility of for generalized-onset seizure. Primary generalized epilepsy is a
synonym for idiopathic generalized epilepsy (IGE). A secondarily
generalized seizure means a partial-onset seizure that evolves to
generalized tonic-clonic activity. This is to be distinguished
TABLE 101.1 Select Terminology in New versus Old Seizure and from secondary generalized epilepsy, which is a synonym of symp-
Epilepsy Classifications tomatic generalized epilepsy. In symptomatic generalized epi-
1981 terminology 2010 terminology lepsy, the seizures are usually of generalized onset. The term
SEIZURE CLASSIFICATION
secondary generalized epilepsy should be discouraged because of
confusion with secondarily generalized seizure.
Partial seizure Focal seizure
Simple partial seizure Focal seizure without impairment of
consciousness or awareness SEIZURE TYPES
Complex partial seizure Focal seizure with impairment of Partial Seizures (Focal Seizures)
consciousness or awareness, or
“Dyscognitive” seizure Simple Partial Seizures (Focal Seizures without
Secondarily generalized Focal seizure evolving to a bilateral, Impairment of Consciousness or Awareness)
seizure convulsive seizure (involving tonic, Simple partial seizures are seizures in which consciousness is
clonic, or tonic and clonic
not altered at any point throughout the course of the seizure.
components)
The 1981 ILAE classification divides them into four major
EPILEPSY CLASSIFICATION categories:
Epilepsies and epileptic Separated into the following categories: 1. With motor signs.
syndromes Electroclinical syndromes
2. With somatosensory or special sensory symptoms.
Distinctive constellations
Epilepsies attributed to and organized
3. With autonomic symptoms or signs.
by structural-metabolic causes 4. With psychic symptoms (see Box 101.1).
Epilepsies of unknown cause Although most simple partial seizures would be classified
Idiopathic epilepsies Genetic epilepsies in one of these categories, it is quite possible for a simple
Cryptogenic epilepsies Epilepsies of unknown cause
partial seizure to have manifestations that belong in more
than one category. For example, simple partial seizures may
Symptomatic epilepsies Structural/metabolic epilepsies start with a sensory experience which then evolves into motor
secondary to specific structural or activity. Simple partial seizures of purely subjective nature are
metabolic lesions or conditions, but
often referred to as auras or isolated auras. The manifestations
which do not fit a specific
electroclinical pattern.
of simple partial seizures depend on the brain region involved
in the ictal discharge. However, it is important to recognize
Epilepsies 1567
that for simple partial seizures as well as other partial-onset

seizures, the seizure activity may originate in silent areas, and 101
the first clinical manifestations may reflect seizure spread to
other brain regions. Nevertheless, simple partial seizures and
auras may have important lateralizing and localizing value.
For example, focal clonic or tonic activity is usually contralat-
eral to the hemisphere involved in seizure activity. Somato-
sensory auras, visual auras, and auditory auras are often useful
in suggesting localization and lateralization of the epilep-
togenic zone. However, some auras are nonspecific and may
be seen with a variety of localizations.
Auras are typically short in duration, lasting seconds to
minutes. Some patients may experience a prodrome, a difficult-
to-describe feeling that a seizure may occur. Prodromes may
last hours or even days and have to be distinguished from
auras. On the other hand, auras may occasionally be pro-
longed, in which case they are called aura continua, which is a
form of simple partial status epilepticus.
The most recent recommendation of the ILAE Commission
on Classification and Terminology suggested eliminating the
term simple partial. Instead, it recommended descriptors of Fig. 101.3 Figure-of-four posturing, usually seen in transition
focal seizures according to degree of impairment during a from focal to generalized activity. The sign lateralizes seizure activity
seizure. Seizures without impairment of consciousness or contralaterally to the extended upper extremity.
awareness are divided into those with observable motor or
autonomic components and those only involving subjective
sensory or psychic phenomena (Berg et al., 2010). head jerking (Niaz et al., 1999). The evolution from tonic to
clonic activity is gradual and not always simultaneous in all
Complex Partial Seizures (Focal Seizures with affected body parts. A phase of high-frequency tremor has
Impairment of Consciousness or Awareness or been referred to as the tremulous or vibratory phase of the seizure
(Theodore et al., 1994). Clonic activity typically decreases in
Dyscognitive Seizures) frequency over time, with longer intervals between jerks
Complex partial seizures are characterized by altered con- towards the termination of the seizure. The clonic activity may
sciousness during the seizure. Impairment may be very subtle, end on one side of the body first, so that clonic activity may
manifesting with slight confusion, fuzziness, or slowing of then appear lateralized to one side. In addition, there may be
responses. A patient may have some recollection of events or a late head turn ipsilateral to the hemisphere of seizure origin
total amnesia for the event. Complex partial seizures may have (Wyllie et al., 1986). After the motor activity stops, the indi-
a simple partial onset. It is sometimes difficult to determine vidual is usually limp and has a loud snoring respiration often
if consciousness was impaired. The patient may be totally referred to as stertorous respiration. During the course of recov-
conscious but unable to respond verbally because of aphasia ery, there may be variable agitation. The speed of recovery is
or unable to respond or react because of motor inhibition. expected to be slower, with longer and more severe seizures.
When the simple partial onset is purely subjective, it is com-
monly referred to as an aura. Partial (Focal) Seizure Semiology in Relation
Complex partial seizures may arise from any lobe but most to Localization
commonly arise from the temporal lobe; the frontal lobe is
the second most common site of seizure origin. Complex Partial (Focal) Seizures of Temporal Lobe Origin. Tem-
partial seizures may include motor activity. The most common poral lobe seizures most often are of mesial temporal amy-
type of motor activity in this seizure type is automatism, gdalohippocampal origin, in association with the pathology
described earlier. The different complex partial seizure pat- of hippocampal sclerosis. Patients commonly have isolated
terns in seizures arising from different lobes of the brain will auras, and complex partial seizures tend to start with an aura.
be discussed in the next section. The most common aura is an epigastric sensation frequently
with a rising character (French et al., 1993). Other auras occur
less commonly and include fear, anxiety, and other emotions,
Partial Seizures Evolving to Generalized Tonic-Clonic déjà vu and jamais vu, nonspecific sensations, and autonomic
Activity (Focal Seizure Evolving to a Bilateral, changes such as palpitation and gooseflesh. Olfactory and
Convulsive Seizure (Involving Tonic, Clonic, gustatory auras are uncommon and are more likely with
tumoral mesial temporal lobe epilepsy (MTLE).
or Tonic and Clonic Components)) Complex partial seizures may start with an aura or with
These seizures may start as simple partial, complex partial, or altered consciousness. With nondominant temporal lobe sei-
simple partial evolving to complex partial. The transition to zures, the patient may remain responsive and verbally interac-
secondary generalization usually involves versive head turning tive. However, recollection of conversations is unusual. Altered
in a direction contralateral to the hemisphere of seizure onset consciousness is often associated with an arrest of motion and
(see Fig. 101.1), and focal or lateralized tonic or clonic motor speech. Speech arrest is not synonymous with aphasia and does
activity. The pattern of evolution may be clonic-tonic-clonic not distinguish dominant and nondominant temporal lobe
in some instances. The generalized tonic phase may be asym- seizures. Automatisms are one of the most prominent mani-
metrical, with flexion on one side and extension on the other. festations, and oroalimentary automatisms are the most
This has been called figure-of-4 posturing (Kotagal et al., 2000) prevalent. Extremity automatisms also occur and are most
(Fig. 101.3). Some asymmetry and asynchrony may also occur commonly manipulative, with picking or fumbling. This type
in the clonic phase, resulting in a slight degree of side-to-side of automatism is not of direct lateralizing value. However, the
Epilepsies 1567.e1
101
eFig. 101.3 Figure of 4 posturing, usually seen in transition from focal to generalized activity. The sign lateralizes seizure activity contralaterally
to the extended upper extremity (left hemisphere on the left, right hemisphere on the right).
contralateral upper extremity is commonly involved in dys- consciousness. Supplementary motor seizures are usually
tonic posturing (Kotagal et al., 1989) or milder degrees of short in duration and frequently arise out of sleep. They tend
posturing and immobility (Fakhoury and Abou-Khalil, 1995; to occur in clusters and may be preceded by a sensory aura
Williamson et al., 1998). This reduces the availability of the referable to the supplementary sensory cortex. The pattern of
contralateral arm for automatisms, so manipulative automa- posturing described with supplementary motor area seizures
tisms tend to be ipsilateral, involving the unaffected upper can occur as a result of seizure spread to the supplementary
extremity. Nonmanipulative automatisms typically consist of motor area from other regions of the brain. In that case, con-
rhythmic movements either distally or proximally. These tend sciousness is frequently impaired. Subjective simple partial
to be contralateral, often preceding overt dystonic posturing seizures may also occur with frontal lobe origin, the most
(Lee et al., 2006; Kuba et al., 2013). Head turning occurs com- common being a nonspecific cephalic aura.
monly. Early head turning is not usually forceful. It typically Complex partial seizures of frontal lobe origin tend to be
occurs at the same time as dystonic posturing and is most very peculiar. They may be preceded by a nonspecific aura or
often ipsilateral (Fakhoury and Abou-Khalil, 1995; William- they may start abruptly, often out of sleep. Their most charac-
son et al., 1998). Late head turning most often occurs during teristic features are hyperkinetic automatisms with frenzied
evolution to generalized tonic-clonic activity. This is usually behavior and agitation (Jobst et al., 2000; Williamson et al.,
contralateral to the side of seizure origin (Williamson et al., 1985). These are often referred to as hypermotor seizures.
1998). Well-formed ictal speech may occur during seizures of There may be various vocalizations including expletives. The
nondominant temporal lobe origin (Gabr et al., 1989). Verbal manifestations can be so bizarre as to suggest a psychiatric
output may at times be tinged with a fearful tone. Complex origin. The seizure duration is short, often less than 30
partial seizures of temporal lobe origin usually last between seconds, and postictal manifestations are brief or nonexistent,
30 seconds and 3 minutes. Postictal manifestations may be further adding to the risk of misdiagnosis as psychogenic sei-
helpful in lateralizing the seizure onset. Postictal aphasia is zures. Frontal lobe complex partial seizures arise predomi-
commonly seen after dominant temporal lobe seizures (Gabr nantly from the orbitofrontal region and from the mesial
et al., 1989). In one study, patients with dominant left tem- frontal cingulate region. However, they can arise from other
poral seizure origin were unable to read a test sentence cor- parts of the frontal lobe. It may be difficult to determine the
rectly in the first minute after seizure termination, but patients region of origin in the frontal lobe based on the seizure mani-
with nondominant right temporal lobe origin were able to festations. It has been suggested that the presence of tonic
read the test sentence within 1 minute of seizure termination posturing on one side points to a mesial frontal origin, as does
(Privitera et al., 1991). rotation along the body axis, which sometimes leads to
Seizures of lateral temporal origin or neocortical temporal turning prone during the seizure (Leung et al., 2008; Rheims
origin are much less common than those of mesial temporal et al., 2008).
origin. They cannot be reliably distinguished based on their Seizures originating in the frontal operculum are associated
semiology, but certain features suggest lateral temporal origin. with profuse salivation, oral facial apraxia, and sometimes
Auditory auras are the most common auras referable to the facial clonic activity (Williamson and Engel, 2008). Seizures
lateral temporal cortex, usually implying involvement of the originating in the dorsolateral frontal lobe may involve tonic
Heschl gyrus. Other types of auras referable to the lateral movements of the extremities and versive deviation of the eyes
temporal cortex are vertigo and complex visual hallucinations and head. The head deviation preceding secondary generaliza-
(usually posterior temporal). Oroalimentary automatisms are tion is contralateral, but earlier head turning can be in either
less common, and the pattern of contralateral dystonic postur- direction (Remi et al., 2011). Seizures may begin with forced
ing and ipsilateral extremity automatisms is also less common thinking. Partial seizures of frontal origin may at times resem-
(Dupont et al., 1999). Early contralateral or bilateral facial ble absence seizures (So, 1998). It is important to recognize
twitching may be seen as a result of propagation to the frontal that seizures originating in the frontal lobe can propagate to
operculum (Foldvary et al., 1997). Seizures of lateral temporal the temporal lobe and produce manifestations typical of
origin tend to be shorter in duration and have a greater ten- mesial temporal lobe seizures.
dency to evolve to generalized tonic-clonic activity than sei-
zures of mesial temporal origin. Seizures originating in the Partial (Focal) Seizures Originating in the Parietal
temporal lobe may have hypermotor semiology characteristic Lobe. The best-recognized seizure type that originates in the
of frontal lobe origin, due to propagation to the frontal lobe parietal lobe is partial seizure with somatosensory manifesta-
(Vaugier et al., 2009; Yu et al., 2013). This is commonly seen tions. The somatosensory experience can be described as tin-
with seizure origin in the temporal pole (Wang et al., 2008). gling, pins and needles, numbness, burning, or pain. The
presence of a sensory march is most suggestive of involvement
Partial (Focal) Seizures of Frontal Lobe Origin. Many of the primary sensory cortex. Sensory phenomena arising
different seizure types can originate in the frontal lobe, from the second sensory area and the supplementary sensory
depending on site of seizure origin and propagation. Simple area are less likely to have a march. Somatosensory auras tend
partial seizures can be motor with focal clonic activity, can to be contralateral to the hemisphere of seizure origin, but
originate in the motor cortex, or can be the result of spread to they may be bilateral or ipsilateral when arising from the
the motor cortex. These seizures may or may not have a Jack- second or supplementary sensory regions. Other auras of pari-
sonian march. Asymmetrical tonic seizures or postural sei- etal lobe origin are a sensation of movement in an extremity,
zures are usually related to involvement of the supplementary a feeling of the body bending forward or swaying or twisting
motor area in the mesial frontal cortex anterior to the motor or turning, or even a feeling of an extremity being absent
strip. The best-known posturing pattern is the fencing posture (Salanova et al., 1995a, b). Some patients may complain of
in which the contralateral arm is extended and the ipsilateral inability to move a limb. Vertigo has been reported, as well
arm is flexed. Tonic posturing may involve all four extremities as visual illusions of objects going away or coming closer
and is occasionally symmetrical. When these seizures originate or looking larger (Siegel, 2003). Some patients may have
in the supplementary motor area, consciousness is usually initial auras suggesting spread to the occipital or temporal
preserved (Morris et al., 1988). Supplementary motor seizures lobe. Seizures involving the dominant parietal lobe may
are an important exception to the rule that bilateral motor produce aphasic manifestations. Motor manifestations tend to
activity during a seizure should be associated with loss of reflect seizure spread to the frontal lobe. These include tonic
Epilepsies 1569
posturing of the extremities, focal motor clonic activity, and have missed conversation and seems confused as a result. If
version of the head and eyes (Cascino et al., 1993; Ho et al., the only manifestation is altered responsiveness and aware- 101
1994; Williamson et al., 1992a). Negative motor manifesta- ness, with no associated motor component, the absence
tions may occur, with ictal paralysis (Abou-Khalil et al., 1995). seizure is classified as simple absence. Most often, generalized
Seizures may spread to the temporal lobe, producing oroali- absence seizures include mild motor components and are
mentary or extremity automatisms (Siegel, 2003). In one classified as complex absence. The most common motor com-
study, motor manifestations were more likely with superior ponents are automatisms such as licking the lips or playing
parietal epileptogenic foci, and oroalimentary and extremity with an object that was held in the hand before the seizure.
automatisms more likely with inferior parietal epileptogenic Other motor components include clonic, tonic, atonic, and
foci (Salanova et al., 1995a). Visual manifestations seemed autonomic manifestations. Clonic activity may affect the
more likely with posterior parietal lesions. eyelids or the mouth. An atonic component may manifest
with dropping an object or slight head drop or drooping of
Partial (Focal) Seizures Originating in the Occipital
the shoulders or trunk. Tonic components may manifest with
Lobe. The best-recognized occipital lobe seizure semiology is
slight increase in tone.
that of simple partial seizures with visual manifestations
The EEG hallmark of a typical generalized absence seizure
(Salanova et al., 1992). The most common are elementary
is generalized 2.5- to 4-Hz spike-and-wave activity with a
visual hallucinations that are described as flashing colored
normal interictal background (Fig. 101.4). Atypical absence
lights or geometrical figures. These are usually contralateral
seizures are diagnosed primarily based on a slower (<2.5 Hz)
but may move within the visual field. Complex visual hallu-
frequency of the EEG spike-and-wave activity. Less important
cinations with familiar faces or people may also occur. Nega-
distinctions are that the onset and termination of an atypical
tive symptoms may be reported, with loss of vision in one
absence seizure may be less abrupt and the motor com
hemifield. Ictal blindness may occur, with loss of vision in the
ponents a bit more pronounced than seen with typical
whole visual field. Objective seizure manifestations include
absence seizures. Atypical absence seizures usually occur in
blinking, nystagmoid eye movements, and versive eye and
individuals with impaired cognitive function. Affected indi-
head deviation contralateral to the seizure focus. This version
viduals usually have associated seizure types such as general-
may occur while the patient is still conscious or could be a
ized tonic, generalized atonic, and generalized tonic-clonic
component of complex partial seizures.
seizures.
Seizure manifestations that are related to seizure spread to
Additional generalized absence seizure types recently
the temporal or frontal lobe are very common. Oroalimentary
recognized by the ILAE include myoclonic absences. The key
automatisms are typical of seizures that spread to the temporal
manifestation of these seizures is a prominent rhythmic
lobe, whereas asymmetrical tonic posturing typifies spread to
myoclonus predominantly affecting the limbs (Bureau and
the frontal lobe; both types of spread can be seen in the same
Tassinari, 2005b). Otherwise, myoclonic absences resemble
patient (Williamson et al., 1992b). Spread to the temporal or
typical absence seizures with respect to impairment of con-
frontal lobe is so common with occipital lobe seizures that it
sciousness. Another related seizure type recently recognized is
is at times reported in the majority of patients (Jobst et al.,
eyelid myoclonia with absence. The eyelid myoclonia consists of
2010b). Ictal semiology cannot distinguish seizures originat-
pronounced rhythmic jerking of the eyelids, usually associated
ing from the mesial versus lateral occipital region (Blume
with an upward deviation of the eyes and retropulsion of the
et al., 2005). Evolution of occipital seizures to secondary gen-
head (Caraballo et al., 2009). There may or may not be associ-
eralization is commonly reported.
ated generalized spike-and-wave activity on EEG. Absence sei-
zures may evolve to generalized tonic-clonic activity (Mayville
Partial (Focal) Seizures Originating in the Insular Cortex et al., 2000).
Insular epilepsy is uncommon and also frequently unrecog-
nized because of the inability to record directly from the
insula with scalp electrodes. Subjective symptoms that should
Generalized Myoclonic Seizures
suggest seizure origin in the insula include laryngeal discom- Myoclonic seizures are muscle contractions lasting a fraction
fort, possibly preceded or followed by a sensation in the chest of a second (<250 msec), in association with an ictal EEG
or abdomen, shortness of breath, and paresthesias around discharge (Blume et al., 2001). The myoclonic jerk can be
the mouth or also involving other contralateral body parts generalized, affecting the whole body, or could affect just the
(Isnard et al., 2004). Objective seizure manifestations include upper extremities or (rarely) the head or trunk, or even
dysarthria/dysphonia, sometimes evolving to complete mute- the diaphragm. The myoclonic jerks may affect one side of
ness. With seizure progression in some patients, tonic spasm the body at one time, but typically the other side is affected
of the face and upper limb, head and eye rotation, and at times at other times. The jerks can be single or could occur in an
generalized dystonia occur (Isnard et al., 2004). Hypersaliva- arrhythmic cluster. It should be noted that myoclonus is not
tion is also very common and can be impressive. Insular-onset always epileptic (Faught, 2003). Myoclonus can be generated
seizures may spread to other brain regions and can be dis- anywhere along the central nervous system (CNS). Epileptic
guised as temporal lobe, parietal lobe, or frontal lobe epilepsy myoclonus is generated in the cerebral cortex and is usually
(Ryvlin, 2006; Ryvlin et al., 2006). associated with a single or brief serial spike-and-wave or
polyspike-and-wave activity.
Generalized Seizures Negative myoclonic seizures consist of a very brief pause in
muscle activity rather than a brief muscle contraction (Rubboli
Generalized Absence Seizures and Tassinari, 2006). Just as with positive myoclonus, negative
Typical absence seizures are characterized by a sudden blank myoclonus can be generalized, bilateral with limited distribu-
stare with motor arrest, usually lasting less than 15 seconds tion, or even focal, typically with shifting lateralization.
(Commission on Classification and Terminology of the Inter- Myoclonic seizures may be immediately followed by a loss
national League Against Epilepsy, 1981). The individual of tone. The seizure type is called myoclonic-atonic. Historically
is usually unresponsive and unaware. The seizure ends as it was called myoclonic-astatic. The seizures are brief (1 second
abruptly as it starts, and the patient returns immediately to a or less) but may be associated with falls and injuries. The
baseline level of function with no postictal confusion but may EEG shows generalized spike-and-wave or polyspike-and-wave
Fig. 101.4 Generalized absence seizure displayed with referential montage using linked ear reference. Spike-and-wave discharges are
bifrontally predominant.
discharge. The slow wave is prolonged and associated with the seizures may be followed by atypical absence, resulting in
electromyographic (EMG) silence characteristic of the atonic what appears to be a more prolonged postictal state. This has
phase. Myoclonic seizures may precede a more sustained tonic been referred to as tonic-absence seizure (Shih and Hirsch,
contraction, and the resultant seizures may be referred to as 2003). Generalized tonic seizures occur most often out of
myoclonic-tonic seizures (Berg et al., 2010). Generalized myo- sleep and drowsiness.
clonic seizures may cluster just before a generalized tonic-
clonic seizure occurrence. Epileptic Spasms
Epileptic spasms have similarities to generalized tonic seizures
Generalized Clonic Seizures but a shorter duration that is intermediate between general-
Unlike myoclonic seizures, which are single jerks (but may ized myoclonic and generalized tonic seizures (Blume et al.,
occur in arrhythmic clusters), each generalized clonic seizure 2001), with a typical duration of 0.5 to 2 seconds. The pattern
consists of a series of rhythmic jerks. Generalized clonic sei- of contraction is “diamond-shaped,” with intensity of contrac-
zures are uncommon and particularly rare in adults (Noachtar tion maximal in the middle of the spasm and less at the
and Arnold, 2000). They are more frequently seen in certain beginning and end. Epileptic spasms are also called infantile
epileptic syndromes of infancy and childhood. For example, spasms and salaam attacks. Because their occurrence is not
clonic seizures are a common seizure type of severe myoclonic restricted to infants, the preferred current term is epileptic
epilepsy of infancy (Dravet syndrome). Clonic seizures are spasms. The classic epileptic spasm involves neck and trunk
also noted in progressive myoclonic epilepsies. flexion and arm abduction with a jackknife pattern, but exten-
sion may be seen. Epileptic spasms typically occur in clusters
Generalized Tonic Seizures recurring every 5 to 40 seconds. In a cluster, the initial spasms
may be subtle or mild, increase in intensity as the cluster
Generalized tonic seizures are typically brief seizures, lasting
progresses, and decrease in intensity again toward the end of
a few seconds to 1 minute. Their onset may be gradual or
the cluster (Bleasel and Lüders, 2000).
abrupt. They may be initiated with a myoclonic jerk. They
can vary in severity from subtle, with slight increase in neck
tone with upward deviation of the eyes, to massive, with
Generalized Tonic-Clonic Seizures
involvement of the axial muscles and extremities. Proximal Generalized tonic-clonic (GTC) seizures are dramatic and the
muscles are the most affected. Most commonly there is neck best recognized form of seizures. They are commonly referred
and trunk flexion as well as abduction of the shoulders and to as grand mal, but this term is archaic and does not distin-
flexion of the hips. However extension may also occur. Tonic guish seizures of focal onset from those with a generalized
seizures may be asymmetrical, which could result in turning onset. Generalized tonic-clonic seizures do not have an aura,
to one side. The pattern of muscle involvement may change but they may be preceded by a prodrome—the vague sense a
over time so that there may be a change in the position of the seizure will occur—lasting up to hours. Seizure onset is abrupt,
limbs over the course of the seizure. Autonomic changes may most often with loss of consciousness and a generalized tonic
occur, with tachycardia, pupil dilation, and flushing. Involve- contraction, but some seizures may be initiated with a series
ment of respiratory muscles could cause apnea and cyanosis. of myoclonic jerks, leading to the term clonic-tonic-clonic
The tonic contraction may end with one or more pauses that seizure. The tonic phase may have asymmetrical movements,
result in a few clonic jerks. A postictal state with confusion and these often change from seizure to seizure. One such com-
may occur, but recovery is usually rapid. However, tonic monly encountered asymmetry is versive head turning, which
Epilepsies 1571
is not evidence of a focal onset (Chin and Miller, 2004; Niaz have a common etiology and prognosis. Two important divi-
et al., 1999). The tonic phase includes an upward eye devia- sions were used in the classification. The first separated epi- 101
tion with eyes half open and the mouth open. Involvement of lepsies with generalized-onset seizures, called generalized
the respiratory muscles usually produces a forced expiration epilepsies, from epilepsies with partial-onset seizures, referred
that produces a loud guttural vocalization, often referred to as to as localization-related, partial, or focal epilepsies. The other
the epileptic cry. Cyanosis may occur during the tonic phase in division separated epilepsies of known etiology (named symp-
association with apnea. The tonic phase gradually evolves to tomatic epilepsies) from those of unknown etiology. Epilepsies
clonic activity. The transition can be with initially high- of unknown etiology were named idiopathic if they were pure
frequency and low-amplitude motion, often referred to as a epilepsy and “not preceded or occasioned by another condi-
vibratory phase. With seizure progression, the frequency of tion.” These epilepsies were considered to have no underlying
clonic jerks decreases, and the amplitude may initially increase cause other than a possible hereditary predisposition. Thus,
but later decreases just before the seizure stops. In the immedi- they were presumed genetic. The idiopathic epilepsies were
ate postictal state the individual is limp and unresponsive. also defined by an age-related onset and clinical and EEG
Respiration is loud and snoring in character (stertorous). The characteristics. Epilepsies of unknown etiology were called
postictal state is often followed by sleep, although the indi- cryptogenic if they were presumed symptomatic, but with an
vidual may awaken briefly with postictal confusion. Tongue occult etiology. Although the term cryptogenic remains widely
biting commonly occurs and most often affects the side of the used in the epilepsy field, confusion exists concerning its exact
tongue. Incontinence of urine is common, and incontinence meaning, which has resulted in a recommendation to replace
of stool may also occur. After awakening, patients often have it with the term probably symptomatic (Engel, 2001). The 1989
a pronounced headache and generalized muscle soreness. classification of epilepsies and epileptic syndromes also sub-
Generalized tonic-clonic seizures rarely last more than 2 divided symptomatic partial epilepsies based on lobar ana-
minutes. The severity may vary. The postictal state seems to tomical localization of the epileptogenic zone into temporal,
correlate with severity and duration. frontal, parietal, and occipital lobe epilepsy. Temporal lobe
epilepsy was further subdivided into amygdalohippocampal
Generalized Atonic Seizures and lateral temporal, and frontal lobe epilepsy into seven
subgroups: supplementary motor, cingulate, anterior fron-
Generalized atonic seizures are associated with very brief, topolar, orbitofrontal, dorsolateral, opercular, and motor
sudden loss of tone and vary from extremely subtle, manifest- cortex. The abbreviated classification is found in Box 101.2.
ing with only a head drop, to generalized loss of tone and The 1989 classification of epilepsies and epileptic syn-
falling. Atonic seizures may result in falling if the person is dromes merits updating because of the recognition of new
standing, then called a drop attack. However, drop attacks may epileptic syndromes and the discovery of the genetic basis for
be the result of both generalized atonic and generalized tonic several known epilepsies. The most recent report of the ILAE
seizures. There is a very brief loss of consciousness and brief commission on classification simplified the classification of
postictal confusion. Seizures are usually very brief, lasting 1 epilepsies by eliminating the division of localization-related
second to a few seconds. They may be preceded by a brief and generalized epilepsies (Berg et al., 2010). Instead, it
myoclonic jerk, in which case the seizure type is called suggested a listing of epilepsies by age of onset, distinctive
myoclonic-atonic. Very brief atonic seizures are typical of the constellations, or underlying cause (Box 101.3). The list incor-
syndrome of myoclonic-astatic epilepsy (Doose syndrome) porated newly identified or characterized epileptic conditions.
(Oguni et al., 2001). More prolonged atonic seizures can be The report also recommended addressing underlying etiolo-
seen with Lennox-Gastaut syndrome or other symptomatic gies with the terms genetic, structural/metabolic, and unknown
generalized epilepsies. Despite their brief duration, general- cause, thus replacing the terms idiopathic, symptomatic, and cryp-
ized atonic seizures can result in serious injury and are an togenic (see Table 101.1).
important cause of morbidity in epilepsy.
Epileptic Syndromes and Constellations
Generalized-Onset Seizures with Focal Evolution
An epileptic syndrome was defined as a complex of signs and
Generalized-onset seizures rarely may evolve to focal seizures symptoms that define a unique epilepsy condition with differ-
(Deng et al., 2007; Williamson et al., 2009). This seems to ent etiologies. A syndrome must involve more than just a
occur with either myoclonic or absence seizures. The clinical seizure type (Engel, 2006). One important attribute of syn-
manifestations most often are behavioral arrest and staring, dromes is the characteristic age at onset. The most recent revi-
with minor automatisms. However, focal motor manifesta- sion recommended that the term syndrome be restricted to a
tions may also occur. This type of seizure tends to be pro- clinical entity that is reliably identified by a cluster of electro-
longed and may be associated with postictal confusion clinical characteristics (Berg et al., 2010). It recommended using
(Williamson et al., 2009). the term constellation for epilepsies that do not quite qualify to
represent a syndrome; yet they are diagnostically meaningful
CLASSIFICATION OF EPILEPSIES AND forms of epilepsy that may have implications for clinical treat-
ment, particularly surgery. The classification of epilepsies and
EPILEPTIC SYNDROMES epileptic syndromes published in 1989 divides epilepsies into
The classification of seizures addresses single seizure events localization-related (focal, local, partial) and generalized. The
and not epilepsy as a condition. The 1989 classification of basis for that subdivision is that most patients will have either
epilepsies and epileptic syndromes tried to organize epilepsies partial-onset seizure types only or generalized-onset seizure
and epilepsy syndromes (Commission on Classification and types only. However there are syndromes in which both partial
Terminology, 1989). It defined an epileptic syndrome as “an and generalized seizure types may coexist in the same individ-
epileptic disorder characterized by a cluster of signs and symp- ual, or the epilepsy may express itself with generalized seizure
toms customarily occurring together; these include such items types in some individuals and partial seizure types in others. As
as type of seizure, etiology, anatomy, precipitating factors, age a result, the 2010 revision recommended dropping the partial-
of onset, severity, chronicity, diurnal and circadian cycling, generalized subdivision (Berg et al., 2010). In addition, it rec-
and sometimes prognosis.” A syndrome does not necessarily ommended using the term genetic for the “idiopathic” epilepsies
BOX 101.3 Electroclinical Syndromes and Other Epilepsies from 2010 revision of terminology
ELECTROCLINICAL SYNDROMES ARRANGED BY AGE Epilepsy with generalized tonic-clonic seizures alone
AT ONSET Progressive myoclonus epilepsies (PME)
Neonatal Period Autosomal dominant epilepsy with auditory features (ADEAF)
Other familial temporal lobe epilepsies
Benign familial neonatal epilepsy (BFNE)
Early myoclonic encephalopathy (EME) Less-Specific Age Relationship
Ohtahara syndrome Familial focal epilepsy with variable foci (childhood to adult)
Infancy Reflex epilepsies
Epilepsy of infancy with migrating focal seizures DISTINCTIVE CONSTELLATIONS
West syndrome Mesial temporal lobe epilepsy with hippocampal sclerosis (MTLE
Myoclonic epilepsy in infancy (MEI) with HS)
Benign infantile epilepsy Rasmussen syndrome
Benign familial infantile epilepsy Gelastic seizures with hypothalamic hamartoma
Dravet syndrome Hemiconvulsion-hemiplegia-epilepsy
Myoclonic encephalopathy in nonprogressive disorders
EPILEPSIES ATTRIBUTED TO AND ORGANIZED BY
Childhood STRUCTURAL-METABOLIC CAUSES
Febrile seizures plus (FS+) (can start in infancy) Malformations of cortical development
Panayiotopoulos syndrome Neurocutaneous syndromes
Epilepsy with myoclonic atonic (previously astatic) seizures Tumor
Benign epilepsy with centrotemporal spikes (BECTS) Infection
Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) Trauma
Late-onset childhood occipital epilepsy (Gastaut type) Angioma
Epilepsy with myoclonic absences Perinatal insults
Lennox-Gastaut syndrome Stroke
Epileptic encephalopathy with continuous spike-and-wave during
sleep (CSWS) EPILEPSIES OF UNKNOWN CAUSE
Landau-Kleffner syndrome (LKS) CONDITIONS WITH EPILEPTIC SEIZURES THAT ARE
Childhood absence epilepsy (CAE) TRADITIONALLY NOT DIAGNOSED AS A FORM OF
EPILEPSY
Adolescence-Adult
Benign neonatal seizures
Juvenile absence epilepsy (JAE)
Febrile seizures
Juvenile myoclonic epilepsy (JME)
From Berg, A.T., Berkovic, S.F., Brodie, M.J., et al., 2010. Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE
Commission on Classification and Terminology, 2005–2009. Epilepsia 51, 676–685.
that were presumed to be genetic in nature. The discussion that period, severe seizure manifestations, and an EEG pattern of
follows will briefly describe selected syndromes and constella- burst-suppression, in which periods of high-voltage EEG activ-
tions following the order suggested by the latest ILAE recom- ity are separated by periods of generalized attenuation (Aicardi
mendations (see Box 101.3). and Ohtahara, 2005; Djukic et al., 2006; Ohtahara and
Yamatogi, 2006).
Benign Familial Neonatal Epilepsy Early myoclonic encephalopathy is characterized by focal
myoclonus involving limbs or face that is very frequent,
Benign familial neonatal epilepsy was previously referred to sometime continuous, shifting from one region to another.
as benign familial neonatal convulsions (Plouin and Anderson, Generalized massive myoclonus may appear shortly thereaf-
2005). This rare, dominantly inherited disorder is due to ter, as will focal motor seizures. Epileptic spasms typically
mutations affecting voltage-gated potassium channel genes develop later in the course of the disorder. Neurological
(KCNQ2, KCNQ3) (Biervert and Steinlein, 1999). Affected status is abnormal, either at birth or with the development
infants are usually full term and appear normal at birth. In of clinical seizures, but most infants are hypotonic. The
80% of instances, seizures start on the second or third day of prognosis is poor. There is increased mortality in the first
life, although some infants may develop seizures later in the few years of life, and survivors have considerable develop-
first month of life. The seizures are typically clonic but often mental delay.
preceded by a tonic component. They are more often unilat- Ohtahara syndrome is characterized by epileptic spasms as
eral but can also be bilateral. The seizures remit within 2 to 6 the predominant seizure type, but a third of affected infants
months. There is a slight increase in the risk of later epilepsy also have other seizure types, including focal motor seizures,
(11%–15%). hemiconvulsions, and generalized motor seizures. The epilep-
tic spasms are associated with generalized attenuation on EEG.
Early Myoclonic Encephalopathy and The prognosis is also poor, with very high mortality in the first
few years of life, and severe mental and physical handicap in
Ohtahara Syndrome survivors. The EEG may evolve from the initial suppression-
Early myoclonic encephalopathy and Ohtahara syndrome burst pattern to a hypsarrhythmia pattern, typical of West
have much in common, including age at onset in the neonatal syndrome.
Epilepsies 1573
West Syndrome febrile status epilepticus at around 6 months of age, and then
recurrent generalized or shifting hemiclonic seizures are seen, 101
West syndrome has a later age at onset, with a peak onset often triggered by fever. After 1 year of age, other seizure types
between 3 and 7 months of age. It is characterized by a clinical appear, including myoclonic seizures, absence seizures, and
triad of epileptic spasms, arrest or deterioration of psychomo- complex partial seizures as well as atonic seizures at times. The
tor development, and a characteristic EEG pattern called hyps seizures are drug resistant and may be exacerbated by some
arrhythmia (Dulac and Tuxhorn, 2005). The disorder is sodium channel blockers such as carbamazepine and lamot-
heterogeneous in its etiology. Epileptic spasms are usually the rigine. A delay or arrest in development may occur, and even
initial manifestation. They tend to occur in clusters, some- regression may be seen, typically after episodes of prolonged
times multiple times a day. Approximately two-thirds of seizure activity (Dravet et al., 2005; Scheffer et al., 2009). The
infants have brain lesions. Psychomotor development may be prognosis is poor; the majority of individuals develop intel-
abnormal prior to onset, but there is a clear deterioration after lectual disability and at times ataxia and spasticity.
onset. The spasms may have asymmetries, which are more Borderline severe myoclonic epilepsy of infancy may
likely when there is a focal brain lesion. The prognosis is vari- include variations such as epilepsy with the absence of myo-
able, with a small portion of patients recovering quickly clonic seizures or even other seizure types.
without sequelae. This is more likely to happen in the absence It has now become recognized that Dravet syndrome
of brain pathology. Otherwise, the prognosis is unfavorable, accounts for a large proportion of individuals previously diag-
with more than 70% developing mental retardation and other nosed with vaccine encephalopathy (Berkovic et al., 2006).
cognitive disabilities. The treatment of infantile spasms has The fever associated with vaccination may cause an earlier age
some important differences from treatment of other seizure at onset of Dravet syndrome, but it does not affect the eventual
types. Steroids such as corticotropin (adrenocorticotropic course of the condition (McIntosh et al., 2010).
hormone [ACTH]) and prednisone are helpful, particularly in
the absence of underlying known pathology. Genetic Epilepsy with Febrile Seizures Plus
Hypsarrhythmia is characterized by high-voltage disorgan-
ized EEG activity with slow waves and multifocal spikes and Genetic Epilepsy with febrile seizures plus (GEFS+) appears to
sharp waves punctuated by periods of generalized attenuation be autosomal dominant in inheritance, often due to a sodium
(Fig. 101.5). When a spasm occurs it is usually during a channel mutation most often in the SCN1A or SCN1B gene
period of attenuation. The attenuation may have superim- (Escayg et al., 2001; Wallace et al., 2002). It can also be due
posed high-frequency, low-voltage EEG activity. The periods to a mutation in the γ2 subunit of the γ-aminobutyric acid
of attenuation are typically very short in duration, lasting 1 to (GABA)-A receptor (Harkin et al., 2002). No mutation has
2 seconds. been identified in the majority of families. The condition has
a heterogeneous phenotype in affected individuals, even
within the same kindred (Scheffer and Berkovic, 1997; Singh
Dravet Syndrome et al., 1999) (Fig. 101.6). Some individuals have only the
Dravet syndrome, also called severe myoclonic epilepsy of infancy, typical febrile seizure phenotype, with febrile seizures disap-
is usually due to a de novo mutation affecting the SCN1A gene pearing by 6 years of age. Other individuals have febrile seizures
encoding the α1 sodium channel subunit (Claes et al., 2001). plus, which refers to febrile seizures persisting beyond 6 years
De novo mutations account for about 95% of cases. It may of age or febrile seizures intermixed with afebrile generalized
also be due to a nonsense mutation of the GABRG2 GABAA tonic-clonic seizures. Other individuals even have other
receptor subunit (Huang et al., 2012). The typical clinical pres- seizure types such as generalized absence or myoclonic sei-
entation is that a previously normally developing infant has zures. Less common seizure types are myoclonic-atonic and
Fig. 101.5 Hypsarrhythmia pattern with disorganized high-voltage slow background activity, multifocal spikes and sharp waves, and a
period of attenuation.
Febrile seizures Febrile seizures then epilepsy of unknown

only classification
Febrile seizures Febrile seizures then Febrile seizures then
then TLE generalized epilepsy single afebrile convulsion
Febrile seizures then epilepsy with generalized and partial seizures
Fig. 101.6 Pedigree of a family with autosomal dominant GEFS+, demonstrating phenotypic heterogeneity in affected individuals.
partial seizures typical of temporal lobe origin (Abou-Khalil Benign Epilepsy with Centrotemporal Spikes
et al., 2001; Scheffer et al., 2007).
Benign epilepsy with centrotemporal spikes (BECTS) is also
Panayiotopoulos Syndrome referred to as benign rolandic epilepsy. This is the most common
form of idiopathic partial epilepsy in children (Dalla Bernar-
The onset of seizures in Panayiotopoulos syndrome is typi- dina et al., 2005). Seizures begin between 3 and 13 years of
cally between 1 and 14 years of age, with a peak at 4 to 5 years age, with a peak between 5 and 8 years. Affected children will
(Covanis et al., 2005). Seizures include autonomic manifesta- have had a normal development and normal cognitive func-
tions, particularly ictal vomiting, altered responsiveness and tion. Seizures typically start with paresthesias affecting one
arrest of activity, and deviation of the eyes to one side. Auto- side of the face, particularly around the mouth, then contrac-
nomic manifestations are particularly pronounced (Caraballo tion of that side of the face evolving into clonic activity of the
et al., 2007). Seizures can be very prolonged, lasting longer face. Increased salivation and drooling occurs. Consciousness
than 30 minutes, qualifying for complex partial status epilep- is preserved in the vast majority of children if the seizure does
ticus. Seizures predominate during sleep. The EEG shows not secondarily generalize. Seizures are typically nocturnal
multifocal spikes but with posterior predominance. Despite and generally have a low rate of recurrence, so treatment is not
the alarming seizure manifestations, prognosis is generally always necessary. The natural history is characterized by spon-
good. Seizures are infrequent, with about a quarter of patients taneous remission around the time of puberty. Patients with
having only one seizure and half having two to five at most. BECTS may have cognitive and behavioral problems while
Remission typically occurs within 1 to 3 years of onset. the condition is active, but long-term prognosis is excellent
(Camfield and Camfield, 2014).
Epilepsy with Myoclonic Atonic Seizures (Myoclonic BECTS has long been thought to have a genetic basis, but
Astatic Epilepsy or Doose Syndrome) the concordance in identical twins is low, suggesting that other
mechanisms may play a role (Vadlamudi et al., 2004). The
This presumed genetic epilepsy is characterized by seizure
diagnosis of BECTS depends on the clinical presentation as
onset between 18 and 60 months of age (Guerrini et al.,
well as the EEG. The typical EEG abnormality is high-voltage
2005). The characteristic seizure types are myoclonic and
central-midtemporal blunt sharp waves activated in sleep (Fig.
myoclonic-atonic seizures, present in all affected children.
101.7). These can become bilateral independent in deeper
Tonic-clonic seizures are also seen in a majority of children.
sleep. It is not uncommon to see atypical fields, particularly
Atypical absence seizures are also common and frequently
posterior temporal or parietal. The incidence of generalized
associated with reduced muscle tone. Pure atonic seizures may
spike-and-wave discharges in affected individuals is increased
also occur. Tonic seizures are less frequently seen. Generalized
(Beydoun et al., 1992; Drury and Beydoun, 1991).
tonic-clonic seizures are most often the seizure type that
results in the diagnosis of epilepsy, with smaller seizures
noticed thereafter. Seizures can be easily precipitated by inap-
Autosomal Dominant Nocturnal Frontal Lobe Epilepsy
propriate treatment with carbamazepine. The course of the Age at seizure onset in autosomal dominant nocturnal frontal
condition is somewhat unpredictable. In more than half of lobe epilepsy is highly variable but is most often younger than
affected children, the seizures go into remission. More than age 20, with a mean between 8 and 11 years. Seizures typically
half of patients also have normal cognitive function, with less arise out of sleep. In their most pronounced expression, they
than half having mild to severe mental retardation. A worse may be hypermotor with vigorous frenetic movements of the
prognosis is predicted by generalized tonic-clonic seizures in extremities such as thrashing, kicking, or bicycling. The sei-
the first 2 years of life and early status epilepticus (Kelley and zures may be asymmetrical tonic, sometimes with evolving
Kossoff, 2010). posturing, or may have a mixture of hypermotor and tonic
Epilepsies 1575
101
Fig. 101.7 Characteristic sleep electroencephalographic recording in patient with benign epilepsy with centrotemporal spikes, demon-
strating frequent negative right midtemporal sharp waves (at T8) with field extending to right posterior temporal (P8) and right central
(C4) regions. Note simultaneous positivity in bifrontal regions.
manifestations. The seizures are usually stereotyped. They are absence seizures. Approximately two-thirds of patients also
typically short in duration, lasting less than 30 seconds. They have other seizure types, particularly generalized tonic-clonic
can be so short as to simply manifest with paroxysmal arousal seizures. Seizures tend to be resistant to monotherapy and
(Provini et al., 1999). The condition is often misdiagnosed as often require dual therapy with valproate and ethosuximide
a sleep disorder or psychogenic seizures (Scheffer et al., 1995). or one of these agents in combination with lamotrigine.
This disorder is genetically heterogeneous (De Marco et al., Myoclonic absences tend to disappear over time, but gen-
2007) but typically due to mutations in the neuronal nicotinic eralized tonic-clonic seizures may persist. Patients may have
acetylcholine receptor (Steinlein et al., 1995). Carbamazepine mental retardation preceding the onset of the seizures, and
appeared particularly effective in this condition. Interestingly, some may show decline over time, particularly those with
the mutated nicotinic receptors were found to be more sensi- generalized tonic-clonic seizures.
tive to carbamazepine than to valproate (Picard et al., 1999).
Lennox-Gastaut Syndrome
Late-Onset Childhood Occipital Epilepsy (Gastaut Type) Lennox-Gastaut syndrome is defined by a triad of several
The age at onset of seizures in late-onset childhood occipital seizure types including generalized tonic, generalized atonic,
epilepsy ranges from 3 to 16 years, with a mean age of 8 and atypical absence seizures, a characteristic interictal EEG
(Covanis et al., 2005). The seizures are of occipital lobe onset abnormality of generalized slow spike-and-wave discharges
and manifest with visual symptoms. The ictal phenomena (<2.5 Hz) in waking and bursts of paroxysmal fast activity
include elementary visual hallucinations, complex visual hal- (≈10 Hz) in sleep (Fig. 101.8), and cognitive dysfunction
lucinations and illusions, visual loss in one field or total blind- (Arzimanoglou et al., 2009; Beaumanoir and Blume, 2005).
ness, eye deviation, and eye blinking. There may be progression Drop attacks due to either generalized atonic or generalized
of seizure manifestations with spread beyond the occipital tonic seizures, tend to be the most debilitating seizure type
lobe, particularly lateralized or generalized tonic-clonic activ- because of associated injuries. The age of onset is between 3
ity. Consciousness is usually preserved if seizure activity does and 10 years with a peak between 3 and 5 years. Lennox-
not spread beyond the occipital lobe. Postictal headache is a Gastaut syndrome may start de novo or may evolve, for
very common symptom, resulting in confusion with migraine. example from West syndrome. Seizures tend to be drug-
The interictal EEG is characterized by occipital spikes and resistant. Lennox-Gastaut syndrome tends to be a chronic dis-
sharp waves that can be extremely frequent, and typically acti- order even though epilepsy may become less active over time.
vated with eye closure. The discharges can be so frequent as Almost half of these patients may appear normal before onset
to raise concern for an ictal pattern. The activation with eye of seizures, but deterioration occurs, and the cause is probably
closure has been termed fixation-off photosensitivity. multifactorial.
Epilepsy with Myoclonic Absences Epileptic Encephalopathy with Continuous Spike-and-

Epilepsy with myoclonic absences is a syndrome with male
Wave during Sleep and Landau Kleffner Syndrome
predominance and starts between 1 and 12 years of age, with The common features of the related conditions of epileptic
a mean of 7 years (Bureau and Tassinari, 2005a). Its most encephalopathy with continuous spike-and-wave during sleep
distinctive seizure type is myoclonic absences. These seizures (CSWS) and Landau Kleffner syndrome (LKS) are a decline in
include impairment of consciousness of variable degree and cognitive function in association with an EEG pattern of con-
very prominent myoclonus involving primarily the upper tinuous spike-and-wave activity during slow wave sleep (Fig.
extremities but also the legs. The duration varies from 10 to 101.9). In both conditions the associated seizures are often
60 seconds, and seizures typically recur several times a day. easy to control, and the predominant clinical manifestations
The associated EEG usually shows 3-Hz generalized rhythmic are related to the EEG abnormality in sleep (Nickels and
spike-and-wave activity similar to what is seen in typical Wirrell, 2008; Tassinari et al., 2005).
Fig. 101.8 Typical electroencephalographic findings in Lennox-Gastaut syndrome, with slow spike-and-wave activity in waking (top)
and paroxysmal fast activity in sleep (bottom).
In the case of LKS, the cognitive decline is specifically in CSWS differs from LKS in that a larger proportion of indi-
the area of speech. The condition is often called acquired viduals have pre-existing neurological abnormalities, and the
epileptic aphasia. This disorder typically appears between 2 cognitive regression is more likely to be global and associated
and 8 years of age, with a peak between 5 and 7 years. The with motor impairments.
most common initial manifestation is verbal auditory agnosia.
The language disturbance will usually progress despite good
control of clinical seizures. In fact, clinical seizures may not
Childhood Absence Epilepsy
even occur in about a quarter of patients. The evolution is CAE syndrome, previously referred to as petit mal or pyk-
variable. Spontaneous remissions may occur within the first nolepsy, typically starts between the ages of 4 and 10 years
year. Classical antiepileptic drugs (AEDs) may be ineffective. with a peak between 5 and 7 years (Hirsch and Panayi-
Benefits have been reported with valproate, levetiracetam, and otopoulos, 2005). Affected children are normal in their devel-
benzodiazepines, which reduce the EEG abnormality. Steroids opment and neurological status. The key seizure type is
and immunoglobulins have been reported to be helpful. Sur- generalized typical absence seizures occurring many times a
gical treatment with multiple subpial transections has been day. In association with seizures, the EEG shows generalized
advocated (Morrell et al., 1995). synchronous and symmetrical spike-and-wave activity with a
Epilepsies 1577
101
Fig. 101.9 Electroencephalogram in patient with epileptic encephalopathy with continuous spike-and-wave during sleep with normal
background in waking (left) and continuous spike-and-wave activity in deep sleep (right).
frequency around 3 Hz. It is not unusual for the spike-and- (Arsov et al., 2012). This condition responds well to the
wave frequency to be initially faster (up to 4 Hz) and drop by ketogenic diet.
approximately 0.5 to 1 Hz by the end of the ictal discharge.
Seizure duration is brief, usually less than 15 seconds. Seizure Juvenile Absence Epilepsy
frequency is very high, with multiple daily seizures. In 2005
Juvenile absence epilepsy is very similar to CAE except that the
the ILAE proposed strict criteria to define the syndrome,
age at onset is in the second decade, with a peak between ages
which include the absence of generalized tonic-clonic or
10 and 12 (Wolf and Inoue, 2005). The absence seizures are
myoclonic seizures prior to or during the active stage of
not as frequent as in CAE. In addition, the majority of patients
absence seizures. The criteria also exclude eyelid and perioral
also have generalized tonic-clonic seizures. This condition has
myoclonia, high-amplitude rhythmic jerking of the limbs,
a greater tendency for persistence of seizures into adulthood
and arrhythmic jerks of the head, trunk, or limbs (Loiseau
than is the case with CAE.
and Panayiotopoulos, 2005). With this strict definition of the
syndrome, many patients with a predominance of absence
seizures are excluded and cannot be classified as having CAE
Juvenile Myoclonic Epilepsy
(Ma et al., 2010; Valentin et al., 2007), but a very favorable Juvenile myoclonic epilepsy (JME), also known as juvenile myo-
prognosis is expected. Only 8% of patients fulfilling the strict clonic epilepsy of Janz or impulsive petit mal, is common (Thomas
criteria had generalized tonic-clonic seizures, compared to et al., 2005) and accounts for up to 10% of all cases of epi-
30% of those who did not (Grosso et al., 2005), and 65% of lepsy. The age at onset is typically between 12 and 18, but
those satisfying the stricter criteria had a complete seizure epilepsy may start in the first decade in a subgroup of patients
remission, compared to 23% of those who did not. Persist- who appear to have CAE early on. The defining seizure type
ence or relapse of seizures tends to be predominately related is generalized myoclonic seizures, which occur in all patients
to generalized tonic-clonic seizures. In some instances, CAE by definition. Generalized myoclonic seizures typically occur
evolves into JME in the second decade. This will be discussed after awakening, particularly with sleep deprivation. They are
later under that heading. typically mild, predominately affecting the upper extremities.
CAE is thought to be genetically determined, with high Although they are the first seizure type to appear, they are
concordance for monozygotic twins (Berkovic et al., 1998). often not recognized as seizures and not brought to medical
However, the exact mode of inheritance is unknown. Although attention. Patients typically come to medical attention after
some families had a single gene mutation (including a generalized tonic-clonic seizure, which is most likely to
GABAA receptor and calcium channel mutations), most are occur after sleep deprivation or binge drinking of alcohol. The
thought to have polygenic inheritance (Hughes, 2009; Wallace physician has to ask about myoclonus in order to make the
et al., 2001). diagnosis. Approximately one-third of patients also have gen-
For children with pure absence seizures, ethosuximide is eralized absence seizures. JME is clinically and genetically
the treatment of choice (Glauser et al., 2010). Coexistence of heterogeneous (Martinez-Juarez et al., 2006). The most
other seizure types requires a wider-spectrum AED. Absence important group is classic JME, and the second largest is CAE
seizures beginning before 4 years of age could be due to evolving to JME. The latter tends to be more treatment
glucose transporter 1 (GLUT1) deficiency in 12% of patients resistant.
The diagnosis of the condition is based on the clinical Crompton et al., 2010; Hedera et al., 2007). No gene mutation
history and EEG, which shows generalized irregular 4- to 6-Hz has yet been identified.
spike-and-wave activity occurring in bursts. The EEG is most
likely to record discharges after awakening (Labate et al., Mesial Temporal Lobe Epilepsy with
2007). JME is predominantly a lifelong condition, with less Hippocampal Sclerosis
than 25% of patients seizure free off medication in long-term
follow-up (Camfield and Camfield, 2009; Geithner et al., MTLE with hippocampal sclerosis is classified as a distinctive
2012; Senf et al., 2013). However, the majority of patients can constellation rather than a syndrome (Berg et al., 2010).
have seizure remission with medication therapy. The progno- Mesial temporal or hippocampal sclerosis is the most common
sis for seizure freedom is lowest in individuals with CAE pathology noted in surgical specimens from patients undergo-
leading to JME and in individuals who have all three seizure ing temporal lobectomy for drug-resistant temporal lobe
types: generalized myoclonic, generalized tonic-clonic, and seizures. It is characterized by neuronal loss and gliosis pre-
generalized absence seizures (Gelisse et al., 2001; Martinez- dominately affecting CA1 and CA3 sectors of the hippocam-
Juarez et al., 2006). Valproate appears to be the most effective pus, with relative sparing of CA2. Patients with MTLE and
medication for all three seizure types, but its teratogenicity hippocampal sclerosis frequently have a history of antecedent
and some adverse effects limit its use in women of childbear- febrile seizures (up to 80%) (French et al., 1993). The febrile
ing age (Montouris and Abou-Khalil, 2009). Seizures may be seizures are usually complex, in particular prolonged. Even
aggravated by several AEDs that are specific for partial epilepsy though febrile status epilepticus is known to injure the hip-
(Gelisse et al., 2004; Genton et al., 2000). pocampus in some instances, it is not clear that this is the only
JME is thought to have predominantly polygenic inherit- factor at play (VanLandingham et al., 1998). Some studies
ance, but there have also been families with autosomal have shown evidence of prior hippocampal malformation that
dominant inheritance and several identified mutations may predispose to injury (Fernandez et al., 1998; Park et al.,
(Delgado-Escueta, 2007), including a mutation of the GABAA 2010a). In addition, hippocampal sclerosis has been reported
receptor (Cossette et al., 2002). in familial MTLE without prior febrile seizures (Kobayashi
et al., 2003). The age at onset of habitual afebrile seizures is
variable but most commonly is in late childhood or adoles-
Epilepsy with Generalized Tonic-Clonic Seizures Alone cence. The presence of hippocampal sclerosis predicts poor
Epilepsy with generalized tonic-clonic seizures alone includes response to medical therapy (Semah et al., 1998). However,
so-called epilepsy with grand mal on awakening as well as the exact percentage of individuals who are drug resistant has
epilepsy with generalized tonic-clonic seizures that are random varied between studies. It is not unusual for seizures to be drug
in timing. Although the onset is in the second decade in the responsive initially, with long remissions but later evolution
majority of individuals, there is a very wide range. As noted to drug resistance (Berg et al., 2006).
with other IGE syndromes, sleep deprivation is a frequent The seizure pattern has already been described. The clinical
precipitant. Seizures generally respond well to treatment, simi- seizure characteristics cannot reliably distinguish MTLE due to
larly to what has been noted with JME. hippocampal sclerosis from that due to lesions (Wieser, 2004).
The hippocampal sclerosis is usually identified on MRI
showing decreased volume and increased signal in the affected
Autosomal Dominant Epilepsy with Auditory Features hippocampus (Fig. 101.10). Positron emission tomography
Autosomal dominant epilepsy with auditory features (ADEAF) (PET) usually shows temporal hypometabolism that is pre-
is related to a mutation in the leucine-rich glioma-inactivated-1 dominant in the mesial temporal region on the affected side
(LGI1) gene (Ottman et al., 2004). Inheritance, as the name (Fig. 101.11).
indicates, is autosomal dominant. Seizures typically begin in Neuropsychological evaluation commonly demonstrates
adolescence or adulthood, with a mean age at onset of 24. memory dysfunction which may be material specific, with
Affected subjects commonly report an elementary auditory
aura such as buzzing, ringing, humming, or even loss
of hearing. Seizures may start with aphasic manifestations
when the onset is in the dominant lateral temporal lobe (Gu
et al., 2002).
Familial Mesial Temporal Lobe Epilepsy

Familial MTLE is a heterogeneous condition. There is a benign
syndrome, first identified in twins, in which the most promi-
nent aura is déjà vu with frequent simple partial seizures,
infrequent complex partial seizures, and rare secondarily gen-
eralized tonic-clonic seizures (Berkovic et al., 1996). Prior
febrile seizures are uncommon, and magnetic resonance
imaging (MRI) is normal with no hippocampal sclerosis. The
epilepsy is frequently not recognized when the only seizure
type is subjective simple partial seizures, but when recognized
is very responsive to medical therapy.
Other familial MTLE may be associated with prior febrile
convulsions, hippocampal sclerosis on MRI, and less respon-
siveness to medical therapy, at times requiring surgical treat-
ment (Cendes et al., 1998). Fig. 101.10 Left hippocampal sclerosis identified on magnetic
Familial MTLE is most probably polygenic in inheritance resonance imaging T2-weighted oblique coronal image. Note hip-
for the majority of families, even though there are reports pocampal asymmetry, with relatively decreased volume and increased
of autosomal dominant inheritance (Chahine et al., 2013; T2 signal in affected left hippocampus.
Epilepsies 1579
greater involvement of verbal memory when the left hemi- frequent with episodes of status epilepticus. Progressive hemi-
sphere is involved or visual-spatial memory when the right paresis and other deficits occur, depending on the affected 101
hemisphere is involved. Memory impairment tends to be hemisphere. General intellectual decline occurs at the time of
greater with longer duration of uncontrolled seizures, suggest- hemiparesis. Imaging shows progressive hemiatrophy, with
ing evidence of progression. lesser atrophy on the other side (Fig. 101.12). An abnormal
While drug resistance is common, the response rate for increased T2 signal is initially most pronounced in the peri-
surgical therapy is excellent. After temporal lobectomy or sylvian region. PET reveals marked decreased metabolism in
selective amgydalohippocampectomy, 60% to 80% of indi- the affected hemisphere.
viduals are seizure free (Wieser, 2004). An autoimmune etiology is suspected. In some patients,
antibodies to the GluR3 subunit of the glutamate receptor
Rasmussen Syndrome have been identified (Rogers et al., 1994). Some benefit may
occur with intravenous immunoglobulin (IVIG), plasmapher-
Rasmussen syndrome is a chronic progressive disorder of esis, and corticosteroids, but hemispherectomy is generally
unknown etiology, and probably heterogeneous (Hart and required to achieve seizure control.
Andermann, 2005). Seizures most commonly start between 1
and 14 years of age with focal-onset motor seizures. The sei- Progressive Myoclonus Epilepsies
zures can remain simple partial or evolve to complex partial
or secondary generalized tonic-clonic seizures. Seizures usually Progressive myoclonus epilepsies (PME) are a heterogeneous
start in the same hemisphere. They become progressively more group of genetic disorders characterized by myoclonus, gener-
alized tonic-clonic seizures, and progressive neurological dys-
function, predominately with cerebellar ataxia and often with
dementia (Genton et al., 2005). Included in the group are
Unverricht-Lundborg disease, Lafora body disease, mitochon-
drial encephalopathy with ragged red fibers, and ceroid lipo-
fuscinosis, among others. Unverricht-Lundborg disease was
also called Baltic myoclonus, but it is recognized now as a
worldwide condition. It is due to a mutation in the cystatin B
gene (Genton, 2010). The onset is typically between 7 and 16
years of age, initially with action myoclonus then later devel-
opment of tonic-clonic or clonic-tonic-clonic seizures. The
myoclonus worsens progressively and greatly limits motor
function. Ataxia occurs and is generally mild, but it can be very
aggravated by the use of phenytoin. Phenytoin can also cause
Fig. 101.11 Fluorodeoxyglucose positron emission tomography mild dementia.
(FDG-PET) co-registered with computed tomography, demon- Lafora body disease typically starts between 6 and 19 years
strating left temporal hypometabolism predominant in mesial of age. Initial seizures are generalized tonic-clonic or myo-
temporal region. Patient had left hippocampal sclerosis. clonic, but affected individuals may also have simple partial
Fig. 101.12 Rasmussen encephalitis in an 18-year-old man with left focal motor seizures since age 3 and progressive left hemiparesis.
FLAIR MRI shows right hemisphere atrophy with widening of sulci and ventricular enlargement. Atrophy is very pronounced in the right hippo
campus. There is also increased T2 signal on the right most pronounced in the right insular region.
Fig. 101.13 Hypothalamic hamartoma (see arrows) in a subject with gelastic seizures and short stature. Left to right- top row: T1-weighted
coronal, FLAIR coronal; bottom row: T1-weighted axial, T1-weighted sagittal section. There is also cerebral atrophy with widened sulci and
ex-vacuo ventricular enlargement.
visual seizures. The condition progresses with increasingly to 5% of children, mostly between 3 months and 6 years of
severe myoclonus, ataxia, and dementia. Death typically age. It is the most common form of seizures in children
occurs 2 to 10 years after onset of symptoms. In 80% of (Knudsen, 2000) and a benign disorder in the vast majority
patients, this condition is due to a mutation in the laforin of those affected. Most febrile seizures are generalized tonic-
gene. The diagnosis can also be made by detection of Lafora clonic in semiology. They are typically symmetrical, last less
bodies in skin biopsies. than 15 minutes, and usually only one seizure occurs in asso-
Myoclonic epilepsy with ragged red fibers (MERRF) has a ciation with a particular illness. Febrile seizures that satisfy the
variable age at onset. In addition to myoclonus, generalized above criteria are called simple febrile seizures. Complex febrile
tonic-clonic seizures, and ataxia, there may be signs to suggest seizures are defined by one or more of the following three
mitochondrial disease, such as deafness, myopathy, optic criteria: prolonged duration of greater than 15 minutes, focal
atrophy, or lipomas. More than one mitochondrial mutation features (either focal ictal features or lateralized postictal
causes MERRF. It could be diagnosed with muscle biopsy weakness), or the occurrence of more than one seizure in 24
showing typical ragged red fibers. The condition can also be hours or with the same febrile illness. Most affected children
diagnosed with genetic testing from skin or muscle. will not have a recurrence of a febrile seizure in their lifetime.
Approximately 30% to 40% will have at least one recurrence,
Gelastic Seizures with Hypothalamic Hamartoma but multiple recurrences are infrequent. Predictors of recur-
rence are early age at onset (<1 year), the presence of epilepsy
Gelastic seizures with hypothalamic hamartoma typically
or febrile seizures in first-degree relatives, and attendance
starts with gelastic seizures in early life, with other seizures
at daycare, which increases the risk of febrile infectious
also becoming associated later on (Berkovic et al., 2003).
illnesses.
There may be cognitive and behavioral disturbances. Some
Even though febrile seizures are a benign condition and
individuals have precocious puberty and a short stature. MRI
the vast majority of affected children never develop afebrile
reveals a hypothalamic hamartoma that can vary in size
seizures, they do increase the risk of later epilepsy. In one
and appearance (Fig. 101.13). Seizures originate within the
important study, the risk of later epilepsy was 7% by age 25
hamartoma.
years (Annegers et al., 1987). In another study of children
seen in the emergency room for their first febrile seizure, the
Febrile Seizures risk of afebrile seizures was 6% at 2 years (Berg and Shinnar,
Febrile seizures are not traditionally diagnosed as a form of 1996). The factors that predict later epilepsy include pre-
epilepsy per se, even though the condition is characterized by existing neurodevelopmental abnormalities, complex features
epileptic seizures (Berg et al., 2010). The condition affects 2% (prolonged duration, focal features, and multiple occurrences
Epilepsies 1581
per day), a family history of epilepsy, and recurrent febrile sis, focal cortical dysplasia, and hemimegalencephaly; as
seizures. The presence of one complex feature increases the related to abnormal neuronal migration, including lissen- 101
risk to 6% to 8%, two complex features, 17% to 22%, and all cephaly, subcortical band heterotopias, and periventricular
three complex features, 49% (Annegers et al., 1987). Complex nodular heterotopias; and as related to abnormal cortical
features tend to predict an increased risk of partial epilepsy, organization, including polymicrogyria and schizencephaly.
while a large number of febrile seizures and a positive family Some of these malformations are genetically determined—for
history of epilepsy increase the risk of later generalized epi- example, tuberous sclerosis, lissencephaly, subcortical band
lepsy. Febrile seizures may be prolonged to qualify for the heterotopia, and bilateral periventricular nodular heterotopia.
definition of febrile status epilepticus. Febrile status epilepti- Many of these malformations have other associated neurologi-
cus may injure the hippocampus (VanLandingham et al., cal disorders or physical findings, and most are easily diag-
1998), with unilateral increased hippocampal T2 signal on nosed on MRI. Focal malformations associated with epilepsy
MRI in about 11.5% of affected children (Shinnar et al., 2012). are less likely to have other neurological manifestations than
This acute MRI finding is frequently followed by development hemispheric or generalized malformations. The severity of
of hippocampal sclerosis on follow-up imaging (Lewis et al., epilepsy and its response to therapy can be quite variable, but
2014). Another 10.5% of children with febrile status epilepti- it is commonly drug-resistant, prompting evaluation for surgi-
cus had a hippocampal malformation, most commonly cal treatment.
hippocampal malrotation, suggesting that this congenital Risk factors for epilepsy in early life include neonatal sei-
malformation may have predisposed them to febrile status zures and febrile seizures, both of which are conditions not
epilepticus (Shinnar et al., 2012). It is not yet known if these considered forms of epilepsy. However, it is difficult to con-
radiological findings are associated with development of tem- sider these risk factors as causes of later epilepsy.
poral lobe epilepsy. Infections are an important risk factor for epilepsy. The risk
Evidence exists that febrile seizures have a strong genetic of later epilepsy is higher for both meningitis and encephalitis
influence. The inheritance is most probably polygenic in the if seizures occur during the acute illness. The relative risk of
majority of children, but several reports indicate clear auto- later epilepsy was increased 16-fold after encephalitis and
somal dominant transmission in some families. Several muta- fourfold after bacterial meningitis (Annegers et al., 1988). The
tions have been described, some in families with pure febrile risk of later epilepsy was greatest with infection prior to age
seizures and others in families with both febrile seizures and 5. Early occurrence of meningitis or encephalitis prior to age
epilepsy. 4 predicted mesial temporal localization with hippocampal
Some genetic epilepsy syndromes are known to start with sclerosis, and better outcome with temporal lobectomy
febrile seizures. One of these is Dravet syndrome or severe (O’Brien et al., 2002).
myoclonic epilepsy of infancy (see earlier discussion). The
febrile seizures in this condition tend to be prolonged and
often asymmetrical. Fever appears to be a trigger for seizures,
Head Trauma
but the subsequent course of the condition is progressive, with Head trauma is an important risk factor for epilepsy, with the
afebrile seizures and neurological decline eventually develop- greatest risk seen in association with penetrating head injury,
ing. Dravet syndrome is usually due to a truncating mutation head injury with depressed skull fracture, and severe head
in the SCN1A sodium channel or GABRG2 GABAA receptor trauma with prolonged loss of consciousness. In a landmark
subunit gene. GEFS+ is an autosomal dominant syndrome study, mild traumatic brain injury (characterized by absence of
with heterogeneous clinical expression. Some individuals fracture and a loss of consciousness or post-traumatic amnesia
have the typical febrile convulsion syndrome with some for less than 30 minutes) was associated with only a 1.5-fold
febrile seizures that disappear by age 6 years, while others have increase in risk of epilepsy, which was not statistically signifi-
febrile seizures persisting beyond age 6 or occurring in con- cant (Annegers et al., 1998). Patients with moderate head injury,
junction with other seizure types (see Fig. 101.6). defined as loss of consciousness or post-traumatic amnesia for
Single febrile seizures are more likely to be polygenic, 30 minutes to 24 hours or a skull fracture, had a 2.9-fold
whereas families with single-gene inheritance are more likely increase in risk, while those with severe head injury, including
to include recurrent febrile seizures. Digenic inheritance has brain contusion or intracranial hematoma or loss of con-
been described (Baulac et al., 2001b); affected individuals had sciousness or post-traumatic amnesia for more than 24 hours,
two mutations, and those unaffected had either one or no had a 17-fold increased risk. The risk was highest in the first
mutation. year after the injury but remained increased thereafter for a
Since most febrile seizures are benign, there is usually no duration that varied with severity of the injury. For those with
need to treat affected patients with prophylactic daily medica- moderate brain injuries, the risk was markedly increased for
tion. Intermittent medication may be given at the time of up to 10 years only; for those with severe traumatic brain
fever. For example, diazepam may be given orally or rectally injury, the risk continued to be increased. The Vietnam Head
in patients with frequent recurrent febrile seizures. Rectal Injury Study (VHIS), in which 92% of subjects had penetrating
diazepam can be administered for prolonged febrile seizures head injuries, found a 53% prevalence of post-traumatic epi-
(Knudsen, 2000). lepsy approximately 15 years after the injury. The risk was 580
times higher than that of the general age-matched population
in the first year after injury, and it was still 25 times higher
Causes and Risk Factors after 10 years (Salazar et al., 1985). A more recent follow-up
Seizures and epilepsy can result from inherited or acquired study in a subgroup of the original patients found that 12.6%
factors or a combination of both. Several genetic epilepsy of individuals who had post-traumatic epilepsy developed epi-
syndromes were described earlier. The following discussion lepsy more than 15 years after the injury (Raymont et al.,
will focus on acquired causes and risk factors, which vary 2010). Early seizures appeared to be a strong risk factor for late
considerably depending on age. seizures, but early seizures were usually related to the severity
In children, developmental brain malformations are an of the head injury and intracranial lesions.
important cause of epilepsy. These can be generalized, hemi- Changes in the brain reflecting the process of epileptogen-
spheric, or focal. They are also classified as related to abnormal esis are likely in the latent period between the head injury and
cell proliferation or differentiation including tuberous sclero- onset of chronic epilepsy. Among several therapeutic measures
tested for efficacy in preventing epilepsy after head injury, epilepsy is drug resistant, resection of the cavernous malfor-
none have proven effective (Temkin, 2009). However, pheny- mation is associated with excellent results, provided the
toin was effective in preventing seizures in the first week hemosiderin-stained brain tissue surrounding it is removed
(Temkin et al., 1990). Levetiracetam was equally effective in (Awad and Jabbour, 2006). Intraoperative monitoring with
preventing early seizures (Inaba et al., 2013). The new AEDs electrocorticography can also improve surgical outcome (Van
have not been tested for the prevention of post-traumatic Gompel et al., 2009).
epilepsy.
Brain Tumors
Vascular Malformations Brain tumors are a common cause of epilepsy, particularly
The two vascular malformations most commonly associated drug-resistant epilepsy. Most drug-resistant epilepsy occurs
with epilepsy are arteriovenous malformations and cavernous with low-grade tumors, especially those in the temporal lobe
malformations. Venous malformations, also called venous (Rajneesh and Binder, 2009). Benign tumors associated with
anomalies, may be accidental findings not directly related to epilepsy are gangliogliomas, dysembryoblastic neuroepithelial
epilepsy unless associated with a cavernous malformation. tumors (DNET), and low grade gliomas. Excellent seizure
Arteriovenous malformations (AVMs) are high-pressure vascular control most often occurs after removal of gangliogliomas and
malformations with arteriovenous shunting. They are a tangle DNET tumors. As expected, incomplete resection is associated
of feeding arteries and draining veins without intervening cap- with less likelihood of seizure control.
illary bed. They may come to attention during evaluation for Seizures contribute to the morbidity of malignant brain
seizures or after they bleed; they may also be incidental when tumors in approximately a quarter of patients. Grade 3 ana-
imaging is performed for unrelated reasons. Because of the plastic astrocytomas are more likely to present with seizures
high pressure, they are susceptible to bleed at a rate of 1% to at onset than glioblastoma multiforme (Moots et al., 1995).
3% per year, which is the main reason they require therapy.
Surgical treatment is effective, with one series reporting 94% Parasitic Infections
of patients seizure free, most on no AEDs (Piepgras et al.,
Neurocysticercosis is thought to be the leading cause of
1993). Patients with small AVMs were more likely to present
acquired epilepsy in adulthood in the developing world, but
with hemorrhage, whereas those with large AVMs were more
it is an uncommon cause of epilepsy in developed countries.
likely to present with seizures. The best seizure outcome was
Seizures are thought to occur in 70% to 90% of patients (Pal
seen with resection of small AVMs. Endovascular treatment
et al., 2000). Seizures in most patients can be controlled with
with embolization and radiosurgery can also improve seizure
AEDs. When epilepsy is drug resistant, patients with living
control, though to a lesser extent. Stereotactic radiosurgery
cysticerci in the brain can benefit from albendazole, an
rendered more than 50% of patients seizure free and was more
antiparasitic treatment, in combination with dexamethasone
likely to be successful when the preoperative seizure frequency
(Garcia et al., 2004).
was low and the AVM was small (Schauble et al., 2004).
Other parasitic infections are also common causes of sei-
Cavernous malformations consist of blood-filled epithelium-
zures and epilepsy in the developing world, particularly cere-
lined caverns with no discrete arteries or veins (Kraemer and
bral malaria with Plasmodium falciparum.
Awad, 1994). On MRI they have a characteristic “popcorn”
appearance with mixed signal within the lesion and a rim of
decreased signal, reflecting hemosiderin (Fig. 101.14). They
Stroke
may be multiple in approximately a third of cases. Cavernous Stroke increases the risk of seizures and epilepsy at any age,
malformations are low-pressure lesions with a much smaller but it is the most common cause of seizures in the elderly
risk of bleeding than AVMs. They are strongly associated with (Menon and Shorvon, 2009). As in post-traumatic seizures,
epilepsy. If seizures are controlled with medical therapy, there early seizures that occur within 2 weeks of the stroke most
is no clear indication for surgical resection. However, when often do not progress to chronic epilepsy, but they do increase
the risk of chronic epilepsy. As with head trauma, the risk of
chronic epilepsy is highest in the first year after stroke, with a
17-fold increase in the risk compared to population in the
community. Compared to individuals who did not have early
seizures, approximately 30% of individuals who have early
post-stroke seizures develop later epilepsy. This is a 16-fold
increase in risk. Seizures and even status epilepticus can be a
presenting symptom of acute stroke. Nonconvulsive status epi-
lepticus is difficult to detect.
As is expected, strokes involving the cortex are more likely
to produce epilepsy than deep white-matter strokes. The inci-
dence of seizures is also higher in patients with intracerebral
hemorrhage.
Inflammatory and Autoimmune Disorders

Immune disorders increase the risk of epilepsy and seizures.
In systemic lupus erythematosus, the risk of seizures is 12%
to 20% and is more likely with anticardiolipin and anti-Smith
antibodies (Najjar et al., 2008). The risk of epilepsy is also
increased in primary CNS inflammatory conditions such as
multiple sclerosis. Between 2% and 6% of patients with mul-
tiple sclerosis have seizures. Those who do tend to have more
extensive cortical involvement with inflammatory disease. Sei-
Fig. 101.14 Left mesial temporal cavernous malformation. zures are more likely to occur in the context of acute relapse,
Epilepsies 1583
but some patients develop chronic epilepsy. Seizures are a to be 1.5%, but still with an eightfold increase in risk com-
more common acute manifestation of acute disseminated pared to an age-matched population (Scarmeas et al., 2009). 101
encephalomyelitis, noted in approximately 50% of patients. Major depression seemed to increase the risk of epilepsy
However, chronic epilepsy is much less likely, with only about sixfold in patients 55 years or older. This was the case
5% affected. without any prior neurological insult (Hesdorffer et al.,
Hashimoto encephalopathy is a steroid-responsive enceph- 2000). Attempted suicide also increased the risk of epilepsy
alopathy usually presenting with behavioral-cognitive abnor- (Hesdorffer et al., 2006).
malities. Seizures occur in 60% of individuals. Patients have Alcohol abuse is known to be associated with acute with-
elevated antithyroid antibodies, but it is not clear that these drawal seizures within 48 hours of stopping alcohol. However,
antibodies are responsible for the clinical manifestations chronic alcohol intake was also associated with increased risk
(Castillo et al., 2006). of chronic epilepsy, related to the amount of alcohol use. The
Limbic encephalitis is an increasingly recognized cause of increased risk was almost 20-fold for the heaviest drinkers (Ng
epilepsy. Suggested diagnostic criteria include one of distur- et al., 1988).
bance of episodic memory, temporal lobe seizures, or affective Heroin increased the risk of unprovoked seizures threefold,
disturbance plus the presence of either well-characterized while marijuana seemed to confer protection (Ng et al., 1990).
antibodies or unexplained increased signal in the mesial Cocaine may reduce seizure threshold in individuals with epi-
temporal structures, or histopathology of mesial temporal lepsy, but it is not clear that it is an important risk factor for
encephalitis (Bien et al., 2007). It can be paraneoplastic or chronic epilepsy (Koppel et al., 1996).
nonparaneoplastic. Neoplastic cases are associated with small
cell lung cancer, testicular cancer, thymoma, breast cancer, or
teratoma. Limbic encephalitis can also be classified by the
Causes of Acute Symptomatic Seizures
antibody target; associated antibodies may be directed against Acute symptomatic seizures occur in close temporal relation-
nonsynaptic intracellular proteins or against synaptic recep- ship with an acute CNS insult—metabolic, toxic, structural,
tors and channels on neuronal membranes. The latter have a infectious, or inflammatory (Beghi et al., 2010). Many of the
better prognosis with appropriate therapy, with a greater pos- causes of epilepsy already discussed can also cause acute symp-
sibility of reversing the clinical manifestations. The most com- tomatic seizures. Metabolic and toxic causes of acute sympto-
monly noted antibodies seen in nonparaneoplastic limbic matic seizures do not usually cause chronic epilepsy.
encephalitis include anti–N-methyl-D-aspartate (NMDA) recep- Metabolic disturbances known to cause seizures include
tor antibodies, anti-potassium channel complex antibodies hypoglycemia, hyperglycemia, hyponatremia, hypocalcemia,
(usually directed against LGI1 protein), and anti-glutamic acid hypomagnesemia, and uremia (Beghi et al., 2010). Withdrawal
decarboxylase (GAD) antibodies (Dalmau et al., 2008; Malter from chronic alcohol abuse may be associated with general-
et al., 2010; Titulaer et al., 2013). Other neuronal cell mem- ized tonic-clonic seizures as well as other manifestations of
brane targets include AMPA, GABAA and GABAB receptors withdrawal, typically within 48 hours of the last alcohol
(Bataller et al., 2010; Hoftberger et al., 2013; Petit-Pedrol intake. Acute withdrawal from benzodiazepines and barbitu-
et al., 2014). rates can also be associated with withdrawal seizures, more
Immunosuppressive therapies may be effective, particularly commonly when short-acting agents are involved.
in anti-potassium channel complex antibody limbic encepha- Several illicit drugs produce acute symptomatic seizures,
litis (Malter et al., 2010). An immune basis of epilepsy should particularly cocaine and other stimulants taken in excess.
be suspected in individuals who have other autoimmune Several therapeutic medications can trigger acute sympto-
disease, abrupt or recent onset of seizures (particularly if resist- matic seizures at high doses or in susceptible individuals.
ant to AEDs and progressive in frequency and severity), associ- These same medications, as well as metabolic derangements,
ated manifestations such as behavioral changes and psychosis, can also trigger seizures in people with epilepsy, at lower
severe memory disturbances, and abnormal signal on MRI in thresholds than for people without epilepsy.
the hippocampi.
An immune origin is suspected in several well-described
epileptic syndromes. These include West syndrome, Lennox-
SEIZURE PRECIPITANTS
Gastaut syndrome, LKS, and Rasmussen syndrome. All are Some patients with epilepsy report seizure precipitants that
discussed earlier in the chapter. will not trigger seizures in unaffected individuals. More than
50% of subjects with epilepsy reported at least one precipitant
(Frucht et al., 2000; Nakken et al., 2005). Emotional stress and
Other Risk Factors sleep deprivation were the most commonly reported precipi-
Other risk factors have been specifically investigated in tants. Other precipitants were fatigue, fever or illness, flickering
older adults. Several risk factors for stroke are independently light, and menstruation. In some epileptic syndromes and
associated with increased risk of epilepsy, without evidence epilepsies (e.g., benign epilepsy with centrotemporal spikes,
of any stroke. For example, hypertension is associated with frontal lobe epilepsy), seizures occur preferentially in sleep.
a 1.57-fold increase in the risk (Ng et al., 1993). Left ventricu- Several medications can reduce the seizure threshold,
lar hypertrophy without diuretic treatment was associated including tricyclic antidepressants, bupropion, various anti
with an 11-fold increased risk (Hesdorffer et al., 1996). psychotics, CNS stimulants, fluoroquinolone antibiotics, older
Diuretics were protective, as left ventricular hypertrophy antihistaminics, meperidine, and tramadol. Fever can reduce
treated with diuretics carried no increase in risk (Hesdorffer the threshold for seizures in patients with known epilepsy.
et al., 1996). Hyperventilation is well known to precipitate generalized
Dementia, particularly Alzheimer disease, has been associ- absence seizures. It can also precipitate other seizure types
ated with epilepsy, with up to a 10-fold increase in risk com- to a much lesser extent (Arain et al., 2009; Guaranha et al.,
pared to a reference population (Hauser et al., 1986). Patients 2005).
who developed seizures had a younger age at onset of demen- One likely common reason for precipitation of seizures is
tia, with seizures tending to be a late feature first seen an missing antiepileptic medication doses. Breakthrough seizures
average of 6.8 years after onset (Mendez et al., 1994). Using can occur with missing any of the AEDs. However, car-
very conservative criteria, the incidence of seizures was found bamazepine and oxcarbazepine are associated with more
severe seizures upon abrupt withdrawal (Azar et al., 2008b; at 39% at 2 years, 51% at 5 years, and 52% at 8 years (Marson
Marciani et al., 1985). et al., 2005). The risk of recurrence is highest in the first 2
A prominent precipitation of seizures in association with years. Treatment reduced the risk by 60% in one study (First
the menstrual cycle has been termed catamenial epilepsy. This Seizure Trial Group, 1993) and 30% in the second study
is reported in approximately 55% of women (Herzog, 2008). (Marson et al., 2005).
The most common pattern of clustering of seizures is peri- The two factors that most influenced recurrence rate were
menstrual, typically in the 3 days before and 3 days after an abnormal EEG and an abnormal neurological status. Indi-
onset of the period. Less common patterns are periovulatory viduals with a normal EEG and normal neurological status
(occurring around ovulation) and luteal, in association with had a risk of recurrence of 25% at 2 years and 30% at 4 years
inadequate luteal phase cycles. The mechanism of catamenial (Kim et al., 2006).
epilepsy is thought to be related to the opposite effects of The risk of recurrence increases remarkably after a second
estradiol and progesterone on seizure threshold. Estradiol is seizure. In one prospective study in adults the 2- and 5-year
a proconvulsant, whereas progesterone has an anticonvul- risks of recurrence after the first seizure were 27% and 33%,
sant effect. Progesterone therapy has been suggested as a and after the second seizure were 61% and 73% (Hauser et al.,
treatment when catamenial epilepsy is not responsive to 1998).
standard AEDs.
MORBIDITY AND MORTALITY

EPIDEMIOLOGY OF EPILEPSY AND SEIZURES
Morbidity and Comorbidity
Descriptive Epidemiology
Compared to the general population, individuals with epi-
The incidence of epilepsy is defined as number of new cases in lepsy are at risk for increased morbidity and mortality. A large
a unit of time divided by the total population at risk. The European cohort study of predominantly young patients diag-
overall incidence in North America, adjusted for age, varied nosed within the previous 5 years showed a significantly
from 16 to 51 per 100,000 persons per year (Banerjee et al., greater cumulative probability of illness than controls (49%
2009). The incidence is similar in European studies, but by 12 months and 86% by 24 months in patients versus 39%
figures were at times higher in developing countries, up to 111 and 75% in controls) (Beghi and Cornaggia, 2002). The
per 100,000 in a study in rural Chile. Incidence is high in the chance of illness tended to increase with number of seizures,
first decade of life, lowest in adult years until the fifth decade and there was also a significant correlation between the
of life, then higher thereafter. In US studies, the highest inci- number of illnesses and seizure frequency. However, most of
dence was after age 75. The increased incidence in older age the illnesses reported were trivial. Patients with epilepsy dif-
was not seen in developing countries. Incidence is slightly fered from controls predominantly in ear, nose, and throat
higher in males and higher in groups with lower socioeco- complaints. Accidents were also considerably more common
nomic status. The finding was not accounted for by known in patients than controls (17% and 27% by 12 and 24 months
risk factors such as head injury and stroke. compared to 12% and 17% for controls). The number of
Prevalence of epilepsy is defined as number of individuals wounds increased with the number of AEDs, which may reflect
with epilepsy divided by total population at a point in time. impairment of attention as a result of seizure medications.
This is most often active prevalence, referring to active epilepsy Nervous system disorders that were more common in patients
at the time of the study, as opposed to lifetime prevalence, than in controls included headache and vertigo/dizziness (van
which includes anyone who developed epilepsy prior to the den Broek and Beghi, 2004).
study. The age-adjusted prevalence tends to be lower in devel- Psychiatric disorders were not significantly different
oped countries. In door-to-door surveys, the age-adjusted between patients and controls in this study but may have been
prevalence ranged from 2.7 per 1000 in Italy to 7.1 per 1000 underestimated, since the study depended on patient self-
in Mississippi. The lowest prevalence was in India at 2.2 per report. Several studies support an increased incidence of psy-
1000 and the highest in Nigeria at 41 per 1000. Prevalence is chiatric disorders in epilepsy. A cross-sectional study that
higher in males and also higher in groups with low socioeco- included 5834 individuals with epilepsy suggested that
nomic status. persons with epilepsy have double the risk of psychiatric dis-
Cumulative incidence is the estimate of the proportion of orders and an increased risk for neurodegenerative conditions,
individuals who will have developed epilepsy by a certain age. particularly dementias and Parkinson disease, cardiovascular
In Rochester, Minnesota, at age 80 the cumulative risk of epi- disorders, cerebrovascular disorders, upper-gastrointestinal
lepsy was 4%, and the cumulative risk for all unprovoked hemorrhages, fractures, pneumonia, chronic lung diseases,
seizures was more than 5% (Hauser et al., 1993). The cumula- diabetes, and brain tumors (Gaitatzis et al., 2004). A US
tive incidence of all epilepsy was 1.2% through age 24 (Hauser survey also found an almost threefold greater frequency of
et al., 1993). serious mental illness and an increase in physical comorbid
conditions including cancer, arthritis, heart disease, stroke,
asthma, severe headaches, lower back pain, and neck pain
Epidemiology of the First Unprovoked Seizure (Strine et al., 2005). It is likely that individuals with longer
Studies of recurrence after the first unprovoked seizure have duration of epilepsy and drug-resistant epilepsy contribute to
predominantly focused on patients who present with a gener- the higher morbidity in the cross-sectional surveys. The reason
alized tonic-clonic seizure, with or without focal onset. Milder for the increased morbidity is not known. One speculation is
seizures are much less likely to present to medical attention that it could be the result of stress and its adverse effects on
after their first occurrence. A meta-analysis of observational various systems (Yuen et al., 2007).
studies estimated a 2-year recurrence risk of approximately A more recent survey designed to measure a wide spectrum
40% (Berg and Shinnar, 1991). Two large randomized trials of neuropsychiatric and pain comorbidities found several neu-
gave slightly different estimates for recurrence in patients ran- ropsychiatric disorders to be more than twice as prevalent
domized to treatment (Berg, 2008). One predicted a recur- in patients with self-reported epilepsy as in those without
rence risk of 51% at 2 years after the initial seizure (First epilepsy (Ottman et al., 2011). These disorders included bipo
Seizure Trial Group, 1993), and the other estimated the risk lar disorder, attention-deficit/hyperactivity disorder (ADHD),
Epilepsies 1585
and movement disorders/tremor. The last two had not been epilepsy patients, obstructive sleep apnea was more common
reported in previous national surveys. The most prevalent in those with new-onset or newly worsened epilepsy than in 101
comorbidity was depression, reported by 32.5% of cases. The individuals with stable or well-controlled epilepsy (Chihorek
cause of depression in epilepsy may include both psychosocial et al., 2007). In those patients with coexistent epilepsy and
and biological factors. Depression appears more prevalent in sleep apnea, there is evidence that treatment of the sleep apnea
patients with medically intractable complex partial seizures may have a beneficial effect on seizure control (Malow et al.,
(Victoroff et al., 1994). A survey of frequency and severity of 2008). Other sleep disorders associated with epilepsy include
depressive symptoms in community-based patients with epi- insomnia. In particular, sleep-maintenance insomnia was
lepsy or asthma found evidence of depression in 36.5% of reported more frequently than in controls (Khatami et al.,
epilepsy subjects compared to 27.8% of asthma subjects and 2006). Polysomnography in patients with epilepsy demon-
11.8% of healthy controls. Patients with epilepsy are more strates reduced percentage of sleep time spent in rapid eye
likely to be depressed than patients with asthma, suggesting movement (REM) sleep, increased waking after sleep onset,
that depression is not solely related to a chronic illness prolonged REM latency, and increased number of stage shifts
(Ettinger et al., 2004). The presence of depression was associ- (Touchon et al., 1991). The findings are more common with
ated with worse quality-of-life scores. As a result, clinicians temporal lobe epilepsy. The decrease in REM is more pro-
evaluating patients with epilepsy are advised to discuss mood nounced if seizures occurred during the early part of the night
and quality of life as part of the evaluation (Ettinger et al., (Bazil et al., 2000).
2004).
Psychiatric symptoms need to be detected early and treated
effectively, avoiding the erroneous supposition that depres-
Mortality in Epilepsy
sion is a normal reaction to the epilepsy (Garcia-Morales Epilepsy carries a two to three times higher mortality rate than
et al., 2008). The presence of depression should influence the that of the general population (Tomson, 2000). The standard-
selection of AEDs, avoiding drugs that are known to be associ- ized mortality ratio in an early study was 2.3 through 29 years
ated with depression and favoring medications such as lamo- of follow-up (Hauser et al., 1980). The most significant
trigine with a known positive mood effect. In addition, there increase in standardized mortality ratio was noted in the first
should be a low threshold for prescribing specific antidepres- 10 years after diagnosis; the increase was present even when
sant or mood-stabilizing medications, as well as consulting a epilepsy was in remission, suggesting that the increased mor-
psychiatrist. Compared to controls, the risk of suicidal behav- tality was not solely related to seizures. However, standardized
ior and suicide is increased in persons with epilepsy. The mortality ratio remained elevated even after 30 years of
relationship between depression/suicidality and epilepsy is follow-up (Shackleton et al., 1999). The mortality ratio does
bidirectional, with a higher risk of developing epilepsy in depend on the seizure type. For example, generalized tonic-
those with a past history of suicidality, and a higher risk of clonic and myoclonic seizures were associated with increased
suicidality in individuals with epilepsy (Hesdorffer et al., mortality, while absence seizures were not (Hauser et al.,
2006). In subjects who developed epilepsy the incidence 1980). Patients who become seizure free after epilepsy surgery
of depression, anxiety, and suicide attempts was increased have the same mortality rates as the general population
even 3 years before epilepsy diagnosis, suggesting that some (Sperling et al., 1999). The highest mortality is found in epi-
mechanisms underlying reduced seizure threshold may also lepsy patients with mental retardation or cerebral palsy (For-
increase the risk for psychiatric disorders and suicide sgren et al., 2005). The increased mortality is due to a variety
(Hesdorffer et al., 2012). Psychiatric comorbidity at time of of factors including cerebrovascular disease, pneumonia, and
epilepsy diagnosis is an unfavorable prognostic indicator for neoplastic disorders, even after exclusion of primary brain
seizure freedom with pharmacological therapy (Hitiris et al., tumors (Forsgren et al., 2005). One study also found increased
2007; Petrovski et al., 2010). Lifetime psychiatric history was mortality from accidents (Olafsson et al., 1998). However,
also a predictor of worse outcome after anterior temporal deaths in epilepsy may also be related to the underlying cause
lobectomy for drug-resistant temporal lobe epilepsy (Kanner of epilepsy or to seizures themselves. Seizure-related deaths
et al., 2009). include deaths from status epilepticus, accidents and drown-
Other comorbidities associated with epilepsy include ing as a result of seizures, and sudden unexplained death in
migraine. In a large series of children with headache, children epilepsy (SUDEP) (Forsgren et al., 2005).
with epilepsy had a 4.5-fold increased risk of developing SUDEP accounts for about 1.7% of all deaths in epilepsy
migraine over a tension-type headache (Toldo et al., 2010). and 8.6% of deaths in the 15- to 44-year-old age group (Ficker
The rate ratio for migraine was 2.4 for individuals with epi- et al., 1998). The rate of SUDEP in the 20- to 40-year-old age
lepsy in comparison with controls (Ottman and Lipton, group was nearly 24 times that expected for the general popu-
1994). In addition, specific epileptic syndromes have a greater lation (Forsgren et al., 2005). The mechanisms of SUDEP are
association with migraine (Kossoff and Andermann, 2010). not fully understood, but there is strong evidence that SUDEP
The comorbidity of migraine may influence the choice of AED. is related to seizures (So, 2008). When SUDEP is witnessed,
Some AEDs such as topiramate and valproate have proven it is most often associated with a generalized tonic-clonic
effective in migraine prophylaxis and are approved for this seizure near the time of death (Tomson et al., 2005), and the
indication by the US Food and Drug Administration (FDA). vast majority of unwitnessed SUDEP is associated with tongue
Sleep disorders are also a known comorbidity of epilepsy. biting or incontinence, suggesting recent generalized tonic-
Epilepsy patients frequently have excessive daytime sleepiness, clonic seizures (Langan, 2000).
which is multifactorial (Manni and Tartara, 2000). Several Two main hypotheses have been put forth to explain
studies have suggested that the prevalence of obstructive sleep SUDEP, one suggesting cardiac mechanisms and the other,
apnea may be relatively high in individuals with epilepsy as respiratory mechanisms. In support of a cardiac mechanism is
compared with controls (Kaleyias et al., 2008; Manni and the rarely documented phenomenon of ictal bradycardia or
Terzaghi, 2010; Manni et al., 2003). Sleep apnea is even more ictal asystole, particularly in patients with temporal lobe epi-
prevalent in individuals with drug-resistant epilepsy (Malow lepsy. In one study, the maximal ictal heart rate was signifi-
et al., 2000b) and may play a role in drug resistance. Sleep cantly higher in SUDEP patients than epilepsy controls,
apnea may worsen seizure control by fragmenting nocturnal especially with seizures arising from sleep (Nei et al., 2004).
sleep and mimicking sleep deprivation. In one study in older The observation that some seizures increase corrected QT
interval beyond normal limits may also be relevant. This was 2007). Although the SWDs are initiated in the cortex in these
most likely to occur with tonic-clonic seizures and right tem- two rodent models, selective unilateral ablation of the reticu-
poral seizures (Brotherstone et al., 2010). lar (nRT) and ventrobasal (VB) nuclei results in bilateral abol-
The respiratory mechanism was proposed because of evi- ishment of SWD, a finding that demonstrates that even though
dence of pulmonary congestion or even edema on autopsy in the thalamus does not initiate the SWD, it is needed to sustain
SUDEP patients, but the degree of pulmonary congestion is them (Meeren et al., 2009).
not sufficient to cause death. On the other hand, ictal apnea Study of nonhuman models of absence seizures revealed
and hypoxia are common (Bateman et al., 2008; Nashef three critical brain regions required for absence seizures: the
et al., 1996). Pronounced oxygen desaturation occurred even deep layers of the somatosensory cortex and the nRT and
in partial seizures that did not progress to generalized con- relay nuclei (in VB) of the thalamus (Beenhakker and Hugue-
vulsions, most commonly with seizures of temporal lobe nard, 2009; Steriade, 2005). Paroxysmal firing of cortical
onset. The duration of the seizure and electrographic evi- layer VI neurons activates GABAergic neurons in nRT. Feed-
dence of contralateral spread influenced the degree of desatu- forward inhibition from the cortex through the nRT hyper-
ration. The idea of hypoventilation as an initiating factor in polarizes the thalamocortical neurons (TC) in VB. Because
SUDEP is supported by the clinical finding that most patients the nRT neurons are highly interconnected, and because they
are found dead in a prone position (Kloster and Engelskjon, innervate multiple TC neurons, the hyperpolarization of the
1999). A recent analysis suggested that prolonged generalized TC neurons is synchronous. The hyperpolarization removes
EEG suppression was more commonly seen with seizures the deactivation of T-type calcium channels and activates the
recorded in individuals who later died of SUDEP. Beyond 80 hyperpolarization-activated current, Ih. Ih depolarizes the TC
seconds of postictal generalized EEG suppression, the odds of neurons and thereby activates the T-type calcium channels
SUDEP were quadrupled. It is thought that the generalized which mediates further depolarization to the point at which
EEG suppression reflects profound postictal cerebral dysfunc- TC neurons engage in action potential burst firing. The burst
tion that may be a mechanism for central apnea (Lhatoo firing from the TC neurons is projected to both the cortex
et al., 2010). and the nRT. Feedback connections from VB to nRT reacti-
It is now increasingly recognized that patients deemed at vate the nRT neurons, which thereby allows the cycle to
high risk for SUDEP need to be informed about this potential reverberate.
complication. Education about SUDEP is not necessary in Alterations in the physiological properties of the three
patients with well-controlled seizures, but it is important for brain regions that comprise the thalamocortical circuit can
noncompliant individuals who could reduce the risk of result in SWDs. For example, increased tonic GABAA receptor
SUDEP with improved compliance, and for patients with currents in the TC neurons cause seizures in three inbred
drug-resistant epilepsy who are excellent candidates for epi- genetic rodent models of absence epilepsy (Cope et al., 2009).
lepsy surgery, which reduces the risk of SUDEP when success- However, in another rodent model, the Gria4 knockout
ful (So et al., 2009). mouse, it is the reduced excitatory transmission from cortex
to nRT with preserved excitatory transmission from VB to nRT
that enables the excessive oscillation and absence seizures
PATHOPHYSIOLOGY AND MECHANISMS (Paz et al., 2011). Undoubtedly, the generation of additional
Elucidating the pathogenic mechanisms related to different genetic mouse models of absence epilepsy will reveal altera-
epilepsy syndromes will help identify new targets for antisei- tions in other parts of the thalamocortical circuit that cause
zure and antiepileptogenic therapies and reveal how the absence seizures.
normal brain processes information and stores memories. The physiological processes that contribute to other types
Reviewing all the progress made in understanding the patho- of generalized seizures have not been as well-characterized as
genesis of epilepsy syndromes is beyond the scope of this those in absence seizures. In contrast to the studies of patients
section, so we will focus on three common seizure types: with absence epilepsy that revealed involvement of the ventral
generalized seizures, mesial temporal lobe seizures (MTLS), thalamus and frontal cortex, studies of JME patients revealed
and neocortical partial seizures (NPS). involvement of the anterior thalamus, mesial frontal cortex,
supplementary motor area, premotor cortex, and primary
motor cortex. Diffusion tensor imaging (DTI) and fMRI studies
Generalized Seizures of JME patients identified altered connectivity between the
anterior thalamic nuclei and the frontal cortex including the
Physiology supplementary motor area (O’Muircheartaigh et al., 2012).
Absence seizures have the best-characterized pathophysiology Functional MRI and DTI studies exploring mesial frontal lobe
of all the generalized seizures. Studies in both human and connectivity demonstrated increased structural connectivity
animal models identified prominent roles for both the thala- between the prefrontal cortex and motor cortex, reduced con-
mus and the cerebral cortex in absence seizure generation. nectivity between prefrontal and frontopolar regions, and
Intracranial recordings from absence epilepsy patients under- increased connectivity between the occipital cortex and SMA
going ventriculography demonstrated 3 Hz spike-and-wave (Vollmar et al., 2012).
discharges (SWD) occurring simultaneously in the cortex and Studies of Lennox-Gastaut syndrome (LGS), an epilepsy
thalamus; the thalamic rhythm preceded the cortical rhythm syndrome associated with generalized seizures including atyp-
by approximately 1 second (Williams, 1953). Experiments ical absence seizures, revealed different brain networks than
that simultaneously measured EEG and fMRI signals also those found in absence epilepsy or JME. Functional MRI
revealed prominent thalamic and cortical involvement during studies in patients with LGS revealed activation of the brain-
absence seizures. However these EEG-fMRI studies suggested stem and anterior thalamic nuclei and the centromedian
that the discharges began in the cortex and then spread to the nucleus during interictal epileptiform discharges and paroxys-
thalamus (Kay and Szaflarski, 2014). Similarly, electrophysi- mal fast activity (Siniatchkin and Capovilla, 2013). Depth
ological studies of genetic rat models of absence seizures electrode EEG studies of rodent models of Lennox-Gastaut-
revealed that the discharges first occurred in the deep layers of like atypical absence seizures revealed epileptiform activity in
the somatosensory cortex before spreading to the thalamus the cortex, hippocampi, nRT, as well as the midline thalamic
and other cortical regions (Meeren et al., 2002; Polack et al., nuclei (Velazquez et al., 2007; Wang et al., 2009).
Epilepsies 1587
TABLE 101.2 Molecular Consequences of GABAA Receptor Subunit Mutations Associated with Generalized Epilepsy Syndromes
101
Potential therapeutic
Molecular consequence Mutation(s)* intervention(s) References
Nonsense-mediated decay of α1 (975delC, S326fs328X) 1. Upregulation of wild-type allele Lachance-Touchette et al. (2011);
mRNA containing a α1 (K353delins18X) 2. Inhibition of nonsense- Ishii et al. (2014);
premature stop codon γ2 (Q40X) mediated decay Kang et al. (2009b); Maljevic et al.
γ2 (R136X) (2006)
γ2 (IVS6 + 2T→G) Tian et al. (2012)
Kananura et al. (2002)
Misfolding and degradation of α1 (A322D) 1. Upregulation of wild-type allele Bradley et al. (2008); Cossette et al.
nascent polypeptide 2. Administration of small- (2002); Gallagher et al. (2007)
molecule protein-folding
chaperones
Dominant negative reduction of γ2 (S443delC) Knock-down of mutant subunit Tian et al. (2013);
wild-type GABAA receptor γ2 (Q390X) mRNA Ding et al. (2010);
expression γ2 (W429X) Harkin et al. (2002);
Kang et al. (2009a);
Kang et al. (2013)
Formation of insoluble protein γ2 (Q390X) Knock-down of mutant subunit Kang et al. (2010);
aggregates γ2 (W429X) mRNA Sun et al. (2008)
Impaired oligomerization with β3 (G32R) Upregulation of wild-type allele Gurba et al. (2012);
wild-type subunits γ2 (R82Q) Hales et al. (2005);
γ2 (P83S) Kang and Macdonald (2004);
γ2 (R177G) Sancar and Czajkowski (2004);
Wallace et al. (2001); Audenaert et al.
(2006)
Altered electrophysiological γ2 (K328M) Treatment with GABAA receptor Baulac et al. (2001a); Bianchi et al.
properties δ (E177A) pharmacological modulators (2002); Dibbens et al. (2004)
δ (R220H)
GABA, γ-Aminobutyric acid; mRNA, messenger RNA.
*All mutations are numbered starting at the initiation methionine at the N-terminus of the signal sequence.
Histopathology gomerization, formation of insoluble protein aggregates, and

altered electrophysiological properties. Specific potential ther-
A controlled histological study failed to reveal any cellular apies for each of these molecular consequences have been
differences between postmortem brain specimens from CAE, proposed (Table 101.2).
JME, or epilepsy with generalized tonic-clonic seizures upon Mouse models of human genetic generalized epilepsy syn-
awakening patients and those of normal controls (Opeskin dromes have been developed. Tan et al. engineered mice con-
et al., 2000). However, this study did not examine for taining a missense mutation (R82Q) in the GABAA receptor γ2
ultrastructural changes. An analysis of a genetic rat model of subunit that is associated with absence epilepsy and febrile
absence epilepsy revealed morphological differences in den- seizures (Tan et al., 2007). The knockin mice exhibited absence
drite length and arborization in the cortices of epileptic seizures, and electrophysiological recordings demonstrated
animals (Karpova et al., 2005). Therefore, it is possible that reduced GABAA receptor currents in the cortex, but not in the
more detailed pathological studies of human tissue as well as thalamus. This result emphasized the importance of region-
the analysis of tissue obtained from additional animal models specific molecular changes within the epileptic network.
of generalized seizures will reveal other ultrastructural changes Arain et al. reported that heterozygous GABAA receptor α1
that cannot be detected by MRI studies or by routine patho- subunit deletion (Het α1 KO), a model of the frameshift/
logical analysis. truncation α1(S326fs328X) mutation found in absence epi-
lepsy, caused reduced viability and absence seizures in mice
(Arain et al., 2012). Biochemical, immunohistochemical and
Molecular Pathology electrophyiological studies demonstrated that, in the cortex,
Genetic epilepsy syndromes with generalized seizures have heterozygous loss of the α1 subunit resulted in replacement
been associated with mutations in GABAA receptor subunits, of α1-containing GABAA receptors by α3 subunit-containing
voltage-gated ion channel subunits, and the EF-hand calcium receptors, resulting in reduced GABAA-mediated postsynaptic
binding protein, EFHC1 (Macdonald et al., 2010; Suzuki et al., current amplitudes and altered current kinetics, a result that
2004). These mutations cause different molecular conse- would be consistent with cortical disinhibition (Zhou et al.,
quences in the proteins they encode, and elucidation of these 2013).
consequences has identified new potential targets for novel Heterozygous loss of the Efhc1, the mouse homolog
anticonvulsant therapies. For example, mutations in GABAA of the human EFHC1 gene associated with JME, resulted
receptor subunits can cause multiple different consequences in spontaneous myoclonus and a reduced sensitivity to
including elimination of the mutant messenger (m)RNA pentylenetetrazol-evoked seizures (Suzuki et al., 2009). The
through nonsense-mediated decay, misfolding, and degrada- pathophysiological mechanisms caused by Efhc1 deletion
tion of the nascent polypeptides, dominant negative reductions have not been fully elucidated. However, expression of recom-
in wild-type GABAA receptor expression, impaired receptor oli- binant Efhc1 protein in cultured brain slices revealed that
mutant, but not wild-type, Efhc1 disrupted radial and tangen- fast ripples, found in small regions (“microdomains”)
tial migration of neurons and glia by affecting their morphol- throughout the hippocampi. Individual neurons cannot fire
ogy (de Nijs et al., 2012). Possibly, abnormal migration and at these very high frequencies. Rather, it is likely that different
functioning of cortical GABAergic interneurons would cause groups of neurons fire alternately out of phase at slower fre-
cortical hyperexcitability and seizures. quencies, known as ripple frequencies (< 200 Hz) to produce
Altered interneuron function may also contribute to the these 200–600 Hz fast ripples. Neurons in these slower ripple
pathology of Dravet syndrome, a genetic epilepsy syndrome oscillations can be synchronized by fast-spiking interneurons
that confers generalized seizures including myoclonic seizures that form inhibitory synaptic connections with multiple
and atypical absence seizures. Approximately 85% of Dravet pyramidal cells (Klausberger et al., 2003, 2004). This putative
patients possess mutations in the SCN1A gene which encodes mechanism holds that pyramidal cells innervated by the
the α subunit of the neuronal voltage-gated sodium channel same interneuron are hyperpolarized synchronously, thereby
type 1. The majority (78%) of Dravet syndrome SCN1A muta- causing them to fire synchronously after the hyperpolarization
tions are predicted to be particularly disruptive to protein decays. Another putative mechanism holds that electrical (e.g.,
function; these disruptive mutations include amplification, gap junctions and ephaptic coupling), and not synaptic, con-
frameshift, truncation, deletion, or duplication mutations. nections mediate synchrony among pyramidal neurons during
Interestingly, both pyramidal and GABAergic neurons derived fast ripple oscillations (Roopun et al., 2010). It is thought that
from induced pluripotent stem cells from two Dravet patients these fast ripples in distributed microdomains coalesce to
showed increased, not decreased, sodium channel currents, form higher seizures.
hyperexcitability, and spontaneous bursting (Liu et al., 2013). In addition to studying mechanisms for fast ripple genera-
These findings suggested the intriguing possibility that over- tion and synchronization, considerable effort has been applied
compensation by a different sodium channel α subunit could to the elucidation of synchronization mechanisms in macro-
also contribute to the pathophysiology of Dravet syndrome. scopic mesial temporal interictal discharges and seizures
However, different results are obtained when Dravet syndrome (Jefferys et al., 2012). Pyramidal neurons within the CA3 hip-
is modeled in mice. Both heterozygous Scn1a deletion mice pocampal subfield establish strong excitatory synapses with
(Yu et al., 2006) and mice that heterozygously contained the nearby pyramidal neurons and thus the activation of one
Dravet-associated Scn1a R1407X nonsense mutation (Ogiwara pyramidal neuron results in the synchronous firing of many
et al., 2007) experienced spontaneous seizures. The hippo CA3 pyramidal neurons, resulting in a macroscopic interictal
campi of Scn1a deletion mice exhibited reduced sodium cur- discharge. As was discussed in the section concerning the
rents in the interneurons, but not the pyramidal neurons. The synchronization of fast ripples, inhibitory interneurons can
R140X mutation reduced spike amplitudes in cortical layer II/ synchronize macroscopic epileptiform discharges. Just as
III interneurons. These findings suggested that Dravet syn- GABAergic neurons in nRT form synapses with multiple exci-
drome mutations reduce interneuron function resulting in tatory TC neurons in the VB thalamus, GABAergic interneu-
disinhibition. rons in the hippocampus also form synapses with multiple
hippocampal pyramidal cells, which entrains them into
synchronous firing. In addition, because of altered chloride
Mesial Temporal Lobe Seizures gradients, interneurons innervating the axon initial segment
of multiple pyramidal neurons can form excitatory synapses
Physiology and cause multiple pyramidal neurons to fire synchronously
By definition, mesial temporal lobe seizures (MTLS) begin in (Khirug et al., 2008). Moreover, just as feedback inhibition
the limbic structures in the mesial temporal lobe. Intracranial from excitatory TC neurons onto GABAergic nRT neurons gen-
EEG recordings demonstrate that these seizures begin with erates oscillations in the thalamus, feedback inhibition from
periodic spiking or low voltage fast activity in the mesial tem- hippocampal pyramidal neurons to inhibitory interneurons
poral structures. Interestingly, impaired consciousness during also generates oscillations in the hippocampus. Nonsynaptic
MTLS can occur whether or not this ictal activity spreads to mechanisms also promote synchrony among hippocampal
the contralateral temporal lobe. How can one’s consciousness neurons to generate macroscopic epileptiform discharges.
become impaired with unilateral ictal activity? It has been Gap junctions have been well studied in hippocampal
suggested that MTLS disrupt brainstem-thalamic arousal interneurons and have been shown to promote synchronous
systems to cause widespread cortical inhibition of the default- firing and enhance oscillations. Unlike those in interneurons,
mode network, thus resulting in impaired consciousness. gap junctions in pyramidal neurons are relatively rare. If they
Consistent with this hypothesis, intracranial EEG studies in are of sufficient amplitude, the electric fields produced by
patients with MTLS demonstrated significantly greater slow neuronal firing can depolarize nearby neurons and cause
wave activity (not seizure) in the bilateral frontal and parietal them to fire action potentials as well. Computer simulation
neocortices during seizures with impaired versus those with suggests that, depending on the number of neurons firing and
unimpaired awareness (Englot et al., 2010). Moreover, ictal the proximity of adjacent neurons, this type of ephaptic con-
SPECT studies demonstrated that in addition to producing duction can potentially synchronize populations of hippo
temporal lobe hyperperfusion, MTLS also produced hyperper- campal neurons into epileptiform discharges. However, the
fusion in the bilateral mediodorsal thalamus and hypoper- study of ephaptic conduction in hippocampal seizures is still
fusion in bilateral frontal and parietal association cortices being conducted.
(Blumenfeld et al., 2004). Finally, increased thalamocortical
synchrony during MTLS may also contribute to impaired
awareness and provide a pathogenic link between MTLS and
Histopathology
the generalized seizures discussed in the preceding section Mesial temporal lobe epilepsy often presents with distinctive
(Blumenfeld, 2012). cellular changes in the hippocampus (Sutula and Dudek,
The mechanisms that cause excessive firing and hypersyn- 2007). Histological studies of hippocampi from experimen-
chrony are less well elucidated in MTLS compared with tal animal models of chronic epilepsy, as well as those
absence seizures. While absence seizures are believed to be resected from human patients, demonstrate neuronal loss in
initiated by paroxysmal cortical discharges, MTLS are often the dentate gyrus and CA1 and CA3 subfields. Instead of syn-
preceded by very high frequency activity (200–600 Hz) called apsing with inhibitory interneurons as they do in normal
Epilepsies 1589
hippocampi, dentate granule cell axons (mossy fibers) sprout the physiological, histological, and molecular causes of
and provide excitatory synapses (misdirected back to the NFS are associated with the site of onset and underlying 101
dentate molecular layer) with principal neurons. In addition etiology.
to sprouting and aberrant innervation, mossy fibers from
epileptic human and animal hippocampi demonstrated
increased synaptic release of zinc, which can potentiate gluta-
Physiological Abnormalities
mate and inhibit GABA synaptic currents (Buhl et al., 1996; Similar to generalized and mesial temporal seizures, an EEG-
Mitsuya et al., 2009; Shumate et al., 1998). These histologi- fMRI study found that interictal discharges associated with
cal changes most likely contribute to the development of NFS activated widely distributed neuronal networks (Fahoum
epilepsy. et al., 2012). Both frontal lobe and temporal lobe interictal
Quantitative MRI studies and neuronal cell counts in surgi- discharges activated bilateral cingulate gyri. Frontal lobe
cally resected hippocampi revealed that hippocampal atrophy interictal discharges also activated frontal operculum, thala-
and reduced neuronal densities correlated with increased ratio mus, and internal capsule. Temporal lobe interictal discharges
of the occurrence of pathological fast ripples to normal ripples activated mesial temporal region, insula, and cerebellum.
(Staba et al., 2007). The mechanisms by which these histologi- Frontal lobe, temporal lobe, and posterior quadrant discharges
cal changes contribute to seizure development are unknown, deactivated the default mode network.
but computational models suggest that processes such as neu- Similar to epilepsy syndromes associated with MTLS, syn-
ronal loss and circuit reorganization alter the in-phase firing dromes with NFS are also associated with pathological fast
of neuronal clusters, which may contribute to the formation ripples. In a study of patients with neocortical epilepsy, Wang
of pathological fast ripples (Ibarz et al., 2010; Stacey et al., et al. (2013) found that fast ripples (250–500 Hz) were
2009). detected in the seizure onset zone (SOZ, as defined by first
ictal onset), but only in a minority of patients (19%). Slower
frequency ripples (80–250 Hz) that were associated with a
Molecular Pathology sharp wave also correlated with the SOZ and were found in a
Hedera et al. (2007) identified a large family with an auto- majority (67%) of patients. Ripples that were not associated
somal dominant form of mesial temporal lobe epilepsy with interictal epileptiform activity were not correlated with
(MTLE) and mapped the locus to a 7 cM region on chromo- the seizure onset zone.
some 4q13.2-q21.3. Similarly, Striano et al. analyzed 15
Italian families with familial MTLE, but no chromosomal
locus was identified (Striano et al., 2008). Identifying the
Molecular Pathophysiology
genes responsible for these monogenic MTLE syndromes will Autosomal dominant nocturnal frontal lobe epilepsy
enable the creation of genetically modified mice possessing (ADNFLE) is one monogenic form of a genetic epilepsy syn-
the mutations and help elucidate their pathogenesis. drome with NFS. The seizures usually begin in childhood,
Although specific genetic mutations have not yet been asso- cluster during NREM sleep or shortly before awakening, and
ciated with MTLE, molecular analyses of resected surgical typically consist of an aura (somatosensory, special sensory,
specimens from human mesial temporal epilepsy patients and psychic, autonomic) followed by tonic, clonic, and hyperki-
from experimental animal models of epilepsy revealed changes netic movements. Mutations in both neuronal nicotinic ace-
in the expression of multiple neurotransmitter receptors tylcholine receptor subunits (AChR, α2, α4, and β2) as well
including GABAA, GABAB, NMDA, AMPA (α-amino-3-hydroxy- as sodium-activated potassium channels (KCNT1) are associ-
5-methyl-4-isoxazoleproionic acid), and metabotropic gluta- ated with ADNFLE.
mate receptors, as well as voltage-gated ion channels and The physiological and biochemical consequences of many
aquaporin proteins (Brooks-Kayal et al., 1998; Eid et al., 2002; ADNFLE-related AChR mutations were tested with recom-
Lee et al., 2004; Oliveira et al., 2010; Peng et al., 2004; Tang binant AChR expressed in cultured heterologous cells (Marini
et al., 2004). Because these proteins help maintain neuronal and Guerrini, 2007). Most of the mutations tested in this
excitability and connectivity, one would expect that their manner were found to increase AChR activity (i.e., gain-of-
altered expression could contribute to hypersynchrony. One function). For example, the β2(V287I) mutation reduced the
of the best-studied molecular changes in MTLE models is rate of AChR desensitization and the α4(S248F) mutation
the alteration of GABAA receptor expression (Brooks-Kayal reduced the EC50 for nicotinic agonist. Gain of AChR function
and Russek, 2012). Work done by a long-standing collabo was also seen in two knockin mice with α4 subunit ADNLFE
ration between the Brooks-Kayal and Russek laboratories mutations (Klaassen et al., 2006). Both genotypes of mutant
elegantly uncovered changes in brain-derived neurotrophic mice exhibited frequent behavioral and electrographic sei-
factor (BDNF)-mediated signaling in the rat pilocarpine zures that were exacerbated by nicotine. By causing a gain-of-
model of status epilepticus and MTLE. Enhancement of BDNF function in the AChR on presynaptic GABAergic terminals on
signaling modifies a complex biochemical cascade that ulti- cortical neurons, the ADNFLE mutations augmented cortical
mately reduced GABAA receptor α1 subunit transcription and nicotine-evoked inhibitory currents. As has been discussed in
increased α4 subunit transcription. Because GABAA receptors our previous sections on generalized seizures and MTLS,
composed of α4 subunits have very different physiological GABAergic interneurons innervate multiple pyramidal neurons
properties than those composed of α1 subunits (Lagrange and their activation increases neuronal synchrony. Therefore,
et al., 2007), the increased α4 and reduced α1 subunit expres- the authors suggested that the gain-of-function ADNFLE
sion likely contributes to epileptiform rhythms in the mutations cause seizures by increasing cortical synchrony.
hippocampi. At least four KCNT1 missense mutations have also been
associated with ADNFLE. Recently, Milligan et al. expressed
recombinant wild-type and mutant KCNT1 channels in
Neocortical Focal Seizures (NFS) Xenopus oocytes and tested the effects of these mutations on
Neocortical focal seizures are much more heterogeneous than KCNT1 function (Milligan et al., 2014). Interestingly, all the
generalized seizures or MTLS. NFS can originate in any region mutations increased the KCNT1 peak current amplitudes. The
of the neocortex and can be associated with traumatic, devel- mechanism by which a potassium channel gain-of-function
opmental, neoplastic, or vascular lesions. Not surprisingly, could result in seizure has not yet been determined.
Besides ADNFLE, autosomal dominant epilepsy with zures, syncope, classical migraine, and a number of sleep
auditory features (ADEAF) is a second monogenic epilepsy and movement disorders. These will be discussed in greater
syndrome with NFS. At least 36 mutations in the leucine- detail.
rich-glioma-inactivated gene 1 (LGI1) have been associated
with ADEAF. Interestingly, antibodies to the LGI1 protein are
found in the CSF in a subset of patients with autoimmune
Psychogenic Nonepileptic Seizures
encephalitis with seizures (Lai et al., 2010). LGI1 is a secreted Psychogenic nonepileptic seizures (PNES), also called psychogenic
protein that interacts with voltage-gated potassium channels, nonepileptic events, pseudoseizures, or pseudoepileptic seizures, are
the cell adhension molecules ADAM22 and ADAM23, and the most common imitators of seizures and epilepsy in referral
the neurite growth inhibitor, Nogo receptor 1 (Sagane et al., centers. These are emotionally triggered attacks not associated
2008; Schulte et al., 2006; Thomas et al., 2010). Studies of with any paroxysmal epileptic activity in the brain. Most are
recombinant wild-type and mutant LGI1 expressed in heter- the result of somatoform disorder, with a variety of reported
ologous cells revealed that the majority of ADEAF mutations traumatic antecedents, particularly sexual or physical abuse in
reduced LGI1 secretion. Heterozygous LGI1 deletion mice women (Duncan and Oto, 2008). Antecedents or historical
have a lower threshold for audiogenic seizures than wild-type precipitants of PNES include head injury, which is also a
mice (Chabrol et al., 2010). To date, however, the neurophysi- common and important risk factor for epilepsy. In one study,
ological mechanisms that cause the audiogenic seizures are 33% of patients with head injury and seizures had PNES on
not known. video-EEG monitoring (Hudak et al., 2004). PNES may also
appear after surgery and can be one explanation for apparent
failure of epilepsy surgery (Ney et al., 1998; Parra et al., 1998;
DIFFERENTIAL DIAGNOSIS Reuber et al., 2002). This emphasizes the need for video-
Seizures and epilepsy have many imitators, some of which are EEG evaluation of patients who have had recurrence of sei-
age-specific. In infants, the list includes apnea, either central zures after epilepsy surgery. A diagnosis of fibromyalgia or a
or obstructive, which can be a seizure manifestation but can history of chronic pain were found to be predictors of PNES
also be nonepileptic. Jitteriness associated with a variety of (Benbadis, 2005).
metabolic disturbances can imitate clonic or myoclonic sei- PNES are diagnosed in a considerable proportion of
zures. Exaggerated startle can also be mistaken for tonic sei- patients referred for drug-resistant seizures. The population-
zures. After the neonatal period, early childhood imitators based incidence has been estimated at between 1.4 and
of seizures include shuddering attacks and stereotypies or 4.6 per 100,000 person-years of observation. In one study,
repetitive behaviors that can be mistaken for seizures. Gastro- the incidence was highest between 15 and 24 years of age
esophageal reflux may be associated with posturing (Sandifer (Sigurdardottir and Olafsson, 1998) and in another between
syndrome); a greater occurrence of spells following feeding 25 and 45 years of age (Szaflarski et al., 2000). All studies
may be a clue to the diagnosis. Breath-holding spells represent agree that there is a higher prevalence in women (70%–80%).
a form of syncope that may be associated with tonic posturing The various patterns of clinical manifestations of PNES can be
and a few jerks (Laux and Nordli, 2005). Either cyanosis or classified in three broad categories: psychogenic motor sei-
pallor can accompany these breath-holding spells, and both zures with prominent motor activity, psychogenic minor
are precipitated by injury or frustration, but cyanotic spells are motor or trembling seizures with tremor of the extremities,
preceded by crying. and attacks with motionless unresponsiveness or collapse
Imitators of epilepsy that are more common in old age (Groppel et al., 2000; Meierkord et al., 1991; Selwa et al.,
include transient ischemic attacks (TIAs) and transient global 2000). In children, prolonged staring and unresponsiveness
amnesia. Transient ischemia generally causes negative symp- was the most common pattern, while motor activity was more
toms with loss of function such as weakness or numbness, common in adolescents (Kramer et al., 1995).
whereas seizures involving sensory or motor cortex are more The diagnosis of PNES depends on prolonged video-EEG
likely to produce positive symptoms such as twitching or par- monitoring with recording of typical attacks. The use of
esthesias. However, seizures may occasionally present with suggestion may facilitate the precipitation and recording of
only negative symptoms, and TIAs rarely present with limb attacks. Hyperventilation and photic stimulation are usually
shaking. Limb shaking as a feature of TIAs has been associated adequate suggestion techniques; suggestion methods should
with high-grade stenosis or occlusion of the internal carotid not involve patient deception. In some individuals, suggestion
artery (Persoon et al., 2010). Although TIAs tend to be longer may precipitate atypical attacks; to verify that recorded events
in duration than seizures (most seizures last < 2 minutes and are typical of what occurs at home, it is crucial to seek the
most TIAs last >2 minutes), limb-shaking TIAs are short, input of family members who have witnessed attacks. PNES
usually shorter than 5 minutes and even shorter than 1 minute. may coexist with epilepsy. Early studies suggested that more
One feature that could distinguish them from seizures is pre- than 50% of patients with PNES also have epilepsy, but most
cipitation by rising or exercise and association with weakness studies now agree on a much smaller proportion, probably
of the affected limb (Persoon et al., 2010). TIAs can be misdi- not more than 10% or 15% (Benbadis et al., 2001; Lesser
agnosed as seizures, but the more common scenario is to et al., 1983; Martin et al., 2003).
misdiagnose negative motor seizures or sensory seizures as A number of studies have tried to identify features that
TIAs. The presence of a sensory march should be suggestive of suggest psychogenic nonepileptic seizure origin (Avbersek and
an epileptic nature. Sisodiya, 2010). In a comparison of epileptic generalized
Transient global amnesia is a condition in older individuals tonic-clonic seizures and PNES with motor activity, features
characterized by memory loss without impairment of other that predicted PNES were out-of-phase upper and lower
cognitive function, and affected subjects are able to engage in extremity movements, absence of vocalization or vocalization
complex activities. Most transient global amnesia episodes last at the very onset of seizures, forward pelvic thrusting, absence
hours and are single events, although they may repeat in a of whole-body rigidity, and side-to-side head movements. No
minority of individuals. The nature of transient global amnesia single feature was totally predictive by itself, and these features
is not totally clear. were particularly strong predictors when combined (Gates
Conditions that can imitate seizures and epilepsy through et al., 1985), but such clinical features can also be seen in
much of the lifespan include nonepileptic psychogenic sei- frontal lobe complex partial seizures and other hypermotor
Epilepsies 1591
seizures (Saygi et al., 1992). Other features that may help factor in the misdiagnosis of syncope as seizures. Although
discriminate PNES from epileptic seizures include pseudo syncope with myoclonus has been referred to as “convulsive 101
sleep at onset (Benbadis et al., 1996b); preictal behavioral syncope,” there is no associated EEG discharge, and the origin
changes (Moore et al., 1998); discontinuous seizure activity; is thought to be in the brainstem. Syncope can have a variety
prolonged seizure duration; eye closure during unresponsive- of mechanisms, some benign and others serious. In younger
ness (Chung et al., 2006; DeToledo and Ramsay, 1996); resist- individuals, the most common is neurally mediated syncope.
ance to eye opening; eye fluttering; certain vocalizations This can be triggered by a variety of factors including intense
such as stuttering, gagging, gasping, screaming, weeping, or pain, emotion, and standing for prolonged periods of time in
moaning; emotional display during events; emotional triggers; hot or crowded places. In addition, syncope can be precipi-
precipitation of typical events by suggestion; and attacks tated in some individuals by micturition, defecation, or cough.
occurring in the clinic waiting room or admitting office (Ben- Neurally mediated syncope tends to have a prodrome of light-
badis, 2005). Tongue biting and incontinence occur more headedness, nausea, pallor, cold sweating, graying of vision,
commonly with epileptic seizures but are also frequently and hearing becoming distant, as well as other visual or audi-
reported by patients with PNES (Peguero et al., 1995). Injuries tory hallucinations (Carreño, 2008; Crompton and Berkovic,
to the tongue during epileptic seizures tend to affect the side 2009; Lempert et al., 1994). Syncope may also be due to
of the tongue. Biting the tip of the tongue or the lip was sug- orthostatic hypotension, cardiac arrhythmias, and structural
gestive of PNES (DeToledo and Ramsay, 1996). Self-injury was cardiopulmonary disease (Carreño, 2008; Crompton and
also reported by patients with PNES, but one study suggested Berkovic, 2009). Syncope due to cardiac arrhythmia is usually
that burn injuries were specific for epileptic seizures (Peguero more abrupt with no preceding symptoms. In the differentia-
et al., 1995). The presence of postictal stertorous respiration tion of syncope from seizures, features that favor syncope
is very helpful to diagnose epileptic convulsive seizures (Sen include known heart disease, prior confirmed syncope, pre-
et al., 2007), whereas shallow rapid respiration was more cipitation by prolonged standing or rising to an upright posi-
likely after PNES (Azar et al., 2008a). tion, presence of dehydration, the typical neurocardiogenic
While the diagnosis of PNES depends in large part on the syncope prodrome described earlier, description of pro-
absence of EEG changes with typical attacks, the neurologist nounced pallor by witnesses, absence of tonic or clonic activ-
has to be aware that some epileptic seizures have no EEG cor- ity, description of multifocal myoclonus lasting less than 15
relate. For example, frontal lobe complex partial seizures of seconds, and recollection of loss of consciousness. Features
orbitofrontal or cingulate origin commonly have no associ- that would favor seizures include previous seizures, known
ated EEG changes, nor do supplementary motor seizures. For cortical brain lesion, presence of tongue biting, incontinence,
definitive diagnosis, it is often necessary to record multiple cyanosis, postictal confusion, postictal headache, and lack of
attacks and observe changes in conjunction with AED with- recollection of loss of consciousness (Crompton and Berkovic,
drawal. Epileptic seizures may secondarily generalize, which 2009). Syncope may rarely trigger an epileptic seizure
provides a definitive diagnosis. In one study comparing (Stephenson et al., 2004). These seizures, referred to as anoxic-
patients with frontal lobe complex partial seizures and patients epileptic seizures, are to be distinguished from the much more
with PNES, there was no significant difference in the history common nonepileptic “convulsive” syncope.
of psychiatric disease, ictal pelvic thrusting, rocking of body,
side-to-side head movements, or rapid postictal recovery
(Saygi et al., 1992). Of interest, turning to a prone position
Migraine
occurred only in frontal lobe complex partial seizures. Noc- Epilepsy and migraine both present with paroxysmal mani-
turnal occurrence, short ictal duration, younger age at onset, festations as a result of cerebral cortex involvement (Kossoff
stereotyped movements, and abnormal MRI or EEG favored and Andermann, 2010). Types of migraine that are most
frontal lobe complex partial seizures. Others have also sug- likely to be confused with seizures are classical migraine with
gested that while epileptic seizures are very stereotyped, PNES visual or somatosensory aura, basilar migraine, and acute
tend to have a lot of variability. However, this notion has been confusional migraine (Carreño, 2008; Kossoff and Ander-
disputed (Seneviratne et al., 2010). mann, 2010). Occipital lobe seizures may be followed by a
Pseudo-status epilepticus is a common occurrence in PNES, migraine-like headache that makes it hard to distinguish
reported in a greater proportion of patients than status epilep- them from a classical migraine with a visual aura. Helpful
ticus in patients with epilepsy (Dworetzky et al., 2006). As distinguishing features include duration of the aura. The aura
expected, it tends to be resistant to treatment with AEDs, until in migraine typically lasts 5 to 60 minutes (Carreño, 2008),
the development of stupor or coma, which may lead to intuba- reflecting that cortical spreading depression (the main patho-
tion. Its early recognition is essential to prevent potentially physiology of migraine) results from a slow depolarization
harmful interventions. that spreads at about 3 mm/min (Crompton and Berkovic,
2009). In contrast, epileptic discharges propagate at a much
higher speed; epileptic auras are usually less than 30 seconds
Syncope in duration. Another helpful distinction is that the visual
Syncope is an abrupt transient loss of consciousness caused by aura in migraine is most commonly a fortification spectrum
decreased cerebral perfusion. It is an important condition in or scintillating scotoma, whereas colored circles are the
the differential diagnosis of epilepsy in the elderly as well as most common aura in occipital lobe seizures (Carreño, 2008;
teenagers and young adults. Although syncope is mostly rec- Kossoff and Andermann, 2010). Migraine without headache,
ognized by loss of posture and limp unresponsiveness, the also called migraine equivalent, can be an even more difficult
majority of closely observed individuals will have brief tran- diagnostic challenge. Basilar migraine starts with brainstem
sient motor manifestations early after loss of consciousness. manifestations that include dysarthria, vertigo, changes in
The most common motor manifestation is myoclonus that is hearing, diplopia, and ataxia, and then involves loss of
most often multifocal and arrhythmic (Lempert et al., 1994). consciousness.
Other motor manifestations may also occur, including postur- Migraine and epilepsy have a greater overlap than would
ing, head turning, upward eye movement, oral automatisms, be expected by chance. The prevalence of each is increased in
and righting movements (Lempert et al., 1994). The motor the presence of the other, and some epileptic syndromes (e.g.,
manifestations, particularly myoclonus, are an important benign epilepsy with occipital paroxysms, benign epilepsy
with centrotemporal spikes) have a particularly higher inci- produce consistently unilateral posturing. Other helpful dis-
dence of migraine (Kossoff and Andermann, 2010). In tinguishing features are that consciousness is always preserved,
addition, a rare condition referred to as “migralepsy” (or and there is no postictal change. However, the condition
migraine-triggered epilepsy or migraine-triggered seizures) is char- responds very well to AEDs. The attacks in paroxysmal nonki-
acterized by seizures that occur during or shortly after the nesigenic dyskinesia are longer (minutes to hours as compared
migraine aura. Certain antiepileptic medications such as val- to seconds), less frequent, and precipitated not by movement
proate and topiramate are used successfully in migraine but rather by alcohol, caffeine, stress, excitement, or fatigue.
prophylaxis, but others such as oxcarbazepine or car- The attacks do not usually respond to AEDs (Fahn and Frucht,
bamazepine do not seem to be effective. However, acute abor- 2008). Hyperekplexia is an inherited disorder in which there is
tive therapy for the two conditions is totally different. an exaggeration of startle reflexes (Crompton and Berkovic,
2009). The exaggerated startle has to be distinguished from
startle-evoked seizures, which are most often of supplemen-
Sleep Disorders tary motor origin.
Parasomnias are the most important imitators of seizures in the
category of sleep disorders (see Chapter 102). These include
sleep walking (somnambulism), sleep talking, night terrors, EVALUATION AND DIAGNOSIS
confusional arousals, and REM behavior disorder. They may The clinical history is always a cornerstone in the evaluation
imitate frontal lobe seizures that occur preferentially or even of seizures and epilepsy. Other elements of the evaluation
exclusively in sleep. Somnambulism, sleep talking, and night depend on the clinical presentation; different testing is recom-
terrors typically start in childhood and tend to disappear in mended in patients presenting with new-onset seizures,
adolescence. They are most likely to arise out of slow-wave patients with recently drug-resistant seizures, or patients pur-
sleep in the first half of the night, usually after a latency of 90 suing epilepsy surgery. This section will therefore be subdi-
minutes from sleep onset. Frontal lobe seizures are more likely vided based on the particular presentation.
to arise out of stage 1 or 2 sleep (Carreño, 2008). These events
are more likely to be seizures if they occur in the first hour of
sleep or in the transition between waking and sleep. REM Evaluation of Recent-Onset Seizures and Epilepsy
behavior disorder is characterized by loss of muscle atonia
Evaluating an individual with one or more attacks that could
during REM sleep, which results in acting out dreams. The
represent seizures always starts with an in-depth history. Tests
behavior includes verbalization and vocalization, as well as
such as EEG and brain imaging should primarily supplement
motor activity that may be violent (e.g., kicking, punching)
the history and help classify seizures/epilepsy and identify
and getting out of bed. Affected individuals will be aware that
underlying pathology. Ideally, at the end of the evaluation, the
they have been dreaming and may report the content of their
seizure diagnosis and classification are confirmed, an epilepsy
dreams. REM behavior disorder is more likely in the second
syndrome has been diagnosed if that is possible, and any
half of the night when REM sleep is most likely to occur
structural etiology has been identified. The best treatment
(Carreño, 2008). REM behavior disorder rarely starts before
options can then be determined, and in some cases it may be
age 50; it is most often a chronic disorder associated with a
possible to predict prognosis.
synucleinopathy, particularly Lewy body dementia (Cromp-
ton and Berkovic, 2009).
Some manifestations of narcolepsy can imitate seizures.
History
These include sleep attacks, cataplexy, sleep paralysis, and hal- The patient with possible seizures should be asked about
lucinations during the transition between waking and sleep. potential seizure triggers, any symptoms preceding the event,
Attacks of cataplexy are brought on by emotional stimuli and and recollection of what happened during the event. However,
are characterized by loss of muscle tone, which may result in in many instances the patient can only provide an incomplete
loss of posture. Cataplexy may include some jerky motions or distorted account because of altered consciousness; it is
that could imitate seizure activity. However, an important therefore crucial to obtain an independent history from a
distinguishing feature is total preservation of consciousness witness. If possible, more than one witness should be inter-
and complete memory of the events. The association with viewed to assess the consistency of the description, because
other manifestations of narcolepsy should help establish the the recollection of events by the witness may also be distorted
diagnosis. by panic. The final account of the event should list its compo-
nents in temporal order starting with prodrome, aura, objec-
tive manifestations, and then postictal signs and symptoms.
Paroxysmal Movement Disorders The interviewer should ask about urinary incontinence, tongue
Paroxysmal movement disorders that can be confused with biting, postictal confusion, and postictal muscle soreness.
epilepsy include nonepileptic myoclonus, paroxysmal dyski- Additional questions to be asked depend on the specific dif-
nesia, and hyperekplexia (Crompton and Berkovic, 2009). ferential diagnosis in each case. In instances when multiple
Myoclonus may be generated at any level of the CNS; epileptic attacks have occurred, the family may have captured events on
myoclonus is generated at the level of the cortex and is usually home video. Review of such video segments can be extremely
associated with a scalp EEG discharge. In the case of focal helpful.
cortical myoclonus, the distinction can be harder to establish The past medical history may identify important risk factors
(Crompton and Berkovic, 2009). Paroxysmal dyskinesia can for epilepsy or for other disorders. This should include a
be classified into two broad categories: kinesigenic and non- history of gestation, birth, developmental milestones, and ill-
kinesigenic, both usually familial (Fahn and Frucht, 2008). In nesses in infancy and childhood. Of particular importance are
paroxysmal kinesigenic dyskinesia, the attacks are often brought febrile seizures and CNS infections such as meningitis or
on by a sudden movement or startle, usually after a period of encephalitis, all of which are associated with increased risk of
inactivity. The movements are any combination of chorea, epilepsy. Any head trauma should be investigated with ques-
athetosis, ballism, and a dystonic posture (Fahn and Frucht, tions about loss of consciousness and its duration, and history
2008). They can be bilateral or alternate sides, which is helpful of depressed skull fracture or other intracranial pathology.
in distinguishing them from epileptic seizures that generally Other epilepsy risk factors to investigate will depend on age
Epilepsies 1593
at onset—for example, history of stroke becomes important lepsy as focal or generalized, and even help identify the spe-
when epilepsy starts in old age. cific syndrome in some instances. 101
Family history of afebrile seizures and other paroxysmal The routine EEG is typically 20 to 30 minutes long. It
disorders as well as family history of febrile convulsions should include standard activation procedures such as hyper-
should be obtained. The family history can be optimized by ventilation and photic stimulation. The waking recording
first asking the patient or informed relative about the number should include eyes-open and eyes-closed conditions. Ideally
of first-degree and second-degree relatives in every category. there should also be a recording of drowsiness and sleep, but
This may help with the recall of who is affected. It is often best that may be difficult to obtain without sleep deprivation.
to obtain family history from a senior female relative who is Routine EEG is unlikely to record actual seizures, with the
likely to be more informed about the family than younger and exception of generalized absence seizures that can be easily
male members. precipitated by hyperventilation in the untreated patient. The
Review of systems should be expanded with respect to CNS main contribution of a routine EEG is the recording of
abnormalities. If specific syndromes are suspected, the review interictal epileptiform activity, which includes spikes, sharp
of systems should include symptoms related to other organs waves, spike-and-wave discharges, and polyspike-and-wave
that may be affected in these syndromes. discharges.
A number of criteria help identify discharges as epilepti-
Physical and Neurological Examination form. They are typically of high voltage in comparison with
the surrounding EEG activity. Their duration is 70 to 200 msec
The most important aspects of the examination will vary
for sharp waves and less than 70 msec for spikes; when
depending on age and specific circumstances. In children,
recorded from the scalp, epileptiform discharges are usually
careful examination of the skin is important for identification
longer than 20 milliseconds. Epileptiform discharges tend to
of neurocutaneous disorders that are often associated with
have more than one phase, and the predominant component
epilepsy. Dysmorphic features may suggest certain chromo-
is negative. That negative component tends to be asymmetri-
somal abnormalities. The neurological examination may
cal; when the epileptiform discharge is recorded from the first
reveal abnormalities of mental status or motor and reflex
input in a channel, it has a shorter and lower-voltage ascend-
asymmetries that could help with lateralization of the epilep-
ing segment and a longer and higher-voltage descending
togenic zone in focal epilepsy. However, most individuals will
segment (Gotman, 1980) (Fig. 101.15). Epileptiform dis-
have a normal neurological examination.
charges tend to have an aftergoing slow wave, and they tend
to arise from an abnormal background. The criteria men-
Electroencephalography tioned above are not necessarily all satisfied. However, the
The EEG is a graphic representation of voltage change over more criteria satisfied, the more confident one can be about
time. Each EEG channel records the potential difference the epileptiform nature of the discharge. Many physiological
between two electrode positions on the scalp. In referential potentials and normal variants are sharp in configuration and
recordings, the first input in each channel represents the may be misdiagnosed as epileptiform. In fact, misinterpreta-
active electrode, while the second input represents the tion of the EEG is one of the most common reasons for
reference—which is ideally neutral but often is not. In bipolar overdiagnosis/misdiagnosis of epilepsy. Another reason is
recordings, each channel represents the difference in poten- inadequate history and failure to obtain a thorough descrip-
tial between adjacent electrodes organized in a logical tion of events from witnesses (Smith et al., 1999).
montage. The vast majority of epilepsy centers use digital The first interictal EEG is normal in about 50% of patients
EEG recordings that allow reformatting of EEG montages and with epilepsy (Salinsky et al., 1987). Additional routine EEGs
the judicious use of filters to optimally visualize interictal can improve the yield, but there is little to be gained after four
EEG activity as well as the ictal onset. When the history is normal EEGs. With multiple recordings, more than 90% of
consistent with seizures or epilepsy, the EEG is the most individuals with epilepsy will have epileptiform EEG abnor-
helpful test to confirm the diagnosis, help classify the epi- malities recorded (Salinsky et al., 1987). Several studies have
Fig. 101.15 Left temporal epileptiform discharges emanating from an abnormal background. Note the asymmetrical waveform of sharp
waves.
explored ways to improve the yield of the first EEG in epilepsy. of choice for identifying brain pathology in patients with new-
One study found that a sleep-deprived EEG was superior to a onset seizures or epilepsy, and in that setting is preferably
routine EEG and to an EEG with medication-induced sleep obtained with and without contrast. If it is possible to wait for
(Leach et al., 2006). Another study found that a 4-hour out- an MRI, the emergency CT scan can be skipped.
patient video-EEG study added considerably to the yield of a In children with new-onset seizures, imaging may require
20-minute EEG, particularly in patients with partial epilepsy conscious sedation or general anesthesia. An imaging study is
(Modur and Rigdon, 2008). Timing of the EEG is also impor- not always required and may be omitted in children with a
tant. In generalized epilepsy, a morning EEG is more likely to confident diagnosis of a benign or genetic epilepsy syndrome
yield epileptiform abnormalities than an afternoon EEG such as CAE or BECTS. If there is any indication for a neu-
(Labate et al., 2007). In patients with JME, a slightly sleep- roimaging study, MRI is preferred. Published guidelines rec-
deprived EEG obtained predominantly after a nap is the most ommend elective MRI in the presence of unexplained cognitive
useful, since both seizures and epileptiform discharges are or motor impairment or neurological exam abnormality,
more likely after arousal from sleep. partial-onset seizure, an EEG not characteristic of a benign
Epileptiform discharges are more likely to be focal in partial epilepsy of childhood or IGE, or in children younger
patients with focal seizures and more likely to be generalized than 1 year of age (Hirtz et al., 2000). Emergency imaging is
in patients with generalized-onset seizures. The EEG can also recommended in any child exhibiting a prolonged post
record generalized absence seizures, which are reliably preictal focal deficit.
cipitated with hyperventilation in the untreated child, and
can demonstrate interictal epileptiform discharges that are Other Testing
characteristic of certain syndromes (see Figs. 101.4, 101.5,
101.7–101.9). For most patients with focal seizures, the locali- Most patients presenting to the emergency room with their
zation of epileptiform discharges corresponds to the epilep- first seizure will have blood studies performed routinely, but
togenic zone, but this is not always true. Some patients with the value of such testing is not established. While a small
seizures arising from one temporal lobe may have bitemporal proportion of patients have metabolic abnormalities with the
independent epileptiform discharges. Temporal lobe epilepti- first seizure, most abnormalities are not clinically significant.
form discharges may also be predominant in patients who Metabolic blood testing should be guided by specific clinical
have epilepsy of frontal, parietal, or occipital origin. Some circumstances based on the history and examination. Pub-
patients with generalized-onset seizures may have focal or lished guidelines suggested obtaining blood glucose, blood
multifocal epileptiform discharges in addition to generalized cell counts, and electrolyte panels, particularly sodium, in
discharges. specific clinical circumstances (Krumholz et al., 2007). A
Besides its diagnostic role, the EEG can help determine lumbar puncture is only indicated if there is reason to suspect
prognosis after a first seizure. An abnormal EEG has been an infectious or inflammatory etiology (e.g., if the patient is
consistently associated with an increased risk of seizure recur- febrile). Toxicology screening should similarly be restricted to
rence in both children and adults, particularly if the abnor- specific clinical circumstances.
mality is epileptiform. In untreated patients, the risk of seizure
recurrence was increased by a factor of 1.54 if the EEG was
abnormal (Kim et al., 2006).
Evaluation of Drug-Resistant Seizures
The routine EEG has important limitations. It is an indirect and Epilepsy
assessment because it does not usually record the ictal events When seizures are drug resistant, it is important to reassess the
for which the patient is seeking evaluation. Some patients may diagnosis of epilepsy. Reevaluation of the history may identify
have both epileptic and nonepileptic seizures or may have features suggestive of a nonepileptic origin of attacks or incor-
nonepileptic seizures together with epileptiform EEG abnor- rect classification of seizures that resulted in an incorrect thera-
malities that reflect a seizure tendency in the absence of actual peutic choice. The task may be facilitated by having the
seizures. Some patients with partial epilepsy may have general- description of multiple events to assess precipitating factors
ized EEG abnormalities reflecting an inherited generalized and variability or consistency of the seizure manifestations.
seizure tendency even though they do not have generalized- The patient should be questioned about potentially remedi-
onset seizures. Because of all these reasons, prolonged EEG- able factors such as alcohol or drug abuse, abuse of caffeine,
video monitoring may be superior for definitive diagnosis of the use of concomitant medications that can reduce the seizure
events in question. However, prolonged video-EEG monitor- threshold, sleep deprivation, or poor compliance with pre-
ing is expensive and therefore reserved for patients who have scribed treatment. Most often, additional investigation is
had recurrent attacks with atypical manifestations and a needed, particularly prolonged EEG or video-EEG recordings
nondiagnostic routine or sleep-deprived EEG. Video-EEG to capture typical events for definitive diagnosis.
monitoring is also indicated for patients who continue to have
seizures despite adequate treatment, raising the possibility of
incorrect seizure diagnosis or classification.
Prolonged Electroencephalographic Recordings
Prolonged EEG or video-EEG monitoring increases the prob-
ability of capturing events. Modalities include short-term video-
Neuroimaging EEG for 2 to 8 hours, ambulatory EEG with or without video,
Neuroimaging is always indicated in adults with new-onset and long-term video-EEG (usually in an epilepsy monitoring
seizures or epilepsy to identify structural causes of epilepsy, unit). Short-term monitoring is ideal for individuals whose
some of which may require treatment of their own (Krumholz attacks are very frequent or can be provoked by certain stimuli.
et al., 2007). After the first unprovoked seizure, imaging in It is often very useful for young children who tend to have
adults has a clinically significant yield of about 10%, leading multiple daily attacks. Its advantages include that it can be an
to the diagnosis of disorders such as a brain tumor or other outpatient procedure, making it convenient and less expen-
structural lesions. Computed tomography (CT) remains the sive. Ambulatory EEG also has the advantage of being an
test most likely to be obtained in the emergency room after outpatient procedure, and it allows for patients to be evaluated
the initial seizure, but because of bone streak artifact will often in their natural environment with its stressors and other
miss temporal lobe pathology. MRI is the imaging modality seizure triggers. Although it can theoretically be performed
Epilepsies 1595
with concomitant video, video monitoring is not usually part The ictal symptomatogenic zone is the region that produces
of this procedure, and the exact correlation between EEG and the seizure manifestations. If the epileptogenic zone is in 101
clinical changes is not possible. The absence of concomitant primary sensory or motor cortex, the initial seizure manifes-
video makes it difficult to eliminate artifact as the source of tations may be related to the function of that cortex; in that
apparent discharges. Ambulatory EEG is nevertheless useful to situation, the ictal symptomatogenic zone corresponds to
evaluate EEG changes with attacks that occur daily and involve the ictal onset zone. However, in many instances, the ictal
loss of consciousness, since events with loss of consciousness onset zone is located in silent cortex, and the initial clinical
are expected to produce EEG changes if they are epileptic in manifestations reflect activation of distant nonsilent areas
nature. Ambulatory EEG is less useful for evaluation of subjec- along the path of seizure propagation. The ictal symptoma-
tive events or other events without altered consciousness, togenic zone may be more valuable for lateralization than
which may be simple partial seizures. This is because simple exact localization, because it is most likely that seizures will
partial seizures often have subtle or even no associated EEG spread within the hemisphere of origin before spreading to
change. the contralateral hemisphere. However, this is not always
Inpatient video-EEG monitoring may be the most defini- the case.
tive long-term video-EEG modality, as it allows observation in The epileptogenic lesion is a structural brain abnormality that
conjunction with AED withdrawal. This is necessary when is presumed to be the cause of the epilepsy and is usually
attacks are infrequent and partially controlled with medica- identified on MRI. The relationship of the epileptogenic lesion
tions. The recording can continue for several days up to weeks to the seizure onset zone is variable. Some lesions such as
if needed. Withdrawal of AEDs may unmask epileptiform EEG cortical dysplasia or hypothalamic hamartoma are intrinsi-
abnormalities (true with some AEDs such as benzodiazepines, cally epileptogenic, and seizures may arise from within the
valproate, and levetiracetam) and may also allow greater lesion. On the other hand, seizures usually arise from brain
seizure propagation that can confirm the diagnosis for some surrounding cavernous malformations and benign tumors. In
seizures of unclear nature. Methods that can be used to help the case of very large lesions, seizures may arise from one
precipitate attacks include hyperventilation, photic stimula- aspect of the surrounding brain. It is important to keep in
tion, sleep deprivation, and other precipitants reported by the mind that certain lesions may be accidental findings and not
patient. Inpatient long-term video-EEG monitoring is the best necessarily related to the epilepsy. For example, arachnoid
modality for localization of the epileptogenic zone in patients cysts and venous malformations are often unrelated or indi-
undergoing evaluation for epilepsy surgery. rectly related to the epilepsy (through association with cortical
malformation) (Arroyo and Santamaria, 1997; Morioka et al.,
2006; Paetau et al., 1992). Another important factor to keep
Evaluation of Patients for Epilepsy Surgery in mind is that there may be multiple lesions, only one of
Some 35% of patients with partial-onset seizures are resistant which is responsible for seizure generation. In general, the
to AED therapy (Kwan and Brodie, 2000a), making them can- identification of an epileptogenic lesion greatly improves the
didates for epilepsy surgery. Unless there is a clear contraindi- confidence of congruent electrical localization of the ictal
cation to such surgery, these patients typically undergo a onset and irritative zones. Failure to remove the epileptogenic
presurgical evaluation, the goal of which is to localize the lesion partially or completely is an important cause of surgical
epileptogenic zone. The epileptogenic zone is defined as the failure (Cendes et al., 1995; Clarke et al., 1996).
zone whose resection is necessary and sufficient to eliminate The functional deficit zone, responsible for functional defi-
seizures (Lüders, 2008; Rosenow and Lüders, 2001). This zone cits, can be measured in a variety of ways including neuro-
cannot be directly defined by any test but can be estimated by logical examination, neuropsychological testing, interictal
a number of other zones. EEG focal attenuation and slow activity, local glucose uptake
The ictal onset zone (also called seizure onset zone or pace- by PET, or local cerebral blood flow by interictal PET with
maker zone) is the area of cortex that is generating seizures [15O]H2O or interictal single-photon emission computed
(Carreño and Lüders, 2008). This zone, if accurately defined, tomography (SPECT). While the functional deficit zone may
is contained within the epileptogenic zone but may be smaller include the epileptogenic zone, it is often considerably larger.
than the epileptogenic zone. Thus it is possible that seizures For example, hypometabolism may involve the whole tem-
start in a section of the epileptogenic zone, but other parts of poral lobe and even extend beyond the temporal lobe in
that zone are able to take on the function of seizure generation patients with temporal lobe epilepsy and hippocampal scle-
once the ictal onset zone is removed. Identifying and defining rosis, in whom the epileptogenic zone may be limited to
the ictal onset zone can be challenging, since the earliest the hippocampus and parahippocampal gyrus (Henry and
detected ictal activity may have already undergone consider- Roman, 2011).
able spread from where the seizure actually originated. Even The remainder of this section will discuss individual ele-
when recording the EEG directly from the brain with implanted ments of the presurgical evaluation.
electrodes, the ictal onset zone may be missed unless the
electrodes were placed directly over that zone.
The irritative zone is the zone that generates interictal epi-
Neurological History
leptiform discharges. In the most straightforward situation, Identifying specific risk factors in the history can help predict
the irritative zone is localized within the epileptogenic zone. the epileptogenic lesion. For example, a history of febrile
However, in some cases there may be multiple irritative zones, status epilepticus in infancy has a strong correlation with the
only one of which corresponds to the epileptogenic zone. One pathology of hippocampal sclerosis (Cendes et al., 1993).
of the more common scenarios is bilateral mesial and lateral Meningitis and encephalitis occurring prior to age 5 are also
temporal irritative zones in a patient with a unilateral mesial associated with temporal lobe epilepsy and hippocampal scle-
temporal epileptogenic zone. The relationship between the rosis, whereas the same risk factors occurring after age 5 appear
irritative zone and the epileptogenic zone may be even more to predict neocortical epileptogenic zones (Marks et al., 1992;
complex. For example, a mesial frontal epileptogenic zone O’Brien et al., 2002). Similarly, earlier head trauma may also
may have a corresponding mesial frontal irritative zone that predict hippocampal sclerosis, though hippocampal sclerosis
cannot be detected by scalp EEG, and bilateral temporal irrita- may also be seen after head trauma at an older age (Diaz-
tive zones that do not generate seizures. Arrastia et al., 2000; Marks et al., 1995). The description of
the seizure aura and other early seizure semiology helps with Magnetic Resonance Imaging
the localization of the ictal symptomatogenic zone. Certain
auras are characteristic of mesial temporal localization, while A high-resolution MRI is crucial for definition of the epilep-
elementary auditory hallucinations at seizure onset favor a togenic lesion (see Figs. 101.10 and 101.14). For optimal detec-
lateral temporal localization, and elementary visual hallucination of mesial temporal sclerosis, the MRI should include
tions favor an occipital localization (Henkel et al., 2002; oblique coronal images perpendicular to the axis of the hip-
Palmini and Gloor, 1992). The description of seizure semiol- pocampus, including T1-weighted, T2-weighted, and FLAIR
ogy by witnesses is also helpful, particularly for lateralization. (fluid-attenuated inversion recovery) sequences. These images
However, since the recording of clinical seizures is an impor- should ideally have a slice thickness of at most 1.5 mm.
tant component of presurgical evaluation, analysis of video- Ideally the MRI should also include a sequence with
EEG recorded seizure semiology supersedes the description T1-weighted thin adjacent images for reformatting and surface
provided by witnesses for the purpose of localization and rendering. The use of surface coils together with 3-tesla MRI
lateralization. can be very helpful in the definition of cortical dysplasia
(Knake et al., 2005). In addition, methods of postprocessing,
Neurological Examination such as texture or morphometric analysis, can also be very
helpful in identifying cortical dysplasia (Bernasconi et al.,
The neurological examination can identify focal neurological 2001; Wagner et al., 2011). Diffusion tensor imaging helps
deficits that help define the functional deficit zone, but the define white-matter tracts. Asymmetries may help in lateraliza-
examination is most often noncontributory. tion in temporal lobe epilepsy (Ahmadi et al., 2009). Three-
dimensional reconstruction of white-matter tracts, also known
EEG and Video-EEG Recordings as tractography, allows visualization of altered connectivity in
EEG/video-EEG is a cornerstone of the presurgical evaluation, association with cortical dysplasia (Colombo et al., 2009).
contributing to the localization of four zones. The interictal Diffusion-weighted imaging is occasionally useful in localiza-
focal attenuation and focal slow activity contribute to the tion and lateralization (O’Brien et al., 2007; Wehner et al.,
definition of the functional deficit zone; the fields of the 2007).
interictal epileptiform discharges define the irritative zones;
and the electrographic localization of seizure onset helps
define the ictal onset zone. However, it is important to recog-
Positron Emission Tomography
nize that what appears to be the initial localization of the ictal PET imaging uses positron-emitting isotopes to image metabo-
discharge may represent seizure activity propagated from a lism, perfusion, synthesis of neurotransmitters, and receptor
distant location not directly accessible to EEG electrodes. density. The synthesis of positron-emitting ligands requires a
There is evidence to suggest that for ictal EEG activity to be cyclotron on site. As a result, PET availability has been
visible on scalp EEG, it should involve at least 10 cm2 of relatively limited to major academic centers. At present, the
cortex (Tao et al., 2007). Therefore, the initial ictal onset may most commonly used ligand is 18F-fluorodeoxyglucose (FDG),
be visible only after considerable seizure spread. The use of which allows the imaging of glucose uptake/metabolism in
additional electrodes beyond the International 10-20 elec- the brain. FDG-PET is almost always an interictal study; ictal
trode placement can be useful. This includes additional PET is usually fortuitous and difficult to plan. FDG-PET con-
closely spaced electrodes in the 10-10 system, or electrodes tributes to the definition of the functional deficit zone.
outside of the 10-10 system, such as true anterior temporal Approximately 80% of patients have a discrete region of
electrodes, sphenoidal electrodes, zygomatic electrodes, or hypometabolism that has a good correlation with the side of
cheek electrodes. the epileptic focus in temporal lobe epilepsy (Abou-Khalil
For patients in whom the ictal onset zone cannot be prop- et al., 1987). The region of PET hypometabolism is usually
erly defined by scalp EEG, it may be necessary to implant larger than the epileptogenic zone (see Fig. 101.11). PET
intracranial electrodes, discussed later in this section. The hypometabolism has a greater correlation with the ictal onset
analysis of seizure semiology by video-EEG provides several zone than scalp EEG-defined ictal onset (Engel et al., 1982).
localizing and lateralizing signs that help define the ictal FDG-PET is particularly useful in patients without MRI abnor-
symptomatogenic zone (Loddenkemper and Kotagal, 2005). malities. The identification of temporal hypometabolism cor-
For example, early head turning in temporal lobe epilepsy responding to well-localized electrographic ictal onset and
tends to be ipsilateral to the seizure focus, and late head interictal epileptiform activity on EEG may permit sufficient
turning preceding secondary generalization tends to be con- confidence to proceed with epilepsy surgery without invasive
tralateral (Fakhoury and Abou-Khalil, 1995). Lip smacking monitoring (Carne et al., 2004). FDG-PET can be misleading
and other oroalimentary automatisms are characteristic of in some patients with extratemporal epilepsy, showing tem-
temporal lobe involvement. Extremity dystonic posturing is a poral hypometabolic zones (Radtke et al., 1994). As with other
strong contralateral lateralizing sign (Kotagal et al., 1989). diagnostic techniques, FDG-PET cannot be used in isolation.
While extremity automatisms are not directly lateralizing in PET using flumazenil images central benzodiazepine
general, manipulative automatisms tend to be ipsilateral to receptor density. Zones of decreased benzodiazepine receptor
the seizure focus when associated with contralateral dystonic density are smaller than, and encompassed in, areas of
posturing (Dupont et al., 1999). Nonmanipulative automa- hypometabolism by FDG-PET. They have a greater specificity
tisms tend to be contralateral (Kelemen et al., 2010; Lee et al., for the ictal onset zone (Burdette et al., 1995; Savic et al.,
2006). Unilateral eye blinking tends to be ipsilateral to the 1993). In addition, flumazenil PET may identify heterotopic
seizure focus (Benbadis et al., 1996a). Well-formed ictal neurons not visible on MRI (Hammers et al., 2005). PET scan-
speech is usually indicative of nondominant temporal lobe ning using 11C-α-methyl-l-tryptophan (AMT) images serot-
involvement, whereas postictal aphasia suggests dominant onin synthesis and is helpful in identifying the epileptogenic
temporal lobe involvement (Gabr et al., 1989). Ictal vomit- tuber in patients with tuberous sclerosis and multiple tubers
ing, ictal spitting, ictal drinking, and postictal urinary urgency (Chugani et al., 1998; Fedi et al., 2003). The epileptogenic
have all been associated with right temporal lobe origin, but tuber usually has increased serotonin synthesis. This PET
exceptions have been reported (Loddenkemper and Kotagal, modality has also been found useful in cortical dysplasia
2005). (Chugani et al., 2011; Juhasz et al., 2003).
Epilepsies 1597
101
Fig. 101.16 Ictal single-photon emission computed tomography (SPECT) (top left and middle), magnetic resonance imaging (MRI)
(bottom) and subtracted ictal SPECT co-registered to MRI (SISCOM) (top right) in patient with drug-resistant seizures persisting after
right temporal lobectomy. The two coronal ictal SPECT images demonstrate right orbitofrontal hyperperfusion (arrows) corresponding to a
region of subtle increased T2 signal, thickened cortex, and blurred gray/white junction on MRI (arrows). MRI images from left to right are coronal
fluid-attenuated inversion recovery (FLAIR), coronal T1, and axial T2 images. Surgical pathology was cortical dysplasia with balloon cells. SISCOM
demonstrates hyperperfusion corresponding to the orbitofrontal pathology.
Single-Photon Emission Computed Tomography of abnormal areas. In patients with MTLE, there are decre-
ments in the NAA/creatine ratio that extend along the major-
SPECT uses a gamma-emitting tracer to image regional cere- ity of the hippocampal formation and are more pronounced
bral blood flow. The technique is widely available and is less anteriorly (Hetherington et al., 2004). The contralateral
expensive than PET. Interictally, regions of reduced metabo- hippocampus is involved to a lesser degree, so asymmetries
lism also tend to have reduced blood flow, but interictal are useful in lateralization of MTLE. The NAA/creatine
SPECT is less sensitive than interictal FDG-PET and therefore ratio appears to have a large functional component. The
is not widely used. The main benefit of SPECT is ictal imaging. ratio improves contralaterally with successful epilepsy surgery
When the ligand is injected intravenously (IV) at the very (Kuzniecky et al., 2001). Magnetic resonance spectroscopy
onset of seizures, greater uptake is noted in the ictal onset can also be used to measure other compounds such as lactate
zone (Fig. 101.16). However, if the injection is late, the focal and GABA (Petroff et al., 2001).
hyperperfusion may represent seizure propagation. The value
of ictal SPECT is enhanced by subtraction and co-registration Magnetoencephalography
with MRI (SISCOM) (O’Brien et al., 1998, 2000; Van Paess-
chen et al., 2007). SISCOM is particularly valuable in extratem- Electric currents which produce voltages on the scalp that serve
poral epilepsy and in patients who have had persistent seizures as the basis for EEG also produce magnetic fields that can be
after epilepsy surgery (Wetjen et al., 2006) (see Fig. 101.16). measured with magnetoencephalography (MEG). Just like
EEG, MEG can track magnetic brain activity in real time. It has
an advantage over EEG in that magnetic signals are not dis-
Magnetic Resonance Spectroscopy torted by differences in conductivity between the brain, skull,
Magnetic resonance spectroscopy (MRS) provides quanti and scalp. However, MEG has similar signal drop-off with
tative histochemical information, applied mostly to the distance, which is the inverse square of the distance from the
hydrogen atom and to a lesser extent, phosphorus. The source. MEG does not detect pure hippocampal spikes but can
most commonly measured substances are N-acetyl aspartate detect propagated spikes, and the dipole orientation is then
(NAA), which is localized in neurons and decreased with helpful to distinguish mesial from lateral sources (Knowlton
neuronal injury, and creatine and choline, which are increased and Shih, 2004). MEG appears slightly more sensitive for
with gliosis and increased membrane turnover. The NAA- convexity neocortical sources than EEG, detecting sources
to-creatine ratio is highly sensitive in detecting mesial tempo- involving 3 to 4 cm2 of cortex as opposed to 6 cm2 of cortex
ral structural and functional abnormalities. The ratio is for the EEG. The latest-generation MEG machines typically
decreased in abnormal regions. When data are acquired in contain 300 or more sensors covering most of the head and
parallel from a large number of voxels, the voxels that are allowing accurate estimation of the magnetic source dipole
statistically abnormal can be color coded, generating a map origin.
By using fiducial markers, structural MRI, and core registra- initially designed to lateralize language function, but its use
tion, the magnetic source can be displayed on the structural was later expanded to examine memory lateralization and
MRI, which has been referred to as magnetic source imaging assess the risk of memory loss after temporal lobe surgery. It
(Knowlton and Shih, 2004; Stefan et al., 2011). Magnetic is also useful for defining the functional deficit zone in the
source imaging can be applied to spontaneous magnetic activ- mesial temporal region. For example, if a patient fails memory
ity as well as to event-related magnetic fields. MEG is used testing after injection of the left hemisphere but passes memory
mostly for evaluation of interictal epileptiform activity and testing after injection of the right hemisphere, this suggests
thus helps define the irritative zone. While EEG is best at that the right mesial temporal structures are functionally inad-
recording epileptiform discharges with a vertical dipole (per- equate to support memory. Because the Wada test is invasive,
pendicular to the gyral surface), MEG best records horizontal there have been many efforts to replace it (Abou-Khalil, 2007);
dipoles parallel to the surface, so MEG and EEG are comple- fMRI and MEG appear the most likely candidates.
mentary in this regard. Availability of MEG remains limited to
major academic centers. Invasive EEG Recordings
MEG is also very useful for localization of cortical functions
prior to epilepsy surgery, through the recording and localiza- Surgery may proceed without invasive testing if presurgical
tion of event-related fields. MEG has been used effectively for results are congruous, if there is a structural or clear functional
localization of sensory and language functions (Abou-Khalil, lesion corresponding to consistent electrical localization, and
2007; Papanicolaou et al., 2004). There is evidence to also if there is no definite risk to eloquent cortex. Indications for
suggest that it may be able to lateralize memory functions (Ver invasive EEG include:
Hoef et al., 2008). • An epileptogenic zone that is well lateralized but not well
localized; for example, unclear whether frontal or temporal,
Functional Magnetic Resonance Imaging anterior temporal or posterior temporal, or mesial or lateral
Local cerebral activation produces a local increase in glucose temporal.
metabolism, cerebral blood flow, and cerebral metabolic rate • Bitemporal ictal onsets or bitemporal frequent epileptiform
for oxygen. The cerebral blood flow increase tends to surpass activity.
the increase in cerebral metabolic rate for oxygen so that cer- • An epileptogenic zone that overlaps with functional cortex.
ebral activation results in an increase in the capillary and • Extratemporal or neocortical nonlesional epilepsy.
venous oxygenation level and a relative reduction in deoxyhe- • Ill-defined epileptogenic zone or incongruent data. It is gen-
moglobin. Deoxyhemoglobin is paramagnetic, so an increase erally essential to have a hypothesis for the location of the
in oxygenation produces an increase in magnetic signal. Blood epileptogenic zone in one or two regions prior to invasive
oxygenation level-dependent (BOLD) contrast is the basis of recording.
functional MRI (fMRI); fMRI has been used predominantly for Different types of electrodes can be used for different indi-
localization of cortical functions that have to be spared in cations for invasive EEG. Subdural grid electrodes are useful
epilepsy surgery. It can effectively localize motor and sensory for better localization of a well-lateralized epileptogenic zone
cortex as well as language cortex (Chakraborty and McEvoy, and for mapping of functional cortex with electrical stimula-
2008; Janecek et al., 2013). There is also increasing evidence tion in order to preserve it at the time of surgery. Depth elec-
that it can localize memory functions (Binder et al., 2010). trodes are useful for lateralization of ictal onset in a patient
The use of fMRI for epilepsy localization is more experi- with apparent bilateral mesial temporal foci, or for recording
mental at this point. It usually requires concomitant EEG from relatively inaccessible regions. Subdural or epidural strip
recording during fMRI acquisition (Gotman et al., 2006; electrodes are useful for bilateral coverage or for sampling
Zijlmans et al., 2007). Interictal epileptiform discharges are large areas without craniotomy. Foramen ovale electrodes,
associated with a hemodynamic change that usually has a inserted through the foramen ovale to record from mesial
latency of several seconds. The hemodynamic change can temporal cortex, are useful for lateralization of the epilep-
reflect activation, deactivation, or both. Defining the regions togenic zone in patients with apparent bilateral mesial tem-
of the brain with hemodynamic changes in response to interic- poral foci. Epidural peg electrodes are inserted into an opening
tal epileptiform discharges helps define the irritative zone. in the skull, outside the dura. Their use eliminates muscle
However, only patients with frequent epileptiform discharges artifact. They can be used to sample electrical activity from
can be studied with fMRI. Data-driven methods including large superficial cortical regions.
temporal clustering analysis and independent component Subdural electrodes allow mapping of cortical functions
analysis are being investigated to analyze relevant fluctuations with electrical stimulation if there is a possibility that surgery
in blood flow (LeVan et al., 2010; Morgan et al., 2007). may put these functions at risk. Stimulation of primary motor
or primary sensory cortex typically produces positive responses,
Neuropsychological Testing whereas stimulation of association cortex produces disruption
of function if the patient is engaged in a task that requires the
Neuropsychological testing helps in the definition of the func- function of that cortex. Localization of language cortex requires
tional deficit zone. The battery of tests evaluates cortical func- the patient to be involved in language activities during electri-
tions of left and right temporal, frontal, parietal, and occipital cal stimulation.
lobes. Some tests also help identify mesial versus lateral tem-
poral dysfunction. Localizing information helps to support
other tests in the presurgical evaluation. Neuropsychological MEDICAL THERAPY
testing can also help predict postoperative deficits, particularly
when the planned resection will remove functioning cortex. Medical therapy is generally the first-line treatment after the
diagnosis of epilepsy has been made (Fig. 101.17). Its goal
should be complete seizure freedom in the absence of medica-
Wada Test tion side effects. Since the choice of therapy depends on
The Wada test involves intracarotid injection of anesthetic, seizure and epilepsy classification, ideally there should be
usually amobarbital, to examine language and memory func- enough evidence to diagnose the seizure type and the epilepsy
tions in the contralateral hemisphere. The Wada test was syndrome prior to deciding on initial therapy. The treating
Epilepsies 1599
Epilepsy diagnosis
101
First monotherapy
Second monotherapy or
adjunctive therapy
Refer to epilepsy center;

Reassess diagnosis; video-EEG Not epilepsy
monitoring Revise therapy
Structural
Consider/evaluate for epilepsy
Nonstructural with Yes, proceed with
surgery for TLE with
generalized onset seizures presurgical evaluation
hippocampal sclerosis or focal
then epilepsy surgery
epilepsy with well-defined and
resectable epileptogenic lesion
Revise AED therapy

Continue trials of medical No Dietary therapy may be
therapy: additional one to Continue trials of medical considered sooner in
five AED regimens therapy: additional one to five motivated individuals or
AED regimens those that are tube-fed
Consider VNS, dietary In event of persistent AED

therapy, neurostimulation, failure (whether due to lack of
Good candidate-
corpus callosotomy efficacy or poor tolerability), re-
proceed with epilepsy
evaluate for epilepsy surgery,
surgery
including invasive EEG-video
monitoring if appropriate
Not a surgical candidate

Consider VNS, dietary therapy,
neurostimulation, palliative
epilepsy surgery
Fig. 101.17 Treatment algorithm for epilepsy. Additional steps assume that seizures are not controlled despite adequate trial of well-tolerated
medication.
physician must have a low threshold for reevaluating the diag- pharmacokinetic properties is essential for safe and effective
nosis when therapy fails, particularly when the diagnosis of use (Table 101.3). Choice of the first AED depends primarily
epilepsy is based on history alone without supportive EEG or on the classification of seizure type and epilepsy syndrome
imaging data. (Table 101.4) but should also take into consideration factors
Pharmacotherapy is not always necessary after a single such as age, gender, comorbid conditions, and individual
unprovoked seizure, particularly when the risk of recurrence circumstances. The AED choice should consider the AED’s
appears low, based on known predictors (e.g., with a normal spectrum of efficacy, its specific pharmacological properties
EEG and MRI; see earlier discussion of epidemiology of the in relation to the patient’s specific needs, its safety profile in
first unprovoked seizure) (Krumholz et al., 2015). Rarely, the patient’s age and gender group, as well as its efficacy
some mild forms of epilepsy may not require therapy. For in the patient’s comorbid conditions. Whenever possible,
example, in BECTS, seizures may be infrequent, occur in sleep, these determinations should be based on solid evidence
and remit at puberty. In some patients with JME, seizures are derived from well-designed studies. The AEDs with FDA-
clearly linked to sleep deprivation or binge alcohol consump- approved indications outside of epilepsy include clonazepam
tion, and may be managed with lifestyle adjustments only, (panic attacks); carbamazepine (trigeminal neuralgia); val-
especially when myoclonic seizures are the only seizure type. proate (migraine prophylaxis, acute treatment and mainte-
In the vast majority of individuals, however, medical therapy nance for mania/bipolar disorder); gabapentin (postherpetic
is necessary. neuralgia); lamotrigine (maintenance for bipolar disorder);
topiramate (migraine prophylaxis); and pregabalin (diabetic
peripheral neuropathy, postherpetic neuralgia, fibromyalgia).
Initiating Therapy However, several AEDs are used for a variety of nonepilepsy
The many AEDs available for prescription include classical indications ranging from insomnia to restless legs syndrome
AEDs that were marketed before 1980 and many new AEDs and essential tremor, based on trial data or anecdotal evidence
that have been marketed since 1993. Knowledge of their (Azar and Abou-Khalil, 2008).
TABLE 101.3 Antiepileptic Drug Absorption, Elimination Half-Life, Formulations (Displayed in Order They Were Marketed in the United States)
Oral bioavailability Half-life (hours)*
High: ≥90% Short: ≤10
Intermediate: ≥70 to <90% Intermediate: >10 to <30 Intravenous Extended-release Requires slow
Antiepileptic drug Low: <70% Long: ≥30 formulation oral formulation titration
Phenobarbital High Long X
Primidone High Intermediate X
†
Phenytoin High Intermediate X X
Methsuximide‡ High Long
Ethosuximide High Long
Clonazepam High Long
Carbamazepine Intermediate Intermediate X X
Valproate High Intermediate X X
Felbamate High Intermediate
Gabapentin Low§ Short
Lamotrigine High Intermediate X X
Topiramate Intermediate Intermediate X X
Tiagabine High Short X
Levetiracetam High Short X X
Oxcarbazepine‡ High Intermediate X
Zonisamide High Long
Pregabalin High Short
Lacosamide High Intermediate X
Rufinamide Intermediate Short X
¶
Vigabatrin High Short
Ezogabine/retigabine Low Short X
Clobazam High Long
Perampanel High Long
Eslicarbazepine High Intermediate
*The t1/2 for AED given as monotherapy in a young adult.
†
Parenteral formulation is also available as fosphenytoin, a phenytoin prodrug that can be administered intramuscularly.
‡
Applies to active metabolites (N-desmethylmethsuximide for methsuximide, monohydroxyderivative [MHD] for oxcarbazepine).
§
Gabapentin bioavailability decreases with dose above 900 mg/day, ranging from ≈60% at 900 mg/day to ≈27% at 4800 mg/day given in 3 divided
doses.
¶
The duration of AED effect is much longer than expected for the short t1/2.
For partial-onset seizures, carbamazepine or phenytoin For generalized-onset seizures, the initial AED is dependent
may be used first, but newer drugs have clear pharmacokinetic on the seizure type(s). For pure generalized absence seizures,
advantages, particularly absence of enzyme induction (French ethosuximide is the first drug of choice, based on the recent
et al., 2004a). Although oxcarbazepine and topiramate are the comparative trial in which it had the best balance of efficacy
only ones with official FDA indications, lamotrigine, gabap- and tolerability (Glauser et al., 2010). Valproate was equally
entin, and levetiracetam have clinical trial evidence supporting effective and may be the best choice if there are concomitant
their use as initial monotherapy. A large community-based generalized tonic-clonic seizures or generalized myoclonic sei-
study found that lamotrigine was significantly better than car- zures because ethosuximide efficacy is limited to generalized
bamazepine, gabapentin, and topiramate and had a non- absence seizures. For IGE with generalized tonic-clonic sei-
significant advantage compared to oxcarbazepine with respect zures, valproate was significantly better than both lamotrigine
to time to treatment failure (Marson et al., 2007a). However, and topiramate for time to treatment failure (Marson et al.,
lamotrigine requires slow titration and would not be an 2007b) and may be the first drug of choice for men, in the
appropriate first choice when a rapid onset of action is needed. absence of prohibitive comorbidities. However, valproate is
When rapid therapeutic effect is required, oxcarbazepine and teratogenic, with dose-related increased risk of major congeni-
levetiracetam may be the drugs of choice because they can be tal malformation and permanent cognitive impairment in the
started at an effective dose. Topiramate also requires slow titra- exposed fetus. A different AED should be used first in women
tion. Because of its cognitive adverse effects, it is not generally with IGE, but valproate may be used at a low dose if other
the first drug of choice unless comorbidities (e.g., migraine, AEDs fail to control seizures (Montouris and Abou-Khalil,
obesity) favor its use. 2009). While no AED has official FDA initial monotherapy

TABLE 101.4 Established Efficacy of Antiepileptic Drugs by Seizure Type (FDA Indications and Class I-III Evidence)
FDA-Approved Indications
Monotherapy vs Adjunctive Therapy
Indication* Seizure Type or Syndrome Indication Other Noteworthy Efficacy Evidence
Antiepileptic drug Monotherapy Adjunctive Partial Generalized tonic-clonic Absence Myoclonic LGS IS Therapy and seizure type
Phenobarbital X X X
Primidone X X X
Phenytoin X X X X
Methsuximide X X X Two class IV trials supporting efficacy for
partial-onset seizures
Ethosuximide X X X
Clonazepam X X X† X
Carbamazepine X X X
Valproate X‡ X X X‡ X X‡ Initial monotherapy for generalized tonic-
clonic and myoclonic seizures
Felbamate Conversion to monotherapy§ X X X‖ X‖
Gabapentin X X Initial monotherapy for partial seizures
§ ‖
Lamotrigine Conversion to monotherapy X X X X Initial monotherapy for absence seizures
Topiramate X X X X X‖
Tiagabine X X
Levetiracetam X X X X Initial monotherapy for partial seizures
Oxcarbazepine X X X
Zonisamide X X Initial monotherapy for partial seizures
Pregabalin X X
Lacosamide X X X
Rufinamide X X‖
Vigabatrin X¶ X X X¶
Ezogabine/retigabine X X
Clobazam X X
Perampanel X X
Eslicarbazepine X X
FDA, U.S. Food and Drug Administration; IS, infantile spasms; LGS, Lennox-Gastaut syndrome.
*The FDA indications for older AEDs (first 7 rows) are less specific with respect to monotherapy versus adjunctive indication, and even with respect to seizure type. Official labeling may not specify
monotherapy versus adjunctive therapy for older AEDs marketed prior to 1993.
†
For patients who have failed ethosuximide.
‡
The official FDA indication is initial monotherapy for absence or partial seizures and adjunctive therapy “in patients with multiple seizure types that include absence seizures.” Valproate is widely
Epilepsies
considered a monotherapy drug of choice in patients with idiopathic generalized epilepsy with tonic-clonic or myoclonic seizures.
§
For partial-onset seizures only.
‖
Adjunctive in LGS.
¶
Monotherapy only for infantile spasm.
1601
101
indication for generalized myoclonic seizures, valproate is analog, oxcarbazepine (Picard et al., 1999; Raju et al., 2007).
clearly effective, and levetiracetam, which has FDA approval Dravet syndrome, which is usually caused by a sodium channel
as adjunctive therapy for generalized myoclonic seizures mutation, may have seizure aggravation with the use of
(Noachtar et al., 2008), may also be effective in monotherapy. agents acting on the sodium channel, particularly lamotrigine
Weaker evidence exists for efficacy of topiramate, zonisamide, (Guerrini et al., 1998).
and lamotrigine (lamotrigine may even aggravate myoclonic
seizures in some individuals) (Biton and Bourgeois, 2005; Antiepileptic Drug Considerations Based on Age
Crespel et al., 2005; Genton et al., 2006; Prasad et al., 2003).
For all epilepsy indications, treatment is initiated with an
and Gender
AED monotherapy. In the absence of urgency, it is preferable Age and gender may have an influence on AED selection (Azar
to start at a low dose and titrate slowly, even for AEDs that can and Abou-Khalil, 2008). In the pediatric age group, specific
be started at a higher effective dose. The initial target dose is epilepsy syndromes have implications for AED efficacy. Toler-
often the minimal effective dose that has been demonstrated ability profiles may also be different for children and adults,
in clinical trials, keeping in mind that the pivotal clinical trials which may influence the risk/benefit ratio for specific agents.
may have underestimated or overestimated that dose in some Serious rashes from lamotrigine, behavioral adverse effects
instances. If the initial target dose is not sufficient, the AED from levetiracetam, and oligohidrosis from topiramate and
dose can then be titrated gradually until efficacy is established. zonisamide are more likely in children, while hyponatremia
For patients with infrequent seizures, it may take a long time from oxcarbazepine and aplastic anemia from felbamate are
to determine when an effective dose has been reached. There- much less likely. Valproate-induced liver failure is more likely
fore it is wise for the initial target dose to be an average rather in children younger than 2 years of age. In women of child-
than a minimum effective dose. Before a medication can be bearing potential, certain AEDs may reduce the efficacy of oral
considered ineffective, it usually has to be titrated to the contraception, and valproate is to be avoided for two impor-
highest tolerated dose. If a medication fails due to lack of tant reasons: higher risk of congenital malformations in the
efficacy, the neurologist may choose either replacement mon- exposed fetus and increased risk of polycystic ovaries and
otherapy or adjunctive therapy with another medication. The hyperandrogenism (Lofgren et al., 2007).
available evidence is that the two options do not differ signifi- In the elderly, a key consideration is interaction with other
cantly in either efficacy or tolerability (Beghi et al., 2003; medications, which favors newer nonenzyme-inducing AEDs
Kwan and Brodie, 2000b). If the initial therapy has been com- (Arain and Abou-Khalil, 2009). Some AED adverse effects are
pletely ineffective, then replacement monotherapy is the best more likely in the elderly—for example, reversible parkinson-
choice. If the initial therapy was partially effective, adjunctive ism and cognitive impairment from valproate (Armon et al.,
therapy may be a consideration. If medication failure is due 1996) and hyponatremia from oxcarbazepine, particularly
to lack of tolerability, then replacement monotherapy is the when combined with diuretics or other agents that may lower
clearly preferable option. Replacement monotherapy usually sodium (Dong et al., 2005). Several trials have examined the
requires initially adding the new AED before withdrawing the comparative efficacy and tolerability of AEDs in the elderly.
old agent. However, overnight switch is possible for some Lamotrigine and gabapentin were better tolerated than
AEDs such as carbamazepine and oxcarbazepine (Albani immediate-release carbamazepine in new-onset geriatric epi-
et al., 2004). lepsy (Brodie et al., 1999; Rowan et al., 2005), but no differ-
Adjunctive therapy should take into consideration any ence was found between lamotrigine and extended-release
possible pharmacodynamic or pharmacokinetic interactions carbamazepine (Saetre et al., 2007).
between the medications in question (Table 101.5). Ideally,
the added medication should not have adverse pharmacoki- Pharmacoresistance, Tolerance, and
netic or pharmacodynamic interactions. All AEDs are approved
for adjunctive therapy (French et al., 2004b). Some AED com-
Seizure Aggravation
binations have a suggestion of synergy. For example, the lamo- Persistence of seizures despite AED therapy should always
trigine and valproate combination seems to have greater prompt reevaluation of the diagnosis; one of the most
efficacy than what would be predicted by the efficacy of each common causes of apparent drug resistance is misdiagnosis of
AED alone (Brodie and Yuen, 1997). There is also evidence nonepileptic psychogenic seizures. Other causes of apparent
favoring the combination of lamotrigine and levetiracetam pharmacoresistance include breakthrough seizures related
(Kinirons et al., 2006). to noncompliance, sleep deprivation (particularly in IGE),
At present, the AED mechanism of action (Table 101.6) is alcohol or drug abuse, and co-medications that reduce the
not crucial for AED selection (Guimaraes and Ribeiro, 2010), seizure threshold. In addition, seizures may appear resistant
although there is a suggestion that combining two AEDs with because of incorrect AED selection or inadequate AED use.
different mechanisms may have a greater chance of efficacy Approximately a third of individuals with epilepsy will not
than combining two AEDs with the same mechanism (Brodie become seizure free at follow-up despite adequate AED
and Sills, 2011). On the other hand, mechanism of action may therapy (Kwan and Brodie, 2000a). However, the definition of
be a predictor of adverse effects from pharmacodynamic inter- the exact time point when epilepsy is considered drug resistant
actions. For example, dizziness, ataxia, and diplopia are more has not been agreed upon. An ILAE task force recommended
likely when combining lacosamide with another agent that the definition of drug-resistant epilepsy as “failure of adequate
acts on the sodium channel (Novy et al., 2011; Sake et al., trials of two tolerated, appropriately chosen and used antiepi-
2010). The neurologist will often need to reduce the dose of leptic drug schedules (whether as monotherapies or in com-
the initial AED when adding a second AED with a similar bination) to achieve sustained seizure freedom” (Kwan et al.,
mechanism of action. A better understanding of the epilepsy 2010).
pathophysiology in individual patients may improve the selec- Drug resistance may be related to the underlying epilepsy
tion of AEDs in the future, with a greater role for mechanism pathology. Idiopathic epilepsy is less likely to be drug resistant
of action. than symptomatic epilepsy (Berg et al., 2001b). In one large
There are only rare examples of epilepsy genetics predicting study, 82% of patients with generalized idiopathic epilepsy
AED efficacy. Autosomal dominant nocturnal frontal lobe were seizure free for the past year as compared with only 35%
epilepsy is particularly responsive to carbamazepine and its of symptomatic partial epilepsy, 25% of patients with cerebral
Epilepsies 1603
TABLE 101.5 Hepatic Metabolism, Enzyme Induction/Inhibition, Pharmacokinetic Interactions, and Protein Binding
101
Hepatic Hepatic Affected Affected
Hepatic enzyme enzyme by enzyme by enzyme Protein
metabolism induction Autoinduction inhibition inducers inhibitors binding
High: >90% +Minimal
Intermediate: ++Intermediate
Antiepileptic ≥50% to ≤90% +++Pronounced +Affected High: ≥85%
drug Low: <50% −Absent −Not affected Low: <85%
Phenobarbital Intermediate +++ − − + + Low
Primidone Intermediate +++ − − + + Low
Phenytoin High +++ − − + + High
Methsuximide Low + − − + − Low
Ethosuximide Intermediate − − − + − Low
Clonazepam Intermediate − − − − − High
Carbamazepine High +++ +++ − + + Low
Valproate High − − +++ + + High
Felbamate Intermediate + − ++ + + Low
Gabapentin None − − − − − None
Lamotrigine High + + − + + None
Topiramate Low +* − +* + − Low
Tiagabine High − − − + − High
Levetiracetam None − − − +/− − Low
Oxcarbazepine High ++† − +† + + Low
Zonisamide Intermediate − − − + + Low
Pregabalin None − − − − − None
Lacosamide Low − − − + − Low
Rufinamide High + − + + + Low
Vigabatrin None + − − − − None
Ezogabine/ Intermediate − − − + − Low
retigabine
Clobazam High + − + + + Low
Perampanel High + − − + − High
Eslicarbazepine High + − + + − Low
*Applies to dose ≥200 mg.
†
Applies to dose ≥900 mg.
dysgenesis, 11% of patients with temporal lobe epilepsy due a follow-up report of 1098 patients, seizure-free rates were
to temporal lobe sclerosis, and 3% of patients with dual 49.5% on the first drug regimen, 13.3% on the second
pathology (Semah et al., 1998). Initial seizure frequency was regimen, 3.7% on the third regimen and 1.0% on the fourth
also a predictor (Berg et al., 2001a). In one study, drug resist- regimen (Brodie et al., 2012).
ance was seen in 51% of individuals who had more than 20 Other studies have suggested that continued AED trials
seizures before starting treatment, versus 29% of those who have a greater chance of achieving remission than suggested
had fewer than 20 seizures (Kwan and Brodie, 2000a). Other by the study of Kwan and Brodie. In one study of continued
predictors of drug resistance were history of acute sympto- AED trials in drug-resistant epilepsy, 14% achieved a 6-month
matic or neonatal status epilepticus and focal EEG slowing. terminal seizure remission after 3 years of follow-up with
Age at onset between 5 and 9 years predicted a lower risk of medication therapy only (Callaghan et al., 2007). In a sepa-
resistance (Berg et al., 2001a). rate study, about 16% of all drug introductions resulted in
Resistance to the first AED predicts resistance to the next seizure freedom for more than 12 months, and 28% of patients
AED. In the landmark study of Kwan and Brodie, 47% of were rendered seizure free by a drug introduction over 5 years
patients with newly treated epilepsy became seizure free with of follow-up (Luciano and Shorvon, 2007). Negative clinical
the first AED monotherapy, 13% with the second AED mono- predictors in these studies included history of status epilepti-
therapy, and 1% with the third AED monotherapy. Among cus, younger age at intractability, greater number of failed drug
patients who failed the first AED, 11% became seizure free if therapies, and presence of mental retardation. Shorter-
the first AED was ineffective, while 41% to 55% became duration epilepsy and idiopathic epilepsy were favorable pre-
seizure free if the first AED was not tolerated owing to side dictors. Failure of AED therapy suggests the need to consider
effects or idiosyncratic reaction (Kwan and Brodie, 2000a). In alternative therapies discussed later in this chapter.
1604
TABLE 101.6 Key Known Antiepileptic Drug Mechanisms of Action

High-voltage α2δ-Subunit of
Antiepileptic Sodium Potassium Enhancing Glutamate activated calcium T-Calcium voltage-activated
drug channels channel GABA receptor channels channels calcium channels SV2A Comment
Phenobarbital X X X
Primidone X X
Phenytoin X
Methsuximide ? X
Ethosuximide X
Clonazepam X
Carbamazepine X
Valproate X X X
Felbamate X X X X NMDA receptor antagonism
Gabapentin X
PART III Neurological Diseases and Their Treatment
Lamotrigine X X
Topiramate X X X Kainate and AMPA receptor antagonism
Tiagabine X Inhibition of GABA reuptake
Levetiracetam X
Oxcarbazepine X
Zonisamide X X
Pregabalin X
Lacosamide X Selective enhancing of slow inactivation
of voltage-gated sodium channels
Rufinamide X
Vigabatrin X Irreversible inhibition of GABA
transaminase
Ezogabine/ X Enhancing of transmembrane potassium
retigabine currents
Clobazam X
Perampanel X Noncompetitive antagonism of AMPA
glutamate receptors
Eslicarbazepine X
AMPA, α-Amino-3-hydroxy-5-methyl-4-isoxazole-propionic acid; GABA, γ-aminobutyric acid; NMDA, N-methyl-D-aspartate; SV2A, synaptic vesicle protein 2A.
Epilepsies 1605
Drug resistance does not always manifest early in the course able with benzodiazepines and barbiturates acting on the
of epilepsy. It may develop after a variable latency, may be GABA receptor. In general, dose-dependent adverse effects are 101
overcome with the use of a new AED, and may be punctuated reversible with dose reduction or medication discontinuation.
by periods of drug responsiveness, particularly with the use of Cognitive and behavioral adverse effects of AEDs could be
new AEDs (Schmidt and Löscher, 2005). In the follow-up considered in the category of dose-dependent adverse effects,
study by Brodie and colleagues of 1098 patients with newly although some individuals may be predisposed by virtue of
diagnosed epilepsy, 68% were seizure-free for at least 1 year genetic or other factors. Barbiturates and benzodiazepines are
at the last clinic visit. Upon reviewing the course of seizure best known to affect cognition, but any AED can cause impair-
control, 37% achieved early and sustained seizure freedom, ment of concentration and memory. Among the new AEDs,
22% had sustained seizure freedom after a delay, 16% had a topiramate and zonisamide are the most likely to impair cog-
pattern of alternating seizure freedom and relapse, while 25% nition, while lamotrigine is the least likely. Depression may
never attained seizure freedom (Brodie et al., 2012). In one occur with any AED, and psychosis is an uncommon adverse
group of patients evaluated for resective epilepsy surgery, the effect of many AEDs but seems more likely associated with
mean latency to failure of the second AED was 9.1 years topiramate, vigabatrin, and levetiracetam.
(range, 0–48), and 26% of patients reported at least 1 year of Long-term adverse effects of AEDs are often overlooked but
seizure freedom after the second unprovoked seizure (Berg could be more concerning because they are difficult to reverse
et al., 2003). or at times are irreversible. Common examples include weight
Pharmacoresistance may have more than one mechanism. gain seen with valproate and pregabalin, and weight loss noted
One proposed mechanism is that AEDs do not reach the epi- with topiramate and zonisamide. Barbiturate chronic use may
leptogenic zone in sufficient concentration because of multid- be associated with frozen shoulder and Dupuytren contrac-
rug transporters that transport AEDs out of neurons. A number tures. One of the more recently appreciated chronic adverse
of findings support this hypothesis indirectly, but there is no effects of AEDs is reduction in bone mineral density. This is
direct evidence of causality (Schmidt and Löscher, 2009). most likely to occur with chronic use of enzyme-inducing
Another key hypothesis is that the AED target (e.g., channels, AEDs but has also been associated with valproate and other
receptors) is no longer sensitive to the AED. Disease severity nonenzyme-inducing agents (Ensrud et al., 2004, 2008; Farhat
may play a role and may have common neurobiological factors et al., 2002). It is unclear whether any AED is not detrimental
with pharmacoresistance (Schmidt and Löscher, 2009). to bone density, and bone mineral density reduction may have
Another explanation for the loss of an AED response is toler- different mechanisms with different drugs. It is therefore advis-
ance, which is established with benzodiazepines but likely able to monitor bone density with chronic AED therapy, and
occurs with other AEDs as well (Löscher and Schmidt, 2006). to supplement vitamin D and calcium. Recently the enzyme-
Seizure aggravation may occur with a number of medica- inducing AEDs, carbamazepine and phenytoin, have been
tions (Chaves and Sander, 2005). This is most common in associated with serological markers of vascular risk, amelio-
generalized epilepsy, where AEDs such as carbamazepine, rated upon switching to lamotrigine or levetiracetam (Mintzer
oxcarbazepine, phenytoin, tiagabine, gabapentin, or viga- et al., 2009). Another long-term adverse effect of AEDs is
batrin may increase the number of seizures or provoke the potential for teratogenicity (Kluger and Meador, 2008) as well
appearance of new seizure types (myoclonic or absence sei- as reduced IQ in exposed infants. This adverse effect is most
zures) at a therapeutic level. In addition, any AED may cause pronounced with valproate (Meador et al., 2009).
a paradoxical increase in seizures in some patients. This phe- Idiosyncratic adverse effects are not dose dependent but
nomenon has been documented with levetiracetam (Nakken rather depend on individual patient genetic predisposition.
et al., 2003). A number of AEDs have been reported to increase They most commonly affect organs such as the liver, skin, and
seizure frequency or severity as a manifestation of toxicity, blood. Examples include hepatotoxicity, which may occur
with AED serum levels above “therapeutic” range. This is well with valproate and felbamate; Stevens-Johnson syndrome,
documented for phenytoin but may also occur with other which may occur with several AEDs including phenytoin, car-
agents. Finally, seizure exacerbation may occur in the setting bamazepine, and lamotrigine; and aplastic anemia, which
of AED-induced encephalopathy or with sedation. For may occur with felbamate and (more rarely) carbamazepine.
example, seizures may be exacerbated with valproate-induced There are some predictors for these serious adverse effects. For
encephalopathy, and sedative AEDs may exacerbate tonic sei- example, valproate hepatotoxicity is more likely in children
zures in patients with Lennox-Gastaut syndrome. younger than 2 years, particularly those with mitochondrial
disease (Bjornsson, 2008). Prior immune disorder and prior
cytopenia are risk factors for felbamate-associated aplastic
Medication Adverse Effects anemia (Pellock et al., 2006). In some instances, genetic
It is essential to know the most common and the most serious testing may identify individuals at greater risk of idiosyncratic
adverse effects of AEDs before using them. Such potential reactions, but there is a need for progress in the field of epi-
adverse effects should be discussed with the patient before lepsy pharmacogenomics (Kasperaviciute and Sisodiya, 2009).
prescribing any medication. The most common adverse effects
are dose dependent and will predictably occur if titration con-
tinues (Toledano and Gil-Nagel, 2008). Their appearance
Therapeutic Drug Monitoring
indicates that the dose should be reduced. These adverse Monitoring AED levels should be used predominantly as an
effects are most likely to occur at the time of greatest serum adjunct to clinical decision-making rather than the determi-
concentration following medication intake, in which case they nant of AED dose. An AED is typically titrated to the lowest
could be alleviated without dose reduction by splitting the dose known to be effective, but titration may stop earlier if it
dose, taking the medication with food, or using an extended- is clear that seizure freedom has already been achieved at a
release preparation. Some dose-dependent adverse effects lower dose. Once a clinically effective dose has been reached,
can be predicted by the mechanism of action. For example, a serum drug level is then obtained as a reference. Routine drug
the most common dose-dependent adverse effects with levels are not necessary, and the level does not have to be
medications acting on the sodium channel (phenytoin, car- repeated after that unless a breakthrough seizure occurs. The
bamazepine, oxcarbazepine, lamotrigine) are dizziness, ataxia, new level can be compared to the baseline reference level to
and diplopia. Sedation is common and sometimes unavoid- determine whether a drop in the level played a role in the
seizure. A serum level can also be helpful to determine how very high risk of seizure recurrence; pharmacological therapy
much room there is to increase the dose if seizures have not is expected to be lifelong in the majority of patients.
yet come under control. AED serum levels are valuable to help Most patients will not be diagnosed with a specific syn-
explain lack of AED efficacy at what appears to be a relatively drome whose course is well known. In a study of 294 children
high dose or appearance of adverse effects at a relatively low with nonsyndromic epilepsy followed for more than 10 years,
dose. One explanation for lack of efficacy is noncompliance. complete remission, defined as 5 years seizure free and medi-
If seizures have not come under control and the AED serum cation free, was achieved by 58% of children (Berg et al.,
level is 0, it is likely that the patient is not actually taking the 2011). Good seizure outcome at 2 years and no known under-
medication. Another reason for a low serum level may be fast lying cause of epilepsy were predictors of remission, while
metabolism, either due to genetic factors or due to enzyme older age at onset was independently associated with a poorer
induction by concomitant medication. Similarly, serum levels chance of complete remission.
can be useful to explain toxicity at a relatively low dose. Adverse The decision to withdraw medications must balance the
effects may be due to an elevated serum level as a result of slow potential consequences of seizure relapse and the potential
metabolism (either due to genetic factors or to hepatic or renal benefits of eliminating medication side effects and costs on an
dysfunction) or pharmacokinetic interaction. individual basis (Shih and Ochoa, 2009). The risk of seizure
A therapeutic range is quoted for some AEDs, particularly recurrence after AED discontinuation is lower in children than
classical AEDs such as phenytoin, carbamazepine, and val- in adults, and the potential psychosocial consequences of
proate. Although a useful guide, a value outside the range recurrent seizures are fewer in children. Hence AED with-
should never be the only basis for dosage change. This range drawal is considered sooner in children, usually after 1 or 2
may be helpful for patients with infrequent seizures, for whom years of seizure freedom. In a meta-analysis of AED discon-
ascertainment of effective seizure control may take a very long tinuation, the overall risk of relapse after AED discontinuation
time. For these patients, aiming for a level in the middle of was 25% at 1 year and 29% at 2 years. Relapse was more likely
the range may be advisable. The classical AED for which serum in patients with remote symptomatic seizures than in patients
levels may be the most helpful is phenytoin. Phenytoin has with idiopathic seizures, and with adolescent-onset versus
nonlinear kinetics, and its serum level can fluctuate widely childhood-onset epilepsy; an abnormal EEG was associated
with small changes in dose or bioavailability. When the dose with a relative risk of 1.45. One study found a greater predic-
is being titrated in a patient with difficult-to-control seizures, tive value for serial EEGs obtained after initiating AED with-
it may be difficult to predict when to stop increasing the dose, drawal (Galimberti et al., 1993). Other factors associated with
and the level may have to be checked intermittently during a greater risk of recurrence in other studies are partial seizures
this process. The usually quoted therapeutic range is 10 to and longer than 5 years to attain seizure freedom. Early AED
20 µg/mL. If the level is found to be at 20 µg/mL, additional response predicted successful AED withdrawal in children
titration may result in toxicity. Nevertheless, it is ill advised to (Shih and Ochoa, 2009). A prospective multicenter rand-
reduce the dose for a level above 20 if the patient has good omized study of continued AED treatment versus slow with-
seizure control and no adverse effects. A therapeutic range is drawal over 6 months reported that 41% of those in the
less established for many of the new-generation AEDs. Lamo- withdrawal group relapsed at 2 years, compared to 22% of
trigine levels have been better evaluated than other new AEDs. patients on continued treatment (Medical Research Council
Toxic adverse effects are likely to occur with a level greater than Antiepileptic Drug Withdrawal Study Group, 1991).
20 µg/mL, and few patients are expected to derive therapeutic Additional factors predicting recurrence in adults have
benefit beyond this point (Hirsch et al., 2004). included longer duration of active disease, shorter number of
For two medications that are highly protein bound, protein- years of seizure remission, abnormal psychiatric examination,
free levels may have added value. Phenytoin and valproate are presence of hippocampal atrophy, abnormal neurological
approximately 90% protein bound, and the protein-free findings, IQ below 70, increased number of seizures, partial-
portion is responsible for efficacy and toxicity (Levy and onset seizures, and multiple seizure types (Shih and Ochoa,
Schmidt, 1985). The total level is usually a good predictor of 2009). Seizure relapse in adults will restrict driving privileges
the free level. However, in instances where the proportion of and may endanger employment, particularly in certain occu-
protein binding may be altered, the total serum level is a poor pations. There is also a concern that seizure control may be
predictor of the protein-free level. These situations include low difficult to regain (Schmidt and Löscher, 2005). Hence, dis-
protein states such as malnutrition, hepatic failure, and renal continuation of AEDs in seizure-free adults is usually delayed
failure, the combined use of phenytoin and valproate, which for at least 4 years and occasionally postponed indefinitely.
compete for protein binding, and pregnancy. The elderly may The optimal rate of AED withdrawal after remission has
also have a greater protein-free portion. Valproate has satura- not been established scientifically. Abrupt discontinuation of
tion kinetics for protein binding such that there is a greater AEDs is not appropriate in this setting. Severe seizures have
proportion of free valproate at higher levels. Protein-free been reported during withdrawal of some AEDs, including
serum levels have greater value in guiding therapy in the benzodiazepines, carbamazepine, and oxcarbazepine. It is
special situations noted. generally agreed that AEDs in general and medications associ-
ated with tolerance (e.g., benzodiazepines in particular)
should be withdrawn gradually.
Discontinuation of Antiepileptic Drug Therapy
Owing to the potential adverse effects of AEDs, particularly
long-term adverse effects, discontinuation of AED therapy SURGICAL THERAPY
should be considered when it is no longer necessary. Although
there are several predictors of sustained remission on no medi-
Timing
cations, there is never a guarantee that seizures will not recur If seizures fail to come under control with medications, surgi-
after AED discontinuation. The decision to withdraw AEDs is cal therapy is considered. Exactly when to deem medical treat-
easiest to make when the epileptic syndrome is known to ment a failure has been a matter of debate, but an ILAE task
remit. One example of such a syndrome is BECTS, which is force suggested that failure of two tolerated, appropriately
known to remit at puberty. On the other hand, JME, the most chosen and used AED schedules constitutes medical failure
common idiopathic epileptic syndrome, is known to have a (Kwan et al., 2010). This was in part based on the finding that
Epilepsies 1607
when two AED monotherapies have failed, the chances that temporal pole (Wiebe et al., 2001). Dominant temporal
additional medical therapy will provide complete seizure lobectomies often spare the superior temporal gyrus in an 101
control diminish considerably (Kwan and Brodie, 2000a). It effort to reduce risk of language disturbance, but a randomized
is reasonable at that point to refer the patient to an epilepsy prospective trial did not suggest that this was associated with
center, particularly if the underlying epilepsy is surgically benefit (Hermann et al., 1999). Some centers tailor the resec-
remediable and surgical results are expected to be excellent. tion based on preoperative language functional mapping with
Examples include temporal lobe epilepsy with hippocampal electrical stimulation or fMRI. The hippocampal resection
sclerosis and partial epilepsy with a focal underlying epilep- usually measures about 3 cm. One study suggested that a
togenic lesion. However, if expected surgical results are less more complete hippocampal resection was associated with
favorable, it is reasonable to continue medical therapy using greater chance of postoperative seizure freedom (Wyler et al.,
different monotherapies and various combinations (see Fig. 1995), but the findings were not confirmed in a second study
101.17). In a study by Selwa et al. (2003), continued changes (Schramm et al., 2011).
in AED regimen rendered about 20% of patients who were not For individuals with clear hippocampal sclerosis, selective
candidates for epilepsy surgery seizure free at 4-year follow-up. amygdalohippocampectomy (SAH) is an alternative approach with
It is important to keep in mind that surgical outcome and less risk to language functions and equal outcome for seizure
chances of seizure freedom after postoperative AED with- control (Tanriverdi et al., 2008). The original approach advo-
drawal are better with earlier surgery, so that epilepsy surgery cated by Yasargil was trans-sylvian (Siegel et al., 1990), but the
should not be delayed for too long (Simasathien et al., 2013). same operation could use a transcortical approach through the
Evaluation for epilepsy surgery should probably not be middle temporal gyrus, or an inferior temporal approach. No
pursued for patients who are noncompliant with medications— clear difference in surgical outcome was noted in a study com-
and therefore have not actually failed medical therapy. Nor paring transcortical and trans-sylvian approaches, but phone-
should surgery be pursued for patients with only brief, subjec- mic fluency was significantly improved after transcortical but
tive, simple partial seizures (i.e., isolated auras) since these not after trans-sylvian SAH (Lutz et al., 2004). The “Spencer”
seizures often persist after epilepsy surgery. approach involves resection of the anterior 3 cm of the tempo-
ral pole to expose mesial temporal structures for resection
(Spencer et al., 1984). A favorable surgical outcome with respect
Presurgical Evaluation to seizure control requires inclusion of the parahippocampal
An extensive presurgical evaluation is necessary before consid- gyrus in the surgical resection (Siegel et al., 1990). Recently,
ering epilepsy surgery and has already been discussed in detail laser ablation under real time MR thermographic guidance has
(see Evaluation and Diagnosis). Its purposes are to (1) localize been proposed as an alternative to open resection in patients
the epileptogenic zone (whose resection is necessary and suf- with hippocampal sclerosis (Willie et al., 2014). Its main advan-
ficient to eliminate seizures), (2) identify incongruent evi- tages are decreased surgical morbidity and better cognitive
dence that may indicate the need for additional tests including outcome (Drane et al., 2015). This approach can also be used
invasive EEG, and (3) determine whether planned surgical for other small deep epileptogenic lesions.
resection poses risk to cerebral functions. Essential elements Lesionectomy is a suitable surgical approach when there is a
of the presurgical evaluation include interictal and ictal EEG, well-defined structural lesion such as benign tumor or cavern-
video analysis of recorded seizures, and structural imaging ous malformation. In the latter case, the resection must
with MRI to identify an epileptogenic lesion. Interictal PET include hemosiderin-stained tissue surrounding the malfor-
scanning with FDG and neuropsychological testing are also mation. There is some evidence to support the use of intraop-
commonly part of the presurgical evaluation. In cases where erative electrocorticography to guide the extent of resection
interictal EEG abnormalities are consistently focal and congru- (Van Gompel et al., 2009).
ent with a focal unilateral structural epileptogenic lesion, some Nonlesional neocortical epilepsy usually requires a tailored
have advocated skipping ictal EEG recordings, particularly resection after the ictal onset zone and cortical functions have
where resources are limited. Complex scenarios where there is been defined through intracranial recordings, most often
incongruence in the presurgical data require additional testing using subdural grids.
that should include functional imaging with PET, ictal SPECT, Hemispherectomy is the preferred surgical approach when the
MEG, or even invasive EEG with implanted intracranial elec- epileptogenic zone is well lateralized but widespread in one
trodes. The decision to proceed with surgery should balance hemisphere, and the hemisphere functions are impaired or
the predicted benefits of epilepsy surgery against the predicted expected to become impaired (Limbrick et al., 2009). Examples
risks of functional deficits that might result from surgery. of conditions for which hemispherectomy is often the recom-
mended procedure include Rasmussen syndrome, Sturge-Weber
syndrome, and hemimegalencephaly. The current functional
Surgical Approaches hemispherectomy technique removes temporal and centroparietal
Epilepsy surgery can be classified as either curative or pallia- regions, leaving the frontal and occipital poles with their blood
tive. The aim of curative surgery is to eliminate seizures com- supply but disconnected from the remainder of the brain. Hem-
pletely and potentially produce permanent remission without ispherectomy provides complete seizure control in approxi-
the need for AEDs. Palliative surgery is considered only if mately three-quarters of patients and improved seizure control
“curative” surgery is not viable. in the majority of the remainder (Limbrick et al., 2009). The
The most common epilepsy localization is mesial tempo- disappearance of seizures will often improve the function of the
ral, specifically amygdalohippocampal. The most common remaining hemisphere such that cognitive function and behav-
surgical approach has been a temporal lobectomy in which ior are often improved at follow-up.
lateral temporal cortex is resected first, followed by resection If the epileptogenic zone includes eloquent cortex, resec-
of the amygdala and hippocampus. The resection size is typi- tion may not be possible without unacceptable deficits, and
cally different for dominant and nondominant resection. The the technique of multiple subpial transection (MST) is then con-
lateral resection usually measures around 6 cm from the tem- sidered (Morrell et al., 1989). MST involves disconnection of
poral pole on the right but is less extensive on the left to horizontal intracortical fibers while preserving the integrity of
reduce the chance of language deficits. The typical left domi- vertical connections. The procedure is based on evidence that
nant temporal lobectomy measures about 4 cm from the the ictal discharge often spreads along horizontal fibers,
while cortical functions tend to follow a vertical columnar pocampal sclerosis), unilateral ictal and interictal epileptiform
organization. MST on eloquent cortex is most often per- discharges, and antecedent febrile convulsions (not consist-
formed in conjunction with resection of adjacent nonessen- ently reported). The etiology of head trauma, normal MRI,
tial cortex. More recently, hippocampal transection was and absence of hypometabolism on PET were unfavorable
proposed as a memory sparing procedure for patients with predictors in some studies. Postoperative seizures and epilep-
mesial temporal lobe epilepsy without hippocampal sclero- tiform activity on postoperative EEG were also unfavorable
sis, who are at risk of memory decline from hippocampal predictors. In neocortical epilepsy, well-circumscribed lesions
resection (Uda et al., 2013). (e.g., tumor, cavernoma), complete lesion resection, and focal
Corpus callosotomy (CC) is a palliative surgical procedure beta or gamma activity at ictal onset were favorable predictors,
involving partial or complete disconnection of the corpus cal- while absence of a lesion and generalized spike-and-wave EEG
losum. The procedure is most often used for drop attacks and pattern were unfavorable predictors.
is thought to disrupt rapid bilateral seizure spread responsible AEDs usually have to be continued for at least a period of
for sudden loss of consciousness or loss of posture without time after successful epilepsy surgery, but the number and
warning. CC can change seizures such that seizures may dose of AEDs may be reduced prior to that time. Most com-
become focal or patients may have a warning, giving them time monly, medications are tapered after 1 to 2 years of complete
to protect themselves before further seizure progression. In seizure freedom. However, there is a risk of recurrence in
seizure types where bihemispheric synchrony is required for approximately one-fifth to one-third of patients (Kim et al.,
seizure expression, CC may potentially eliminate clinical 2005; Lee et al., 2008; Park et al., 2010b; Rathore et al., 2011;
seizure manifestations. Drop attacks are the seizure type most Schiller et al., 2000; Schmidt et al., 2004). The risk seems
helped by CC, with benefit in about three-quarters of patients lower in pediatric patients (Lachhwani et al., 2008). Factors
and freedom from drop attacks in more than a third (Tanriv- associated with greater likelihood of recurrence included older
erdi et al., 2009). Generalized tonic-clonic seizures are also age at surgery and longer duration of epilepsy (Al-Kaylani
helped. A two-thirds anterior callosotomy is generally per- et al., 2007; Kim et al., 2005; Lee et al., 2008). Other factors
formed first, with the possibility of extending the callosotomy associated with recurrence were AED reduction before 10
later if there is insufficient improvement. CC is not effective for months (Lee et al., 2008) and normal preoperative MRI
focal seizures, including complex partial seizures of temporal (Schiller et al., 2000).
lobe epilepsy. It is reserved for patients with severe epilepsy, Late relapse is not a rare event. Relapse after a 2-year remis-
falls, and injuries. The most appropriate candidates have symp- sion occurred in 25% of mesial temporal and 19% of neocorti-
tomatic generalized epilepsy, but CC may be considered for cal epilepsy patients in the seven-center study. Only delay to
patients with highly refractory generalized tonic-clonic seizures remission predicted relapse, and only in mesial temporal epi-
in the setting of IGE (Cukiert et al., 2009; Jenssen et al., 2006b). lepsy patients (Spencer et al., 2005). In a study of anterior
temporal lobectomy for temporal lobe epilepsy in 325 patients
Surgical Results and Predictors of followed for a mean of 9.6 years, 55.3% of patients were
seizure free at 2 years, 47.7% at 5 years, and 41% at 10 years
Surgical Freedom (McIntosh et al., 2004). Patients who were seizure free at 2
Epilepsy surgery can be a very effective treatment for patients years postoperatively had a 74% probability of seizure freedom
who are found to be good candidates after a presurgical evaluat 10 years after surgery. Long-term postoperative outcome was
ation. The best surgical outcome has been reported in tempo- examined specifically in 171 patients with MRI-defined hip-
ral lobe epilepsy surgery. The efficacy of temporal lobe epilepsy pocampal sclerosis (Janszky et al., 2005a). Seizure freedom
surgery was confirmed in a randomized controlled trial in was noted in 80% at 6 months, 71% at 2 years, 66% at 3 years,
which 80 patients with temporal lobe epilepsy were randomly and 58% at 5 years. Predictors of outcome varied at different
assigned to immediate temporal lobectomy or additional AED time points: preoperative secondarily generalized tonic-clonic
therapy for 1 year. At 1 year, the difference between the two seizures and ictal dystonia were negative predictors at 2 years;
groups was highly significant: 58% of patients in the surgical longer epilepsy duration and ictal dystonia at 3 years; and only
group and 8% in the medical group were free of seizures longer epilepsy duration at 5 years.
impairing awareness; 38% in the surgical group and 3% in the About a third of patients who are not seizure free immedi-
medical group were free of all seizures including auras (Wiebe ately after surgery eventually achieve long-term seizure freedom
et al., 2001). (Janszky et al., 2005b). Normal MRI findings and secondarily
Many other studies have confirmed efficacy of surgery, with generalized seizures preoperatively were unfavorable predic-
generally better results for MTLE than neocortical epilepsy. In tors; rare postoperative seizures and ipsilateral temporal
a seven-center prospective observational study of resective epi- interictal epileptiform discharges were associated with seizure-
lepsy surgery in patients aged 12 years and older, 339 operated free outcome. Newly administered levetiracetam also showed
patients (297 mesial temporal, 42 neocortical) were followed a significant positive effect on the postoperative outcome, inde-
over 2 years (Spencer et al., 2005). Of these, 66% (223) expe- pendent of other prognostic factors (Janszky et al., 2005b).
rienced 2-year remission, not significantly different between Patients who have failed epilepsy surgery can be considered
medial temporal and neocortical resections (68% and 50%, for reoperation, usually after at least 1 to 2 years. Reoperation
respectively). Seizure remission was defined as 2 years com- is more likely to be successful if the initial surgery missed the
pletely seizure free after hospital discharge, with or without epileptogenic zone or epileptogenic lesion, or if the initial
auras. Only absence of generalized tonic-clonic seizures and resection was incomplete. Between one- and two-thirds of
presence of hippocampal atrophy were significantly and inde- reoperations result in seizure freedom or near-seizure freedom
pendently associated with remission, and only in the mesial (Germano et al., 1994; Gonzalez-Martinez et al., 2007; Holmes
temporal resection group. et al., 1999; Ramantani et al., 2013; Salanova et al., 2005;
Epilepsy surgery significantly improved quality-of-life score Siegel et al., 2004). If the first presurgical evaluation was
measures within 6 months after surgery; subsequent changes extensive and the surgery was appropriate based on the find-
over time were sensitive to seizure-free and aura-free status ings, reoperation is unlikely to be successful.
(Spencer et al., 2007). Other factors reported in some studies Epilepsy surgery has potential adverse effects that may be
as predictors of postoperative seizure freedom after temporal expected in some instances, as well as unexpected complica-
lobe surgery include discrete abnormalities (lesions and hip- tions. A contralateral upper-quadrant visual-field loss is to be
Epilepsies 1609
expected after temporal lobectomy, but this is usually not of improved within 14 days. Improvement was unlikely if no
functional consequence to the patient (Hughes et al., 1999). benefit had been seen by 2 months, although exceptions did 101
Cognitive changes may occur. Dominant temporal lobe epi- exist (Kossoff et al., 2008b).
lepsy surgery carries risks of verbal memory loss in 44% and The mechanism of the ketogenic diet is not well under-
reduced naming in 34% of patients (Sherman et al., 2011). stood. Its benefit may be related to acidosis, ketosis, calorie
Memory may continue to decline for up to 2 years after restriction and decrease in blood glucose, dehydration, or
surgery (Alpherts et al., 2006). There is a suggestion of increase in certain lipids (Sinha and Kossoff, 2005). Predictors
increased risk for memory decline in patients with larger hip- of success included concomitant use of the ketogenic diet and
pocampal volumes (Baxendale et al., 2008). On the other vagus nerve stimulation (Kossoff et al., 2007; Morrison et al.,
hand, memory deficits associated with the function of the 2009). Children receiving phenobarbital in combination with
contralateral temporal lobe may improve postoperatively in a ketogenic diet were less likely to benefit. Adverse effects of
some patients with unilateral hippocampal sclerosis (Baxen- the ketogenic diet include constipation and worsening of
dale et al., 2008). reflux, both of which can be managed with minor adjustments
and stool softeners. Acidosis may occur, mostly at initiation
and in association with acute illness; it can be managed with
OTHER THERAPIES hydration. Unexplained fatigue could be helped by supple-
Other therapies are often considered only after medical mentation with carnitine. The potential adverse effect of
therapy fails and when surgical therapy is not possible or has decreased growth is most likely to occur in the youngest chil-
also failed (Cascino, 2008). However, alternative nonpharma- dren. Renal calculi have been reported in 5% to 6% of indi-
cological therapy should also be considered when patients viduals and may be averted with improved hydration.
may be candidates for surgery, but expectations for complete Hyperlipidemia is of unknown long-term significance.
seizure freedom are low. These alternatives include dietary Indications for the ketogenic diet include refractory sei-
therapy, stimulation therapies, and radiosurgery. zures, regardless of classification. Individuals unable to toler-
ate AED therapy are particularly good candidates for the diet.
The ketogenic diet is easiest to manage in tube-fed patients or
Dietary Therapy infants receiving formula. A ketogenic diet is particularly ben-
Dietary therapy is a very old treatment of epilepsy, first pro- eficial and could be considered first-line therapy for children
posed in 1921 to mimic the effects of fasting by producing with glucose transporter deficiency and pyruvate dehydroge-
ketosis, acidosis, and dehydration (Sinha and Kossoff, 2005). nase deficiency. Other syndromes where the ketogenic diet has
Interest in a ketogenic diet decreased with the introduction of been reported to be specially beneficial include myoclonic-
many new AEDs in the 1990s but increased again with the astatic epilepsy, tuberous sclerosis, Rett syndrome, Dravet syn-
realization that the newer AEDs had only a modest impact on drome, and infantile spasms (Kossoff et al., 2009). Absolute
drug-resistant epilepsy. The ketogenic diet is a very low carbo- contraindications include mitochondrial disorders, pyruvate
hydrate, high fat, and low to adequate protein diet that includes carboxylase deficiency, and β-oxidation defects.
some restriction of total calories (≈75% of age recommenda- Patient compliance with the ketogenic diet has proven dif-
tions). The amount of protein is based on age requirement, ficult, so other diets have been explored in the treatment of
carbohydrates are only 5 to 10 g/day, and the remaining calo- epilepsy. The modified Atkins diet was created to be more palat-
ries come from fat. The ratio of fat to protein plus carbohydrate able and less restrictive than the ketogenic diet. It only restricts
ranges from 2 : 1 to 4 : 1. The diet is typically initiated with a carbohydrates (10 g/day for children and 15 g/day for adults),
fast. Although the fasting is not necessary for therapeutic effi- not protein, fat, or calories. It is modified from the standard
cacy, it does provide a faster onset of action that may help Atkins diet in that the induction phase limiting carbohydrates
improve compliance. Initiation with fasting requires hospital is indefinite, and that fat is not only allowed but encouraged.
admission, which may also be helpful for monitoring unex- Weight loss is not the goal of this diet, but weight loss has
pected adverse effects of the diet and reviewing medications been associated with improvement.
for possible carbohydrate components (Sinha and Kossoff, The efficacy of the Atkins diet has been studied prospec-
2005). Efficacy of the ketogenic diet in children was confirmed tively in children and adults. In one pediatric study, 65% of
in a randomized controlled but unblinded trial: 38% of chil- children had a greater than 50% reduction in seizures (Kossoff
dren who received the diet had a greater than 50% reduction et al., 2006), and in an adult study, 47% had greater than 50%
versus only 6% of controls, and 7% had a greater than 90% reduction at 3 months and 33% at 6 months, but 33% dis-
reduction versus none of the controls (Neal et al., 2008). A continued the diet before 3 months (Kossoff et al., 2008c).
blinded crossover study in children with Lennox-Gastaut syn- The modified Atkins diet also seems to work fairly rapidly;
drome did not reach significance, but this may have been due median time to seizure reduction was 2 weeks. In the adult
to methodological problems (Freeman et al., 2009). In a pro- prospective study, a higher level of ketosis was associated with
spective study of the ketogenic diet in 150 children with drug- improvement early on and weight loss later on (Kossoff et al.,
resistant epilepsy, 3% were seizure free at 3 months and 7% 2008c). Another study suggested consistently strong ketosis
at 12 months; 27% had a greater than 90% decrease in seizure was important for maintaining the efficacy of diet therapy
frequency at 1 year (Freeman et al., 1998). A multicenter study (Kang et al., 2007). The Atkins diet has advantages over the
similarly showed that 10% of children with highly refractory ketogenic diet in that it is easier to initiate in an outpatient
epilepsy were seizure free at 1 year, and 40% had a 50% or setting and requires only limited dietician input. It is more
greater decrease in seizure frequency (Vining et al., 1998). tolerable and has fewer adverse effects than the ketogenic diet.
The ketogenic diet is a little less effective in adolescents and The presence of obesity in other family members may encour-
adults than in children and is also limited by a higher rate of age them to try the diet as well, thus improving the chances
noncompliance in adolescents. The onset of action is very fast. of success for the patient. The modified Atkins diet has also
In one study the median time to first improvement was 5 days, been proposed as an inexpensive treatment option in develop-
with a range of 1 to 65 days. The onset of improvement was ing countries (Kossoff et al., 2008a).
faster in children who were fasted (5 vs 14 days), but there The suggestion that a lower glucose level played a role in
was no difference between 1 and 2 days of fasting. Fasting had dietary efficacy prompted a trial of a low glycemic index diet
no effect on long-term efficacy. Some 75% of children (Muzykewicz et al., 2009). This diet selectively restricts high
glycemic index foods that produce a substantial postprandial recovery) has been reported during routine intraoperative lead
increase in blood glucose and insulin. The diet allows only testing, approximately once for every 1000 implantations. VNS
low glycemic index carbohydrates, with an overall carbohy- is usually programmed to stimulate for 30 seconds alternating
drate intake of 40 to 60 g/day. There was a greater than 90% with 5 minutes of rest, but the duration of stimulation time
improvement in seizure control in about 25% at 3 months, on and stimulation time off can be changed. Some patients
with another 25% experiencing 50% to 90% improvement. seem to derive greater benefit from “rapid-cycle” stimulation,
There was a correlation between efficacy and blood glucose at with 7 seconds of stimulation alternating with 12 seconds of
1 month and 12 months of treatment. rest. The first parameter to be titrated is current intensity, which
Overall, the advantages of dietary therapy are that it is effec- is increased by 0.25 mA steps as needed to achieve benefit.
tive, has a rapid onset of action, and has different adverse Other output current parameters that can be programmed are
effects than seen with AEDs. Disadvantages include that frequency and pulse width. The optimal stimulation param-
dietary therapy may be socially isolating, and compliance is eters have not been well defined and may vary between indi-
difficult to maintain. The less restrictive diets are easier to viduals. In addition to the recurring output current cycles, a
follow, but they also give more opportunity for cheating (Muz- single on-demand stimulation train can be programmed sepa-
ykewicz et al., 2009). rately to abort seizures with the use of a magnet. On-demand
stimulation is particularly helpful to abort or attenuate sei-
zures in individuals who have an aura (Morris, 2003). However,
Vagus Nerve Stimulation the clinical efficacy of on-demand stimulation is difficult to
Vagus nerve stimulation (VNS) was first approved in 1997 as confirm with rigorous investigation.
the only device for the adjunctive treatment of refractory The most common VNS adverse effect is hoarseness, which
partial-onset seizures in adults and adolescents aged 12 years occurs during stimulation cycles. This is to be expected in the
or older. More recently, VNS was also FDA approved as adjunc- majority of patients, but it does improve over time. The same
tive long-term treatment for chronic or recurrent depression is true of other stimulation-related adverse effects of coughing,
that has not responded to antidepressants. Animal data sug- throat pain, dyspnea, and paresthesias (Ben-Menachem,
gested that VNS has acute abortive effects, terminating seizures 2002). VNS may also exacerbate obstructive sleep apnea, so it
that have already started (McLachlan, 1993), and acute pro- is important to diagnose and treat sleep apnea before initiat-
phylactic effects, reducing seizure frequency and severity ing VNS therapy (Malow et al., 2000a; Marzec et al., 2003).
during intermittent stimulation (Takaya et al., 1996). Efficacy The main advantages of VNS are that it does not have the
in patients with drug-resistant epilepsy was confirmed in two AED adverse effects of sleepiness, tiredness, dizziness, or cog-
pivotal randomized blinded controlled studies that demon- nitive dysfunction. It may improve mood and promote alert-
strated 24.5% to 28% short-term reduction in seizure fre- ness, and it gives patients and families a sense of control with
quency (Handforth et al., 1998; The Vagus Nerve Stimulation the use of on-demand stimulation to abort seizures. In addi-
Study Group, 1995). The long-term continuation studies sug- tion, compliance does not require patient effort. However, it
gested increasing benefit over time, with median seizure reduc- does require surgical implantation, and the battery has to be
tion of 34% 3 months after the end of the second double-blind changed every 3 to 10 years depending on the stimulation
trial, and 45% by the end of 1 year. In one cohort followed parameters. It is difficult to predict who will benefit from this
for 12 years, mean reduction in seizure frequency was 26% therapy, but the best candidates are patients who are not good
after 1 year and 52% after 12 years of treatment (Uthman candidates for epilepsy surgery, have frequent seizures, and
et al., 2004). However, seizure freedom is reported in less than have a consistent aura or a slow seizure progression, so that
10% of patients (Ben-Menachem, 2002). Hence, individuals on-demand stimulation could be used to abort seizures. VNS
who are excellent candidates for epilepsy surgery should be has also become frequently used in symptomatic generalized
advised of the much greater chance of seizure freedom with epilepsy before proceeding with corpus callosotomy (Nei
surgical therapy. et al., 2006; Rosenfeld and Roberts, 2009; You et al., 2008).
Even though there are no randomized trials of VNS in
patients with drug-resistant generalized epilepsy, several
studies have supported VNS efficacy in both idiopathic and
Other Stimulation Therapies
symptomatic generalized epilepsy (Ben-Menachem, 2002; Trigeminal nerve stimulation, which had an antiepileptic effect
Kostov et al., 2009; Ng and Devinsky, 2004) (Elliott et al., in a rodent model of epilepsy, can be delivered noninvasively
2011); the same is true for VNS efficacy in children. Thus VNS in humans and is being investigated as an alternative stimula-
efficacy does not seem to be specific for a particular form of tion modality. In a small open-label pilot study, bilateral
epilepsy or particular age. The mechanism of action of VNS stimulation of the ophthalmic branch produced a mean
for epilepsy is not totally clear. Approximately 80% of the reduction in seizure frequency of 59% at 12 months (DeGior-
vagus nerve is composed of afferent myelinated fibers project- gio et al., 2009). A larger blinded randomized controlled trial
ing to the nucleus of the tractus solitarius, which itself has in 50 subjects with partial onset seizures showed a reduction
widespread projections (Ben-Menachem, 2002). In humans in seizure frequency as measured by the response ratio, but
with implanted VNS, imaging of blood flow with PET showed there was no significant difference between groups in the 50%
that VNS increased blood flow in some regions and decreased responder rates (30.2% for the treatment group and 21.1% for
blood flow in others. Increased blood flow in the thalamus the active control group) (DeGiorgio et al., 2013). Of note is
correlated with long-term seizure control (Henry et al., 1999). that the active treatment group showed a significant improve-
In another study using SPECT, acute reduction in amygdala ment in responder rate over the treatment period, from 17.8%
perfusion and chronic reduction in hippocampal perfusion at 6 weeks to 40.5% at 18 weeks.
correlated with clinical efficacy (Van Laere et al., 2002). Repetitive transcranial magnetic stimulation (rTMS), a nonin-
The VNS device consists of a generator, usually implanted vasive cortical stimulation method, was also investigated as a
over the chest under the left clavicle, and electrodes that are treatment for drug-resistant epilepsy, with variable results.
placed around the left vagus nerve and tunneled under the RTMS modulates cortical excitability with high-frequency
skin to connect with the generator. VNS implantation is usually rTMS enhancing and low-frequency rTMS decreasing cortical
an outpatient surgical procedure with rare complications, the excitability in most individuals (Gangitano et al., 2002). Most
most important of which is infection. Asystole (with full studies used daily rTMS sessions for about 1 week, then
Epilepsies 1611
evaluated efficacy 2 to 4 weeks later. A meta-analysis deduced hamartoma. More recently, radiosurgery was explored for
that low-frequency rTMS is moderately beneficial, with more MTLE. A prospective study in three European centers reported 101
improvement in subjects who have cortical dysplasia or neo- 65% of patients seizure free at 2 years after radiosurgery. Five
cortical epilepsy, probably because of greater and more precise patients had transient side effects including depression, head-
access of rTMS therapy to the more superficial seizure foci ache, nausea, vomiting, and imbalance. No permanent neuro-
(Hsu et al., 2011). logical deficit was reported, except nine visual-field deficits.
Various brain targets have been explored for stimulation, However, seizure freedom was delayed for most patients, the
including cortical and subcortical targets. Scheduled open-loop main improvement occurring between 12 and 18 months;
stimulation to various cortical and subcortical structures includ- some patients only became seizure free after 2 years post
ing the thalamus, subthalamic nucleus, cerebellum, and hip- treatment.
pocampus, demonstrated variable success (Jobst et al., 2010a). A US multicenter prospective study randomized patients to
Bilateral stimulation of the anterior nucleus of the thalamus high- or low-dose radiosurgery. At 36 months of follow-up,
was proven effective in a multicenter double-blind rand- 76.9% of patients randomized to the high dose and 58.8%
omized trial and may become available as a clinical option randomized to the low dose were free of seizures for the prior
(Fisher et al., 2010). Median seizure reduction was 14.5% in 12 months (Barbaro et al., 2009). Seizure remission correlated
the control group and 40.4% in the stimulated group during with appearance of vasogenic edema demonstrated on serial
the blinded phase, and there was a 56% median reduction in imaging after approximately 9 to 12 months (Chang et al.,
seizure frequency by 2 years. However, participants in the 2010). The degree of radiation-induced local vascular insult
stimulated group were more likely to report depression or and neuronal loss was dose dependent and predicted long-
memory problems as adverse events. More recently, a small term seizure remission (Chang et al., 2010). Neuropsychologi-
single-blind, controlled trial found bilateral centromedian cal testing showed no definite change in cognitive measures
thalamic nucleus stimulation effective in drug-resistant from baseline at 2 years after radiosurgery (Quigg et al., 2011).
generalized epilepsy, but not frontal lobe epilepsy (Valentin Radiosurgery may have a place in the treatment of drug-
et al., 2013). resistant mesial temporal epilepsy for patients who are
Responsive closed-loop stimulation delivers a stimulus to the opposed to or at greater risk for complications with standard
presumed seizure onset zone in response to seizure detection epilepsy surgery. However, the long-term risk/benefit ratio of
(Jobst et al., 2010a). The concept is based on evidence that radiosurgery needs better definition.
brief stimulation can terminate seizure activity if delivered
early after seizure onset. The generator is implanted in the QUALITY-OF-CARE STANDARDS IN THE
skull and connected to either depth or subdural strip elec-
trodes to deliver stimulation directly to one or two seizure
MANAGEMENT OF EPILEPSY
onset zones. The responsive stimulator device was found to be The Quality Measurement and Reporting Subcommittee of the
effective in a pivotal randomized double-blind, sham stimula- American Academy of Neurology recently developed perform-
tion controlled trial in patients with drug-resistant partial- ance measures for quality of epilepsy care (Fountain et al.,
onset seizures. The reduction in seizure frequency over the 2011) (Table 101.7). The measures are intended for all physi-
blinded evaluation period was 37.9% in the treatment group cians who treat patients with epilepsy, and require documen-
compared to 17.3% in the sham stimulation group (Morrell, tation in the medical records. Some measures are recommended
2011). In the open label extension, median percent reduction for application for all patients at the initial evaluation visit.
in seizures was 44% at 1 year and 53% at 2 years, suggesting These include review or ordering of EEG and neuroimaging;
progressive improvement with time (Heck et al., 2014). The both are important for diagnosis, choice of best therapy, and
device was approved by the FDA as an adjunctive therapy in predicting response to therapy and eventual prognosis. Other
individuals 18 years or older with partial onset seizures who quality measures are recommended for all patients at every
have undergone diagnostic testing that localized no more than visit. These include documentation of seizure type and fre-
2 epileptogenic foci, are refractory to two or more antiepileptic quency since the last visit to stimulate action for achieving
medications, and currently have frequent and disabling sei- complete seizure control; specification of the epilepsy etiology
zures. Responsive stimulation is a suitable treatment option or epilepsy syndrome to maintain awareness of parameters
for patients with bilateral independent seizure foci or with an that need to be monitored for the specific etiology (e.g.,
epileptogenic zone in eloquent cortex not suitable for surgical follow-up imaging for a brain tumor); and inquiry about AED
resection. side effects so that these can be addressed. One measure
In general, the advantages of stimulation include that it is applies to all patients at least once a year; it concerns coun-
reversible and adjustable, unlike resective surgery. However, seling about safety issues. The remaining two measures apply
the optimal stimulation parameters are not generally well to specific populations: periodic consideration of referral to a
defined, and to date, stimulation therapies have been pre- higher level of care, including epilepsy surgery evaluation for
dominantly palliative. The decision to pursue stimulation patients with drug-resistant epilepsy, and specific counseling
therapy has to balance risks and benefits in comparison with for women of childbearing potential about treatment effects
other available therapies. on contraception and pregnancy. It is expected that adherence
to these recommendations will improve care for patients with
epilepsy.
Radiosurgery
Radiosurgery uses a stereotactic frame to immobilize the head
while radiation beams are precisely directed from different
SEIZURE CLUSTERS AND STATUS EPILEPTICUS
angles to a target. The method delivers radiation to the target Seizure clusters, also called acute repetitive seizures and serial
with a steep gradient so that regions within a few millimeters seizures, are closely grouped seizures representing an increase
of the target receive a substantially reduced radiation dose in seizure frequency compared to baseline, usually occurring
(Romanelli and Anschel, 2006). Radiosurgery was initially over the span of minutes to a couple days. Seizure clusters
used for treatment of brain tumors and AVMs not readily may include any type of seizure and may vary in severity,
accessible to standard surgery, with beneficial effect on seizure but by definition there is complete recovery in between sei-
control. It has also been used successfully for hypothalamic zures. Seizure clusters are more common in patients with drug
TABLE 101.7 Recommended Performance Measures for Quality of Epilepsy Care

Measure title Patient group Timing Description
No. 1: Seizure type and current All patients All visits Type(s) of seizure(s) and current seizure
seizure frequency frequency for each seizure type
documented in the medical record
No. 2: Documentation of All patients All visits Etiology of epilepsy or epilepsy syndrome
etiology of epilepsy or reviewed and documented if known, or
epilepsy syndrome documented as unknown or cryptogenic
No. 3: EEG results reviewed, All patients All initial evaluations Results of at least one EEG reviewed or
requested, or test ordered requested, or if EEG was not performed
previously, then an EEG ordered
No. 4: MRI/CT scan reviewed, All patients All initial evaluations Results of at least one MRI or CT scan
requested, or scan ordered reviewed or requested or, if MRI or CT
scan was not obtained previously, then
MRI or CT scan ordered (MRI preferred)
No. 5: Querying and counseling All patients All visits Patients were queried and counseled
about antiepileptic drug side about antiepileptic drug side effects, and
effects querying and counseling were
documented in the medical record
No. 6: Surgical therapy referral Patients with drug-resistant At least every 3 years Consideration of appropriateness for
consideration for intractable epilepsy surgical therapy documented in the
epilepsy medical record
No. 7: Counseling about All patients At least once a year Counseling about context-specific safety
epilepsy-specific safety issues appropriate to patient age,
issues seizure type and frequency, occupation
and leisure activities, etc. (e.g., injury
prevention, burns, appropriate driving
restrictions, or bathing)
No. 8: Counseling for women Female patients of childbearing At least once a year Counseling about how epilepsy treatment
of childbearing potential with potential (12–44 years old) may affect contraception and pregnancy
epilepsy
Adapted from Fountain, N.B., Van Ness, P.C., Swain-Eng, R., et al., 2011. Quality improvement in neurology: AAN epilepsy quality measures: report
of the Quality Measurement and Reporting Subcommittee of the American Academy of Neurology. Neurology 76, 94–99.
CT, Computed tomography; EEG, electroencephalogram; MRI, magnetic resonance imaging.
resistant epilepsy, particularly those with remote symptomatic evidence suggests that the generalized tonic-clonic phase of
epilepsy and extratemporal epilepsy. Patients with seizure primary or secondarily generalized tonic-clonic seizures does
clusters are more likely to have a history of status epilepticus. not last longer than 2 minutes (Jenssen et al., 2006a; Theod-
Seizure clusters themselves may or may not progress to pro- ore et al., 1994) except when it evolves into status epilepticus.
longed seizures or even status epilepticus. Such progression As a result, it has been suggested that vigorous therapy for
may be predictable for individual patients, based on their status epilepticus be initiated after 5 minutes of generalized
seizure history. This may determine the most appropriate tonic-clonic activity (Lowenstein et al., 1999). There is also
treatment for seizure clusters. Mild clusters can be treated with evidence that complex partial seizures that last longer than 10
oral doses of benzodiazepines. However more severe clusters, minutes will likely evolve into status epilepticus (Jenssen
particularly those known to progress to severe prolonged sei- et al., 2006a).
zures or status epilepticus, may require other routes of admin- Any seizure type may evolve into status epilepticus. Status
istration. Rectal diazepam is the only FDA approved treatment epilepticus may be classified based on the seizure type it
for out of hospital administration by nonmedical caregivers evolves from. The most dangerous type of status epilepticus,
(Cereghino et al., 1998). However, a recent trial supported the GCSE, may evolve from a primary generalized tonic-clonic
efficacy of intramuscular diazepam delivered by autoinjector seizure or more often from a secondarily generalized tonic-
(Abou-Khalil et al., 2013). In addition, there are ongoing trials clonic seizure. One form of status epilepticus with a low likeli-
using intranasal midazolam or intranasal diazepam. Buccal hood of irreversible neuronal injury is generalized absence
midazolam is another option that has been in clinical use in status epilepticus, which evolves from generalized absence
a number of countries (Nakken and Lossius, 2011). seizures.
Status epilepticus is broadly defined as seizure activity that A common categorization of status epilepticus divides it
continues for 30 minutes, or recurrent seizures without recov- into convulsive and nonconvulsive status epilepticus. Convul-
ery between attacks. The 30-minute duration has been the sive status epilepticus includes simple partial motor status epi-
subject of debate, since it may delay aggressive therapy, par- lepticus, complex partial status epilepticus with clonic motor
ticularly when prolonged duration can be predicted in the manifestations, generalized myoclonic, generalized tonic, gen-
absence of therapy. Experimental evidence suggests that irre- eralized clonic, and generalized tonic-clonic or GCSE (as a
versible neuronal injury may start after 20 to 30 minutes of result of either secondarily generalized tonic-clonic activity
generalized convulsive status epilepticus (GCSE) (Fujikawa, or primary generalized tonic-clonic seizures). Nonconvulsive
1996; Meldrum and Brierley, 1973), so every effort has to be status epilepticus includes the two major subcategories of
made to stop seizure activity prior to that. A large body of complex partial status epilepticus without clonic activity and
Epilepsies 1613
generalized absence status epilepticus. Status epilepticus that et al., 1998). It is important to recognize that the majority of
consists of subjective simple partial seizure activity is not patients in status epilepticus do not have a history of epilepsy. 101
usually included under either of these classifications. It is often This is particularly true for patients in subtle GCSE, only
referred to as aura continua. 12.7% of whom had prior epilepsy.
Nonconvulsive status epilepticus is generally considered a Status epilepticus is a neurological emergency that requires
less serious medical emergency than convulsive status epilep- prompt intervention. The goal of therapy is to stop seizure
ticus. However, nonconvulsive status epilepticus can be diffi- activity in the brain before neuronal injury has started. In
cult to distinguish from subtle convulsive status epilepticus—which addition, delay in initiating therapy is associated with resist-
is extremely serious, is difficult to treat, and has a poor prog- ance to treatment (Treiman et al., 1998), probably due to
nosis (Treiman et al., 1998). Subtle GCSE is characterized by alteration in the functional properties of GABAA receptors
coma with subtle clonic motor activity or even absent motor (Goodkin et al., 2008; Jones et al., 2002; Macdonald and
activity. Subtle GCSE may evolve from overt GCSE in which Kapur, 1999). Since GCSE is the most serious form, its treat-
treatment has been delayed or has been ineffective. Subtle ment will be discussed first. Treatment of status epilepticus
GCSE may also be seen without prior overt GCSE when there may have to start before arrival in the emergency room. Indi-
has been a serious brain insult such as severe traumatic brain viduals known to have recurrent status epilepticus may
injury, hypoxic injury, or massive strokes. In nonconvulsive respond to rectal diazepam administered by a parent or care
status epilepticus of the generalized absence variety, the patient partner. There is also evidence to support the use of buccal
usually appears awake but may be either unresponsive to midazolam, nasal midazolam, and nasal lorazepam (Arya
verbal stimuli or may have slowed or inappropriate responses. et al., 2011). Even when prehospital treatment was not effec-
In nonconvulsive status epilepticus of the complex partial tive and status epilepticus had persisted upon arrival in the
variety, there is a wide spectrum of impairment of conscious- emergency room, there was evidence that prehospital treat-
ness, responsiveness, or behavior. There may be considerable ment with rectal diazepam was associated with a shorter dura-
cyclical fluctuations in the clinical manifestations. When the tion of status after arrival to the emergency department (Chin
patient is in persistent deep coma, the status epilepticus is et al., 2008). For individuals not prepared for home treatment
more likely to be of the subtle GCSE variety. of status epilepticus, the use of 2 mg of IV lorazepam by para-
The definitive diagnosis of nonconvulsive status epilepticus medics was associated with termination of status before arrival
requires confirmation with EEG. Even GCSE has to be differ- to the emergency room in 59.1% of individuals, compared to
entiated from psychogenic status epilepticus or pseudo-status 21.1% treated with placebo (Alldredge et al., 2001). More
epilepticus, which may require video-EEG for definitive diag- recently, intramuscular autoinjector administration of mida-
nosis. However, the EEG patterns of status epilepticus, particu- zolam by paramedics was found at least as safe and effective
larly nonconvulsive status epilepticus, are not totally specific as intravenous lorazepam for prehospital seizure cessation
(Kaplan, 2007). When the EEG pattern is not specific, the (Silbergleit et al., 2012). Intramuscular midazolam could be
definitive diagnosis also requires observation of a definite administered faster than intravenous lorazepam. At arrival in
clinical response to treatment, or at least restoration of normal the emergency department, 73.4% of 448 subjects in the
EEG activity that was previously absent. In GCSE, a sequence intramuscular-midazolam group were free of seizure activity,
of EEG patterns was reported, starting with discrete recurrent as compared with with 63% of 445 subjects in the intravenous-
seizures separated by interictal slow activity, merging seizures lorazepam group.
with waxing and waning ictal discharge, continuous ictal dis- Upon arrival in the emergency room, treatment of GCSE
charge, continuous ictal discharge punctuated by generalized begins with basic life support measures, specifically attention
attenuation, and then periodic epileptiform discharges on a to airway, breathing, and circulation (Treiman, 2007). Blood
relatively flat background (Treiman et al., 1990). This sequence samples should be drawn for hematological and serum chem-
was proven in an animal model of status epilepticus, and also istry values, as well as AED levels for patients who are already
suspected in human status epilepticus based on EEGs of taking these medications. If blood glucose is low or cannot be
patients studied at different stages of the condition. A similar measured rapidly, IV glucose should be administered, in con-
sequence may also occur in partial status epilepticus, with junction with IV thiamine if there is a concern for malnutri-
asymmetrical or focal EEG features. The last pattern in the tion. Based on the landmark Veterans Affairs Status Epilepticus
sequence, periodic epileptiform discharges on a relatively flat Cooperative Study, lorazepam 0.1 mg/kg was the most effec-
background, is somewhat problematic because periodic sharp tive agent, terminating overt convulsive status epilepticus
discharges are not specific. within 20 minutes in 64.9% of patients (Treiman et al., 1998).
The incidence of status epilepticus is likely underestimated It was much less effective in subtle convulsive status epilep
by published studies. The highest overall incidence, 41 cases ticus, terminating it within 20 minutes in only 17.9% of
per 100,000 per year, was found in the prospective population- patients with a verified diagnosis. Lorazepam was superior to
based study of status epilepticus in Richmond, Virginia phenytoin alone, which controlled overt convulsive status
(DeLorenzo et al., 1996). The incidence is elevated early in within 20 minutes in only 43.6% of patients with verified
life, decreases after that, then increases in the elderly, with up diagnosis. Lorazepam was not significantly superior to pheno-
to 98.9 annual cases per 100,000 persons in that age group barbital (15 mg/kg) or diazepam (0.15 mg/kg) plus pheny-
(Vignatelli et al., 2003). toin (18 mg/kg). However, lorazepam was recommended over
The etiology of status epilepticus is very dependent on age. these treatments, because it is easier to use. If the first treat-
The most common cause in children is febrile status epilepti- ment failed to control status epilepticus, the chances of control
cus, accounting for more than half of cases (Rosenow et al., with the second treatment were minimal and mortality was
2007). In adults, status epilepticus is much more often due to twice as high (Treiman et al., 1998).
acute cerebrovascular accidents, hypoxia, metabolic causes, A standard treatment protocol is necessary for the hospital
and low AED levels (Rosenow et al., 2007). In the case of treatment of GCSE (Table 101.8). Lorazepam is usually the first
GCSE, there is a difference between overt and subtle forms agent used for terminating status. If lorazepam is successful in
with respect to causal factors. The overt form accounts for stopping GCSE, the decision to add another agent depends on
approximately three-quarters of cases, and its leading cause the underlying etiology. Lorazepam’s duration of action is
was remote neurological insult. A life-threatening medical approximately 12 to 24 hours. If the etiology is reversible (e.g.,
condition was the leading cause of subtle GCSE (Treiman status epilepticus due to metabolic or toxic factors), lorazepam
TABLE 101.8 Protocol for Treatment of Status Epilepticus Used at electrical status epilepticus may continue after motor activity
Vanderbilt University stops. If the EEG continues to show ictal activity, the anesthe-
sia has to be deepened to a burst-suppression pattern and even
0–15 min IV: normal saline at TKO
If blood glucose low: 1 amp D50 (50 mL IVP) and start
to complete suppression in some cases. Patients who require
second IV with D5NS general anesthesia to control status epilepticus will generally
Thiamine 100 mg IVP if given D50 or if cachectic/ require long-term maintenance with AEDs. Serum levels of
malnourished/alcoholic AEDs must be in a high therapeutic zone prior to discontinu-
If actively seizing: ation of general anesthesia. If seizure activity recurs upon
Lorazepam IV, 10 mg at <2 mg/min withdrawal of general anesthesia, a number of agents have
Fosphenytoin, max. delivery rate = 150 mg/min, total been used successfully. Valproate, levetiracetam, and lacosa-
dose 20 mg/kg mide have IV formulations and evidence to support efficacy
• Do not use if status is due to a metabolic cause;
in refractory status epilepticus (Agarwal et al., 2007; Aigua-
unlikely to respond to phenytoin
• Reduce delivery rate if AV block or hypotension
bella et al., 2011; Albers et al., 2011; Alvarez et al., 2011; Chen
• Current treatment with phenytoin is not a et al., 2011; Goodwin et al., 2011; Kellinghaus et al., 2011;
contraindication Koubeissi et al., 2011; Misra et al., 2006; Moddel et al., 2009).
High-dose topiramate and felbamate have also been advo-
15–60 min For patients with decreasing seizures after
cated as treatment options (Wasterlain and Chen, 2008).
fosphenytoin load: additional 10 mg/kg of
fosphenytoin
During the treatment of refractory status epilepticus with
For patients continuing to seize who require AEDs, the cause of status has to be investigated and treated
intubation: appropriately (Shorvon, 2011).
Thiopental ± succinylcholine (avoid succinylcholine if The treatment of other forms of status epilepticus may be
possible) less aggressive, depending on the type of status encountered.
Consider additional dose of fosphenytoin 10 mg/kg In complex partial status with partially preserved conscious-
For continuing seizures post intubation: ness and responsiveness, and in simple partial status epilepti-
Midazolam: 0.3 mg/kg by slow IV injection, may cus, aggressive treatment should avoid depressing the level of
repeat at 5-min intervals ×3 doses. Midazolam
consciousness. It is still recommended to start with lorazepam
infusion starts at 2 µg/kg/min; increase by 1 µg/kg/
min every 15 min until seizure activity stops followed by IV fosphenytoin, but if status is still not control-
or: led, IV valproate, IV levetiracetam, and even IV lacosamide
Propofol: 1–2 mg/kg, then 2–10 mg/kg/h may be used. Several studies and analyses support IV valproate
or: efficacy for various forms of status epilepticus (Agarwal et al.,
Pentobarbital: 5 mg/kg loading dose (to achieve 2007; Brigo et al., 2012, 2013; Chen et al., 2011; Malamiri
burst-suppression pattern on EEG with interburst et al., 2012; Mehta et al., 2007; Tiamkao et al., 2013; Yasiry
intervals of approx. 7 sec); repeat load as and Shorvon, 2014). IV levetiracetam and lacosamide have not
necessary to max. of 15 mg/kg, then 1–3 mg/kg/h been subjected to rigorous clinical trials, and their use is based
maintenance dose ×6–12 h; reevaluate patient
mainly on anecdotal experience (Alvarez et al., 2011; Hofler
or:
Phenobarbital: 20 mg/kg at <100 mg/min and Trinka, 2013; Rossetti and Bromfield, 2006; Yasiry and
Shorvon, 2014). The use of general anesthesia should be
AV, Atrioventricular; D, dextrose; EEG, electroencephalogram; IV, avoided if at all possible, because of associated increased risk
intravenous; IVP, IV push; NS, normal saline; TKO, to keep open. of infection and death (Sutter et al., 2014).
Generalized absence status epilepticus may respond to IV
lorazepam but may require additional IV valproate for control.
Generalized myoclonic status epilepticus can be treated with
may be the only treatment necessary. Intravenous diazepam is IV lorazepam, valproate, or IV levetiracetam. Levetiracetam is
not recommended in place of lorazepam because of its rapid the only AED approved by the FDA for treatment of myoclonic
redistribution in adipose tissue, making the duration of its seizures based on class I clinical trial evidence.
effect approximately 15 minutes. Another longer-acting AED Outcome of status epilepticus depends on the underlying
is needed if the underlying etiology is not rapidly reversible. cause, patient age, duration and severity of status epilepticus,
Intravenous fosphenytoin at 18 to 20 mg/kg is usually infused and rapidity of therapy initiation. In the Richmond status
no faster than 150 mg/min. epilepticus study, mortality was 3% for children and 26% for
If GCSE is not controlled after lorazepam 0.1 mg/kg, infu- adults (DeLorenzo et al., 1996). Status epilepticus of less than
sion of 20 mg/kg of fosphenytoin is necessary. An additional 1 hour duration had a 2.7% mortality rate after 1 month,
10 mg/kg can be infused if there is partial response to the compared to 32% for status epilepticus persisting longer than
initial dose of fosphenytoin. If GCSE is still unresponsive to 1 hour (Towne et al., 1994). A recent review suggested that
treatment, endotracheal intubation is necessary at this point. patient age and depth of coma at presentation were the strong-
The neurologist can choose between general anesthesia using est predictors of outcome (Neligan and Shorvon, 2011).
midazolam or propofol, or administration of phenobarbital, However, depth of coma is related to duration of status
20 mg/kg, at a rate of less than 100 mg/min. If the status (including delay in initiating therapy) and underlying illness.
epilepticus appears likely to be refractory, pentobarbital may
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101 Epilepsies

Bassel W. Abou-Khalil, Martin J. Gallagher, Robert L. Macdonald

Axis 2: Seizure type. a truncal rotation. Dystonic posturing is a sustained contraction

Fig. 101.1 Versive eye and head turning in transition to general-

interaction with the environment. Distal nonmanipulative

that for simple partial seizures as well as other partial-onset

Febrile seizures Febrile seizures then epilepsy of unknown

Epilepsy with Myoclonic Absences Epileptic Encephalopathy with Continuous Spike-and-

Familial Mesial Temporal Lobe Epilepsy

Inflammatory and Autoimmune Disorders

MORBIDITY AND MORTALITY

Histopathology gomerization, formation of insoluble protein aggregates, and

Refer to epilepsy center;

Revise AED therapy

Consider VNS, dietary In event of persistent AED

Not a surgical candidate

TABLE 101.6 Key Known Antiepileptic Drug Mechanisms of Action

TABLE 101.7 Recommended Performance Measures for Quality of Epilepsy Care

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