# 06 - 436 Seizures and Epilepsy

### 436 Seizures and Epilepsy

a second patient, the genome of the RPE cell line was sequenced, and 
a mutation was discovered in a known oncogene. The trial was halted 
and a decision made to discontinue the effort for customized cell 
therapy in favor of using RPE cells derived from the national repository 
of banked iPSC lines which undergo extensive gene sequencing and 
quality controls. This outcome serves as a caution for the challenges 
involved in bringing a customized cell therapy to the clinic.

■
■MESENCHYMAL STEM CELLS
By far the largest number of human trials have been performed using 
MSCs sourced from a variety of sites including bone marrow, periph­
eral blood, adipose tissue, umbilical cord, and other sites. Interest in 
the potential utility of MSCs for regenerative therapy began with the 
optimistic report that bone marrow stem cells were pluripotent and 
capable of generating nerve and heart muscle as well as blood cells. 
The possibility that easily obtainable MSCs could be used to regenerate 
injured or diseased cells or organs to treat diseases ranging from stroke, 
neurodegenerative disease, myocardial infarct, and even diabetes, 
generated enormous enthusiasm. The enthusiasm proved irresistible 
to many, and even after the initial reports were discredited—MSCs 
turned out not to be pluripotent stem cells as initially thought—a 
veritable flood of papers began to appear claiming disease-modifying 
activity of MSCs in mouse models of a wide range of degenerative 
disease and injury models. But when it became clear that the MSCs 
were not transforming into or generating new neurons or cardiac myo­
cytes, alternative mechanisms of action were invoked, including the 
release of trophic factors, cytokines, or inflammatory modulators that 
were credited with producing their remarkable restorative effects. The 
relative ease with which blood or adipose tissue can be harvested from 
patients or donors and MSCs extracted has led to a rapidly expanding 
number of clinical trials for conditions ranging from stroke and MS to 
AD, ALS, and PD. Furthermore, a loophole in the regulatory frame­
work of the FDA allows autologous cell therapy to escape regulation 
provided that the cells have not been significantly processed. This lax 
regulation has spawned a veritable industry of stem cell clinics making 
unsubstantiated claims of success in treating nervous system diseases. 
Patients have died from treatments in unregulated clinics operating 
in countries around the world, and three patients became blind in a 
well-publicized incident following stem cell treatments delivered by a 
Florida clinic. The “stem cells” were derived from the patients’ own fat 
tissue and blood. These activities represent the dark side of the stem 
cell revolution perpetrated by practitioners who exploit the desperation 
of patients and their families. Legitimate and effective stem cell thera­
pies will emerge over time, but given the prevalence and abundance 
of misleading information available on the Internet and elsewhere, 
a trusted and well-informed physician can play a key role in helping 
patients navigate the current cell therapy minefield.
PART 13
Neurologic Disorders
■
■MSCS FOR TRAUMATIC BRAIN INJURY
An allogeneic bone marrow–derived MSC line received conditional 
marketing approval in Japan in 2024 for the indication of improving 
chronic motor paralysis resulting from traumatic brain injury. The 
MSCs were transiently transfecting with the human Notch-1 intracel­
lular domain gene to promote FDF-2 secretion in order to “enhance 
their ability to regenerate nerve cells” according to the pharmaceutical 
company that developed the cell-based therapy. The approval fol­
lowed results of a phase 2 clinical trial conducted in Japan and the 
United  States. Forty-six patients with moderate to severe traumatic 
brain injury and chronic motor deficits had MSCs stereotactically 
infused into an area of encephalomalacia identified on MRI scan while 
a sham group of 15 patients had burr holes only. The trial met the 
primary endpoint showing significant improvement in motor function 
at 24 weeks on the Fugle-Meyer Motor Scale (FMMS) (p = .04). Inter­
estingly, a small improvement was noted in the sham-treated group as 
well, indicating the presence of a placebo effect. A larger, double-blind, 
randomized, sham-controlled study is now planned.
■
■PERSPECTIVE
The premise that stem cell biology would herald an era of regenerative 
medicine has fueled exaggerated claims, false starts, and a proliferation 

of bogus clinics. But now we may be on the threshold of a new era of 
stem cell-based therapies for neurologic diseases and disorders includ­
ing PD, spinal cord injury, ALS, and epilepsy. Whether this promise 
becomes reality will depend on the outcome of the first wave of piv­
otal double-blind controlled trials that are now being conducted or 
planned.
■
■FURTHER READING
Ayers JI et al: Different α-synuclein prion strains cause dementia with 
Lewy bodies and multiple system atrophy. Proc Natl Acad Sci USA 
119:e2113489119, 2022.
Batista AF et al: The importance of complement-mediated immune 
signaling in Alzheimer’s disease pathogenesis. Int J Mol Sci 25:817, 
2024.
Carlson GA, Prusiner SB: How an infection of sheep revealed prion 
mechanisms in Alzheimer’s disease and other neurodegenerative 
disorders. Int J Mol Sci 22:4861, 2021.
Condello C et al: Expanding the prion paradigm to include Parkinson 
and Alzheimer diseases. JAMA Neurol 81:1023, 2024.
Eichmüller OL, Knoblich JA: Human cerebral organoids: A new 
tool for clinical neurology research. Nat Rev Neurol 18:661, 2022.
Garton T et al: Neurodegeneration and demyelination in multiple 
sclerosis. Neuron 112:3231, 2024.
Kandel ER et al (eds): Principles of Neural Science, 6th ed. McGraw Hill, 
New York, 2021.
Kim TW et al: Pluripotent stem cell therapies for Parkinson disease: 
Present challenges and future opportunities. Front Cell Dev Biol 
8:729, 2020.
Lee HG et al: Neuroinflammation: An astrocyte perspective. Sci Transl 
Med 15:eadi7828, 2023.
Li Q, Barres BA: Microglia and macrophages in brain homeostasis 
and disease. Nat Rev Immunol 18:225, 2018.
Liu L et al: Microbiota and the gut-brain-axis: Implications for new 
therapeutic design in the CNS. EBioMedicine 77:103908, 2022.
Pallarés-Moratalla C, Bergers G: The ins and outs of microglial 
cells in brain health and disease. Front Immunol 15:1305087, 2024.
Pease-Raissi SE, Chan JR: Building a (w)rapport between neurons 
and oligodendroglia: Reciprocal interactions underlying adaptive 
myelination. Neuron 109:1258, 2021.
Section 2	 Diseases of the Central 
Nervous System
Patricia Dugan, Vikram R. Rao

Seizures and Epilepsy
A seizure (from the Latin sacire, “to take possession of”) is a transient 
occurrence of signs or symptoms due to abnormal excessive or syn­
chronous neuronal activity in the brain. Depending on the distribution 
of discharges, this abnormal brain activity can have various manifesta­
tions, ranging from dramatic convulsive activity to experiential phe­
nomena not readily discernible by an observer. Although a variety of 
factors influence the incidence and prevalence of seizures, ~5–10% of 
the population will have at least one seizure, with the highest incidence 
occurring in early childhood and late adulthood.
The meaning of the term seizure needs to be carefully distinguished 
from that of epilepsy. Epilepsy describes a condition in which a person 
has a risk of recurrent seizures due to a chronic, underlying process. 
This definition implies that a person with a single seizure, or recurrent

seizures due to correctable or avoidable circumstances, does not neces­
sarily have epilepsy (although a single seizure associated with clinical 
or electroencephalographic features portending high risk of recurrence 
may establish the diagnosis of epilepsy). Epilepsy refers to a clinical 
phenomenon rather than a single disease entity because many forms 
and causes exist. However, among the many causes of epilepsy, there 
are various epilepsy syndromes in which the clinical and pathologic 
characteristics are distinctive and suggest a specific underlying etiology.
Using the definition of epilepsy as two or more unprovoked sei­
zures, the incidence of epilepsy is ~0.3–0.5% in different populations 
throughout the world, and the prevalence of epilepsy has been esti­
mated at 5–30 persons per 1000.
CLASSIFICATION OF SEIZURES
Determining the type of seizure that has occurred is essential for 
focusing the diagnostic approach on particular etiologies, selecting 
appropriate therapy, and providing information regarding prognosis. 
The International League Against Epilepsy (ILAE) Commission on 
Classification and Terminology updated their approach to classifica­
tion of seizures in 2017 (Table 436-1). This system is based on the 
clinical features of seizures and associated electroencephalographic 
findings. Other potentially distinctive features such as etiology or cel­
lular substrate are not considered in this classification system, although 
this will undoubtedly change in the future as more is learned about 
the pathophysiologic mechanisms that underlie specific seizure types.
A fundamental principle is that seizures may be either focal or gen­
eralized. Focal seizures originate within networks limited to one brain 
region (note that the term partial seizures is no longer used). Gener­
alized seizures arise within and rapidly engage networks distributed 
across both cerebral hemispheres. Focal seizures are often associated 
with structural abnormalities of the brain. In contrast, generalized 
seizures may result from cellular, biochemical, or structural abnormali­
ties with a more widespread distribution. There are exceptions in both 
cases, however.
■
■FOCAL ONSET SEIZURES
Focal seizures arise from a neuronal network either discretely localized 
within one brain region or more broadly distributed but still within a 
cerebral hemisphere. With the new classification system, the subcate­
gories of “simple focal seizures” and “complex focal seizures” have been 
eliminated. Instead, the classification emphasizes the effect on aware­
ness (intact or impaired) and nature of the onset (motor or nonmotor). 
Focal seizures can also evolve into generalized seizures. In the past, this 
was referred to as focal seizures with secondary generalization, but the 
new system relies on descriptions of the type of generalized seizures 
that evolve from the focal seizure.
The routine interictal (i.e., between seizures) electroencephalogram 
(EEG) in patients with focal seizures is often normal or may show brief 
discharges termed epileptiform spikes, or sharp waves. Because focal 
seizures can arise from the medial temporal lobe or inferior frontal 
lobe (i.e., regions distant from the scalp), the EEG recorded during the 
seizure may be nonlocalizing. However, the region of seizure onset may 
be defined using surgically placed intracranial electrodes.
TABLE 436-1  Classification of Seizuresa
1.	 Focal Onset
(Can be further described as having intact or impaired awareness, motor or 
nonmotor onset, or evolve from focal to bilateral tonic clonic)
2.	 Generalized Onset
a.	 Motor
Tonic-clonic
Other motor (e.g., atonic, myoclonic)
b.	 Nonmotor (absence)
3.	 Unknown Onset
Motor, nonmotor, or unclassified
aBased on the 2017 International League Against Epilepsy classification of seizure 
types. (Data from RS Fisher et al: Operational classification of seizure types by the 
International League Against Epilepsy: Position Paper of the ILAE Commission for 
Classification and Terminology. Epilepsia 58:522, 2017.)

Focal Seizures with Intact Awareness 
Focal seizures can have 
motor manifestations (such as tonic, clonic, or myoclonic move­
ments) or nonmotor manifestations (such as sensory, autonomic, or 
emotional symptoms) without impairment of awareness. For example, 
a patient having a focal motor seizure arising from the right primary 
motor cortex near the area controlling hand movement will experi­
ence involuntary movements of the contralateral left hand. Since the 
cortical region controlling hand movement is immediately adjacent to 
the region for facial expression, the seizure may also cause abnormal 
movements of the face synchronous with the movements of the hand. 
The EEG recorded with scalp electrodes during the seizure (i.e., an ictal 
EEG) may show abnormal focal discharges over the corresponding area 
of cerebral cortex.

Three additional features of focal motor seizures are worth noting. 
First, in some patients, the abnormal motor movements may begin in a 
very restricted region, such as the fingers, and gradually progress (over 
seconds to minutes) to include a larger portion of the extremity. This 
phenomenon, described by Hughlings Jackson and known as a “Jack­
sonian march,” represents the spread of seizure activity over a progres­
sively larger region of motor cortex. Second, patients may experience 
a localized paresis (Todd’s paralysis) for minutes to many hours in the 
involved region following the seizure. Third, in rare instances, the sei­
zure may continue for hours or days. This condition, termed epilepsia 
partialis continua, is often refractory to medical therapy.
CHAPTER 436
Seizures and Epilepsy
Focal seizures may also manifest as changes in somatic sensation 
(e.g., paresthesias), vision (flashing lights or formed hallucinations), 
equilibrium (sensation of falling or vertigo), or autonomic function 
(flushing, sweating, piloerection). Focal seizures arising from the tem­
poral lobe may also cause the sensation of acrid odors (e.g., bleach or 
burning rubber) or tastes (e.g., bitter or metallic), or hearing sounds 
(simple noise or complex sounds), or an epigastric sensation that rises 
to the head. Some patients describe intense internal feelings such as 
fear, a dreamlike sense, depersonalization, déjá vu, or illusions that 
objects are growing smaller (micropsia) or larger (macropsia). These 
subjective, “experiential” events that are not directly observable by 
someone else are referred to as auras.
Focal Seizures with Impaired Awareness 
Focal seizures may 
also be accompanied by a transient impairment of the patient’s abil­
ity to maintain normal contact with the environment. The patient is 
unable to respond appropriately to visual or verbal commands during 
the seizure and has impaired recollection or awareness of the ictal 
phase. The seizures frequently begin with an aura (i.e., a focal seizure 
without cognitive disturbance) that is stereotypic for the patient. The 
start of the ictal phase is often a motionless stare, which marks the 
onset of the period of impaired awareness. The impaired awareness 
may be accompanied by automatisms, involuntary movements that can 
involve basic behaviors, such as chewing, lip smacking, swallowing, 
or “picking” hand movements, or more elaborate behaviors, such as a 
display of emotion or running. The patient is typically disoriented fol­
lowing the seizure, and the transition to full recovery of consciousness 
may range from seconds to hours. Examination immediately following 
the seizure may show an anterograde amnesia or transient neurologic 
deficits (such as aphasia, hemi-neglect, or visual loss) caused by postic­
tal inhibition of the cortical regions most involved in the seizure.
The range of potential clinical behaviors linked to focal seizures is 
so broad that extreme caution is advised before concluding that parox­
ysmal, stereotypic episodes of bizarre or atypical behavior are not due 
to seizure activity. In such cases, additional detailed EEG studies may 
be helpful.
■
■EVOLUTION OF FOCAL SEIZURES TO 
GENERALIZED SEIZURES
Focal seizures can spread to involve both cerebral hemispheres and 
produce a generalized seizure, usually of the tonic-clonic variety 
(discussed below). This evolution is observed frequently following 
focal seizures arising from a region in the frontal lobe but may also 
be associated with focal seizures occurring elsewhere in the brain. A 
focal seizure that evolves into a generalized seizure is often difficult

to distinguish from a primary generalized onset tonic-clonic seizure 
because bystanders tend to emphasize the more dramatic, generalized 
convulsive phase of the seizure and overlook the more subtle, focal 
symptoms present at onset. In some cases, the focal onset of the seizure 
becomes apparent only when a careful history identifies a preceding 
aura. Often, however, the focal onset is not clinically evident and may 
be established only through careful EEG analysis. Nonetheless, distin­
guishing between these two entities is extremely important, because 
there are substantial differences in the evaluation and treatment of 
epilepsies characterized by focal versus generalized onset seizures.

■
■GENERALIZED ONSET SEIZURES
Generalized seizures arise at some point in the brain but immediately 
and rapidly engage neuronal networks in both cerebral hemispheres. 
Several types of generalized seizures have features that place them in 
distinctive categories and facilitate clinical diagnosis.
Typical Absence Seizures 
Typical absence seizures are character­
ized by sudden, brief lapses of consciousness without loss of postural 
control. The seizure usually lasts for only seconds, consciousness 
returns as suddenly as it was lost, and there is no postictal confusion. 
Although the brief loss of consciousness may be clinically inapparent 
or the sole manifestation of the seizure, absence seizures are usually 
accompanied by subtle, bilateral motor signs such as rapid blinking, 
chewing movements, or small-amplitude, clonic movements of the 
hands.
PART 13
Neurologic Disorders
Typical absence seizures are associated with a group of genetically 
determined epilepsies with onset usually in childhood (ages 4–10 
years) or early adolescence and are the main seizure type in 15–20% 
of children with epilepsy. The seizures can occur hundreds of times 
per day, but the child may be unaware of or unable to convey their 
existence. Because the clinical signs of the seizures are subtle, especially 
to parents who may not have had previous experience with seizures, it 
is not surprising that the first clue to absence epilepsy is often unex­
plained “daydreaming” and a decline in school performance recog­
nized by a teacher. Indeed, absence epilepsy is often misdiagnosed as 
an attention deficit disorder.
The electrophysiologic hallmark of typical absence seizures is a 
burst of generalized, symmetric, 3-Hz, spike-and-slow-wave discharges 
that begins and ends suddenly, superimposed on a normal EEG 
background. Periods of spike-and-slow-wave discharges lasting more 
than a few seconds usually correlate with clinical signs, but the EEG 
often shows many more brief bursts of abnormal cortical activity than 
suspected clinically. Hyperventilation tends to provoke these electro­
graphic discharges and even the seizures themselves and is routinely 
used when recording the EEG.
Atypical Absence Seizures 
Atypical absence seizures have fea­
tures that deviate both clinically and electrophysiologically from 
typical absence seizures. For example, the lapse of consciousness is 
usually longer and less abrupt in onset and cessation, and the seizure 
is accompanied by more obvious motor signs that may include focal 
or lateralizing features. The EEG shows a generalized, slow spikeand-slow-wave pattern with a frequency of ≤2.5 Hz, as well as other 
abnormal activity. Atypical absence seizures are usually associated 
with diffuse or multifocal structural abnormalities of the brain and 
therefore may accompany other signs of neurologic dysfunction, such 
as developmental delay. Furthermore, the seizures are less responsive to 
anticonvulsants compared to typical absence seizures.
Generalized, Tonic-Clonic Seizures 
Generalized onset tonicclonic seizures are the main seizure type in ~10% of all persons with 
epilepsy. They are also the most common seizure type resulting from 
metabolic derangements and are therefore frequently encountered in 
many different clinical settings. The seizure usually begins abruptly 
without warning, although some patients describe vague premonitory 
symptoms in the hours leading up to the seizure. This prodrome is 
distinct from the stereotypic auras associated with focal seizures that 
generalize. The initial phase of the seizure is usually tonic contraction 
of muscles throughout the body, accounting for several classic features 

of the event. Tonic contraction of the muscles of expiration and the 
larynx at the onset will produce a loud moan or “ictal cry.” Respirations 
are impaired, secretions pool in the oropharynx, and cyanosis devel­
ops. Contraction of the jaw muscles may cause biting of the tongue. A 
marked enhancement of sympathetic tone leads to increases in heart 
rate, blood pressure, and pupillary size. After 10–20 s, the tonic phase 
of the seizure typically evolves into the clonic phase, produced by the 
superimposition of periods of muscle relaxation on the tonic muscle 
contraction. The periods of relaxation progressively increase until 
the end of the ictal phase, which usually lasts no more than 1 min. The 
postictal phase is characterized by unresponsiveness, muscular flac­
cidity, and excessive salivation that can cause stridorous breathing and 
partial airway obstruction. Bladder or bowel incontinence may occur 
at this point. Patients gradually regain consciousness over minutes to 
hours, and, during this transition, there is typically a period of postictal 
confusion. Patients subsequently complain of headache, fatigue, and 
muscle ache that can last for many hours. The duration of impaired 
consciousness in the postictal phase can be extremely long (i.e., many 
hours) in patients with prolonged seizures or underlying central ner­
vous system (CNS) disease.
The EEG during the tonic phase of the seizure shows a progressive 
increase in generalized low-voltage fast activity, followed by general­
ized high-amplitude, polyspike discharges. In the clonic phase, the 
high-amplitude activity is typically interrupted by slow waves to create 
a spike-and-slow-wave pattern. Generalized seizures tend to terminate 
synchronously over widespread brain regions. The postictal EEG 
shows diffuse suppression of all cerebral activity, followed by slowing 
that gradually recovers as the patient awakens.
There are several variants of generalized motor seizures, including 
pure tonic and pure clonic seizures. Brief tonic seizures lasting only a 
few seconds are especially noteworthy since they are usually associated 
with specific epilepsy syndromes having mixed seizure phenotypes, 
such as the Lennox-Gastaut syndrome (discussed below).
Atonic Seizures 
Atonic seizures are characterized by sudden 
loss of postural muscle tone lasting 1–2 s. Consciousness is briefly 
impaired, but there is usually no postictal confusion. A very brief sei­
zure may cause only a quick head drop or nodding movement, whereas 
a longer seizure will cause the patient to collapse (hence, the less formal 
term, drop attacks). This can be extremely dangerous because there is 
a substantial risk of direct head injury with the fall. The EEG shows 
brief, generalized spike-and-wave discharges followed immediately 
by diffuse slow waves that correlate with the loss of muscle tone. Like 
pure tonic seizures, atonic seizures are usually seen in association with 
known epilepsy syndromes.
Myoclonic Seizures 
Myoclonus is a sudden and brief muscle 
contraction that may involve one part of the body or the entire body. A 
normal, common physiologic form of myoclonus is the sudden jerking 
movement observed while falling asleep. Pathologic myoclonus is most 
often seen in association with metabolic disorders, degenerative CNS 
diseases, or anoxic brain injury (Chap. 318). Although the distinction 
from other forms of myoclonus is imprecise, myoclonic seizures are 
true epileptic events because they are caused by cortical (vs subcorti­
cal or spinal) dysfunction. The EEG shows bilaterally synchronous 
spike-and-slow-wave discharges immediately prior to the movement 
and muscle artifact associated with the myoclonus. Myoclonic seizures 
usually coexist with other forms of generalized seizures but are the 
predominant feature of juvenile myoclonic epilepsy (JME) (discussed 
below).
Epileptic Spasms 
Epileptic spasms are characterized by a briefly 
sustained flexion or extension of predominantly proximal muscles, 
including truncal muscles. The EEG usually shows hypsarrhythmia, a 
chaotic background of diffuse, large-amplitude slow waves and irregu­
lar, multifocal spikes and sharp waves. During the clinical spasm, there 
is a marked suppression of the EEG background (the “electrodecre­
mental response”). The electromyogram (EMG) also reveals a charac­
teristic rhomboid pattern that may help distinguish spasms from brief 
tonic and myoclonic seizures. Epileptic spasms occur predominantly

in infants and likely result from differences in neuronal function and 
connectivity in the immature versus mature CNS.
EPILEPSY SYNDROMES
Epilepsy syndromes are disorders in which epilepsy is a predominant 
feature, and there is sufficient evidence (e.g., through clinical, EEG, 
radiologic, or genetic observations) to suggest a common underlying 
mechanism. Three important epilepsy syndromes are listed below; addi­
tional examples with a known genetic basis are shown in Table 436-2.
■
■JUVENILE MYOCLONIC EPILEPSY
JME is a generalized seizure disorder of unknown cause that appears 
in early adolescence and is usually characterized by bilateral myoclonic 
jerks that may be single or repetitive. The myoclonic seizures are most 
frequent in the morning after awakening and can be provoked by sleep 
deprivation. Awareness is preserved unless the myoclonus is especially 
severe. Many patients also experience generalized tonic-clonic seizures, 
and up to one-third have absence seizures. Although complete remis­
sion is uncommon, the seizures usually respond well to appropriate 
antiseizure medication. There is often a family history of epilepsy, and 
genetic studies suggest a polygenic cause.
■
■LENNOX-GASTAUT SYNDROME
Lennox-Gastaut syndrome occurs in children and is defined by the 
following triad: (1) multiple seizure types (usually including general­
ized tonic-clonic, atonic, and atypical absence seizures); (2) an EEG 
with slow (<3 Hz) spike-and-wave discharges and a variety of other 
abnormalities; and (3) developmental delay. Lennox-Gastaut syndrome 
is associated with CNS disease or dysfunction from a variety of causes, 
including de novo mutations, developmental abnormalities, perinatal 
hypoxia/ischemia, trauma, infection, and other acquired lesions. The 
multifactorial nature of this syndrome suggests that it is a nonspecific 
response of the brain to diffuse neuronal dysfunction. Unfortunately, 
many patients have a poor prognosis due to the underlying CNS dis­
ease and the physical and psychosocial consequences of severe, poorly 
controlled epilepsy. Implanted neurostimulation devices (discussed 
below) are now being investigated for treatment of seizures in LennoxGastaut syndrome and other generalized epilepsies.
■
■MESIAL TEMPORAL LOBE EPILEPSY SYNDROME
Mesial temporal lobe epilepsy (MTLE) is the most common syndrome 
associated with focal seizures with impairment of consciousness and 
is an example of an epilepsy syndrome with distinctive clinical, EEG, 
and pathologic features (Table 436-3). High-resolution magnetic 
resonance imaging (MRI) can detect the characteristic hippocampal 
sclerosis that appears to be essential in the pathophysiology of MTLE 
for many patients (Fig. 436-1). Recognition of this syndrome is espe­
cially important because it tends to be refractory to treatment with 
anticonvulsants but responds well to surgical intervention. Advances in 
the understanding of basic mechanisms of epilepsy have come through 
studies of experimental models of MTLE, discussed below.
THE CAUSES OF SEIZURES AND EPILEPSY
Seizures are a result of a shift in the normal balance of excitation and 
inhibition within the CNS. Given the numerous properties that control 
neuronal excitability, it is not surprising that there are many ways to 
perturb this normal balance and, therefore, many different causes of 
both seizures and epilepsy. Three clinical observations emphasize how 
a variety of factors determine why certain conditions may cause sei­
zures or epilepsy in a given patient.
1.	 The normal brain can have a seizure under the appropriate circum­
stances, and there are differences between individuals in the suscepti­
bility or threshold for seizures. For example, seizures may be induced 
by high fever in children who are otherwise normal and who never 
develop other neurologic problems, including epilepsy. However, 
febrile seizures occur only in a relatively small proportion of chil­
dren. This implies there are various underlying endogenous factors 
that influence the threshold for having a seizure. Some of these fac­
tors are genetic, as a family history of epilepsy has a clear influence 

on the likelihood of seizures occurring in otherwise normal indi­
viduals. Normal development also plays an important role, because 
the brain appears to have different seizure thresholds at different 
maturational stages.
2.	 There are a variety of conditions that have an extremely high likeli­

hood of resulting in a chronic seizure disorder. One of the best exam­
ples of this is severe, penetrating head trauma, which is associated 
with up to a 45% risk of subsequent epilepsy. The high propensity 
for severe traumatic brain injury to lead to epilepsy suggests that the 
injury results in a long-lasting pathologic change in the CNS that 
transforms a presumably normal neuronal network into one that is 
abnormally hyperexcitable. This process is known as epileptogenesis, 
and the specific changes that result in a lowered seizure threshold 
can be considered epileptogenic factors. Other processes associated 
with epileptogenesis include stroke, infection, neurodegeneration, 
and abnormalities of CNS development.
3.	 Seizures are episodic. Seizures occur intermittently, and, depending 
CHAPTER 436
on the underlying cause, people with epilepsy may feel completely 
normal for months or years between seizures. This implies there are 
important provocative or precipitating factors that induce seizures in 
people with epilepsy. Similarly, precipitating factors are responsible 
for causing the single seizure in someone without epilepsy. Pre­
cipitants include those due to intrinsic physiologic processes, such 
as psychological or physical stress, sleep deprivation, or hormonal 
changes. They also include exogenous factors such as exposure 
to toxic substances, certain medications, and intermittent photic 
stimulation from strobe lights or some video games.
Seizures and Epilepsy
These observations emphasize the concept that the many causes of 
seizures and epilepsy result from a dynamic interplay between endoge­
nous factors, epileptogenic factors, and precipitating factors. The potential 
role of each needs to be considered when determining the appropriate 
management of a patient with seizures. For example, the identification 
of predisposing factors (e.g., family history of epilepsy) in a patient 
with febrile seizures may increase the necessity for closer follow-up 
and a more aggressive diagnostic evaluation. Finding an epileptogenic 
lesion may help in the estimation of seizure recurrence and duration of 
therapy. Removal or modification of a precipitating factor may be an 
effective and safer method for preventing further seizures than the pro­
phylactic use of anticonvulsant drugs. An emerging concept holds that 
underlying seizure risk itself fluctuates cyclically, potentially explaining 
why the same precipitating factor (e.g., sleep deprivation) can be well 
tolerated on some occasions but result in a seizure on others.
■
■CAUSES ACCORDING TO AGE
In practice, it is useful to consider the etiologies of seizures based on 
the age of the patient, because age is one of the most important factors 
determining both the incidence and the likely causes of seizures or 
epilepsy (Table 436-4). During the neonatal period and early infancy, 
potential causes include hypoxic-ischemic encephalopathy, trauma, 
CNS infection, congenital CNS abnormalities, and metabolic disorders. 
Babies born to mothers using neurotoxic drugs such as cocaine, heroin, 
or ethanol are susceptible to drug-withdrawal seizures in the first few 
days after delivery. Hypoglycemia and hypocalcemia, which can occur 
as secondary complications of perinatal injury, are also causes of early 
postnatal seizures. Seizures due to inborn errors of metabolism usu­
ally present once regular feeding begins, typically 2–3 days after birth. 
Pyridoxine (vitamin B6) deficiency, an important cause of neonatal 
seizures, is treated with pyridoxine replacement. Idiopathic or familial 
forms of benign neonatal seizures are also seen during this time.
The most common seizures arising in late infancy and early child­
hood are febrile seizures, which are seizures associated with fevers but 
without evidence of CNS infection or other defined causes. The overall 
prevalence is 3–5% and even higher in some parts of the world such as 
Asia. Patients often have a family history of febrile seizures or epilepsy. 
Febrile seizures usually occur between 3 months and 5 years of age and 
have a peak incidence between 18 and 24 months. The typical scenario 
is a child who has a generalized, tonic-clonic seizure during a febrile 
illness in the setting of a common childhood infection such as otitis

TABLE 436-2  Examples of Genes Associated with Epilepsy Syndromesa
GENE (LOCUS)
FUNCTION OF GENE
CLINICAL SYNDROME
COMMENTS
CHRNA4 (20q13.2)
Nicotinic acetylcholine receptor 
subunit; mutations cause alterations in 
Ca2+ flux through the receptor; this may 
reduce the amount of GABA release in 
presynaptic terminals
Sleep-related hypermotor epilepsy (SHE); 
childhood onset; brief, nighttime seizures with 
prominent motor movements; often misdiagnosed 
as primary sleep disorder
KCNQ2 (20q13.3)
Voltage-gated potassium channel 
subunits; mutation in pore regions may 
cause a 20–40% reduction of potassium 
currents, which will lead to impaired 
repolarization
Self-limited familial neonatal epilepsy; autosomal 
dominant inheritance; onset in first week of life 
in infants who are otherwise normal; remission 
usually within weeks to months; long-term 
epilepsy in 10–15%
SCN1A (2q24.3)
α-Subunit of a voltage-gated sodium 
channel; numerous mutations affecting 
sodium currents that cause either 
gain or loss of function; network 
effects appear related to expression in 
excitatory or inhibitory cells
Very common cause of Dravet syndrome (severe 
myoclonic epilepsy of infancy) and some cases 
of Lennox-Gastaut syndrome. Also found in other 
syndromes, including genetic epilepsy with 
febrile seizures plus (GEFS+); autosomal dominant 
inheritance; presents with febrile seizures at 
median 1 year, which may persist >6 years, then 
variable seizure types not associated with fever
PART 13
Neurologic Disorders
LGI1 (10q24)
Leucine-rich glioma-inactivated 1 
gene; previous evidence for role in 
glial tumor progression; recent studies 
suggest an influence in the postnatal 
development of glutamatergic circuits in 
the hippocampus
Autosomal dominant epilepsy with auditory 
features (ADEAF); a form of lateral temporal lobe 
epilepsy with auditory symptoms or aphasia as a 
major focal seizure manifestation; age of onset 
usually between 10 and 25 years
DEPDC5 (22q12.2)
Disheveled, Egl-10, and pleckstrin 
domain containing protein 5; exerts 
an inhibitory effect on mammalian 
target of rapamycin (mTOR)–mediated 
processes, such as cell growth and 
proliferation
Autosomal dominant familial focal epilepsy 
with variable foci (FFEVF); family members 
have seizures originating from different cortical 
regions; neuroimaging usually normal but may 
harbor subtle malformations; recent studies also 
suggest association with benign epilepsy with 
centrotemporal spikes
GRIN2A (16p13.2)
Encodes NMDA receptor (NMDAR) 
subunit GluN2A
Spectrum of phenotypes ranging from benign 
childhood epilepsy with centrotemporal spikes 
(BECTS) to epilepsy-aphasia syndromes such 
as Landau-Kleffner syndrome (LKS) and other 
epileptic encephalopathies
CDKL-5 (Xp22.13)
Encodes cyclin-dependent kinase-like 
5 (CDKL-5), a serine-threonine kinase 
involved in neural maturation and 
synaptogenesis
CDKL-5 deficiency disorder (CDD) results from 
pathogenic mutation in the CDKL5 gene that 
causes absence or nonfunctional CDKL-5 
protein. CDD is a severe developmental epileptic 
encephalopathy characterized by very-earlyonset seizures. X-linked, affects females more 
than males
SLC2A1 (1p34.2)
Glucose transporter protein type 1 
(GLUT1); transports glucose across the 
blood-brain barrier
Loss of function of one allele leads to GLUT1 
deficiency, a severe metabolic encephalopathy 
including intractable epilepsy, complex motor 
dysfunction, and intellectual disability. Milder 
GLUT1 deficiency causes a combination of 
movement disorder (paroxysmal exertional 
dyskinesia) and epilepsy with prominent absence 
seizures, though intellect is often normal
CSTB (21q22.3)
Cystatin B, a noncaspase cysteine 
protease inhibitor; normal protein may 
block neuronal apoptosis by inhibiting 
caspases directly or indirectly (via 
cathepsins), or controlling proteolysis
Progressive myoclonus epilepsy (PME) 
(Unverricht-Lundborg disease); autosomal 
recessive inheritance; age of onset between 6 
and 15 years, myoclonic seizures, ataxia, and 
progressive cognitive decline; brain shows 
neuronal degeneration
EPM2A (6q24)
Laforin, a protein tyrosine phosphatase 
(PTP); involved in glycogen metabolism 
and may have antiapoptotic activity
Progressive myoclonus epilepsy (Lafora’s 
disease); autosomal recessive inheritance; age 
of onset 6–19 years, death within 10 years; brain 
degeneration associated with polyglucosan 
intracellular inclusion bodies in numerous organs
Doublecortin 
(Xq21-24)
Doublecortin, expressed primarily 
in frontal lobes; directly regulates 
microtubule polymerization and 
bundling
Classic lissencephaly associated with severe 
mental retardation and seizures in males; 
subcortical band heterotopia with more subtle 
findings in females (presumably due to random X 
inactivation); X-linked dominant
aThe first seven syndromes listed in the table (SHE, benign familial neonatal convulsions, GEFS+, ADEAF, FFEVF, BECTS, LKS, CDD) are examples of genetic epilepsies 
associated with identified gene mutations. The last three syndromes are examples of the numerous Mendelian disorders in which seizures are one part of the phenotype.
Abbreviation: GABA, γ-aminobutyric acid.

Rare; first identified in a large Australian family; 
other families found to have mutations in CHRNA2 
or CHRNB2, and some families appear to have 
mutations at other loci
Rare; other families found to have mutations 
in KCNQ3; sequence and functional homology 
to KCNQ1, mutations of which cause long QT 
syndrome and a cardiac-auditory syndrome
Incidence of Dravet syndrome is 1 in 20,000 births, 
and de novo SCN1A mutation is found in ~80% of 
cases. Incidence in GEFS+ uncertain; identified 
in other families with mutations in other sodium 
channel subunits (SCN2B and SCN2A) and 
GABAA receptor subunit (GABRG2 and GABRA1); 
significant phenotypic heterogeneity within same 
family, including members with febrile seizures 
only. Avoid sodium channel–blocking antiseizure 
medications
Mutations found in up to 50% of families 
containing two or more subjects with focal 
epilepsy with ictal auditory symptoms, suggesting 
that at least one other gene may underlie this 
syndrome
Study of families with the limited number of 
affected members revealed mutations in ~12% of 
families; thus, may be a relatively common cause 
of lesion-negative focal epilepsies with suspected 
genetic basis. Also associated with mutations in 
the GATOR1 genes NPRL2 and NPRL3
Complex inheritance is implicated, and studies 
have shown considerable inter- and intrafamilial 
phenotypic variability and incomplete penetrance
Ganaxolone is a recently approved antiseizure 
drug that has been shown to significantly reduce 
CDD-associated seizures
Milder forms of epilepsy due to GLUT1 deficiency 
may respond to standard antiseizure medications, 
but the gold standard treatment for refractory 
forms is the ketogenic diet, which bypasses 
defective glucose transport to provide an 
alternative energy supply to the brain
Overall rare, but relatively common in Finland and 
western Mediterranean (>1 in 20,000); precise role 
of cystatin B in human disease unknown, although 
mice with null mutations of cystatin B have similar 
syndrome
Most common PME in southern Europe, Middle 
East, northern Africa, and Indian subcontinent; 
genetic heterogeneity; unknown whether seizure 
phenotype due to degeneration or direct effects of 
abnormal laforin expression
Relatively rare but of uncertain incidence; recent 
increased ascertainment due to improved imaging 
techniques; relationship between migration defect 
and seizure phenotype unknown

TABLE 436-3  Characteristics of the Mesial Temporal Lobe 

Epilepsy Syndrome
History
History of febrile seizures
Rare generalized seizures
Family history of epilepsy
Seizures may remit and reappear
Early onset
Seizures often intractable
Clinical Observations
Aura common
Postictal disorientation
Behavioral arrest/stare
Memory loss
Complex automatisms
Dysphasia (with focus in dominant 
hemisphere)
Unilateral posturing
 
Laboratory Studies
Unilateral or bilateral anterior temporal spikes on EEG
Hypometabolism on interictal PET
Hyperperfusion on ictal SPECT
Material-specific memory deficits on intracarotid amobarbital (Wada) test
MRI Findings
Small hippocampus with increased signal on T2-weighted sequences and loss of 
trilaminar hippocampal internal architecture
Small temporal lobe
Enlarged temporal horn
Pathologic Findings
Highly selective loss of specific cell populations within hippocampus in most 
cases, granule cell layer dispersion, gliosis
Abbreviations: EEG, electroencephalogram; MRI, magnetic resonance imaging; 
PET, positron emission tomography; SPECT, single-photon emission computed 
tomography.
media, respiratory infection, or gastroenteritis. The seizure is likely to 
occur during the rising phase of the temperature curve (i.e., during the 
first day) rather than well into the course of the illness. A simple febrile 
seizure is a single, isolated event, brief, and symmetric in appearance. 
Complex febrile seizures are characterized by repeated seizure activity, 
a duration >15 minutes, or by focal features. Approximately one-third 
FIGURE 436-1  Mesial temporal lobe epilepsy. The electroencephalogram and 
seizure semiology were consistent with a left temporal lobe focus. This coronal 
high-resolution T2-weighted fast spin echo magnetic resonance image obtained at 
3 Tesla is at the level of the hippocampal bodies and shows abnormal high signal 
intensity, blurring of internal laminar architecture, and reduced size of the left 
hippocampus (arrow) relative to the right. This triad of imaging findings is consistent 
with hippocampal sclerosis.

TABLE 436-4  Causes of Seizures
Neonates (<1 month)
Perinatal hypoxia and ischemia
Intracranial hemorrhage and trauma
CNS infection
Metabolic disturbances (hypoglycemia, hypocalcemia, 
hypomagnesemia, pyridoxine deficiency)
Drug withdrawal
Developmental disorders
Genetic disorders
Infants and children 
(>1 month and 

<12 years)
Febrile seizures
Genetic disorders (metabolic, degenerative, primary 
epilepsy syndromes)
CNS infection
Developmental disorders
Trauma
CHAPTER 436
Adolescents 

(12–18 years)
Trauma
Genetic disorders
Infection
Illicit drug use
Brain tumor
Seizures and Epilepsy
Young adults 

(18–35 years)
Trauma
Alcohol withdrawal
Illicit drug use
Brain tumor
Autoantibodies
Older adults 

(>35 years)
Cerebrovascular disease
Brain tumor
Alcohol withdrawal
Metabolic disorders (uremia, hepatic failure, electrolyte 
abnormalities, hypoglycemia, hyperglycemia)
Alzheimer’s disease and other degenerative CNS 
diseases
Autoantibodies
Abbreviation: CNS, central nervous system.
of patients with febrile seizures will have a recurrence, but <10% have 
three or more episodes. Recurrences are much more likely when the 
febrile seizure occurs in the first year of life. Simple febrile seizures 
are not associated with increased risk of developing epilepsy, while 
complex febrile seizures have a risk of 2–5%; other risk factors include 
the presence of preexisting neurologic deficits and a family history of 
nonfebrile seizures.
Childhood marks the age at which many of the well-defined epilepsy 
syndromes present. Some children who are otherwise normal develop 
idiopathic, generalized tonic-clonic seizures without other features that 
fit into specific syndromes. Temporal lobe epilepsy usually presents in 
childhood and may be related to mesial temporal lobe sclerosis (as part 
of the MTLE syndrome) or other focal abnormalities, such as cortical 
dysgenesis. Other types of focal seizures, including those that evolve 
into generalized seizures, may be late manifestations of a developmen­
tal disorder, an acquired lesion such as head trauma, CNS infection 
(e.g., viral encephalitis), or a CNS tumor.
The period of adolescence and early adulthood is one of transition 
during which the idiopathic or genetically based epilepsy syndromes, 
including JME and juvenile absence epilepsy, become less common, 
while epilepsies secondary to acquired CNS lesions begin to predomi­
nate. Seizures that arise in patients in this age range may be associated 
with head trauma, CNS infections (including parasitic infections such 
as cysticercosis), brain tumors, congenital CNS abnormalities, illicit 
drug use, or alcohol withdrawal. Autoantibodies directed against CNS 
antigens such as potassium channels or glutamate receptors are a cause 
of epilepsy that also begins to appear in this age group (although cases 
of autoimmunity are being increasingly described in the pediatric pop­
ulation), including patients without an identifiable cancer. This etiol­
ogy should be suspected when a previously normal individual presents

with fulminant seizures, especially when combined with psychiatric 
symptoms and changes in cognitive function.

Head trauma is a common cause of epilepsy in adolescents and 
adults. The head injury can be caused by a variety of mechanisms, 
and the likelihood of developing epilepsy is strongly correlated with 
the severity of the injury. A patient with a penetrating head wound, 
depressed skull fracture, intracranial hemorrhage, or prolonged post­
traumatic coma or amnesia has a 30–50% risk of developing epilepsy, 
whereas a patient with a closed head injury and cerebral contusion 
has a 5–25% risk. Recurrent seizures usually develop within 1 year 
after head trauma, although intervals of >10 years are well known. 
In controlled studies, mild head injury, defined as a concussion with 
amnesia or loss of consciousness of <30 min, was found to be associ­
ated with only a slightly increased likelihood of epilepsy. Nonetheless, 
some patients experience focal seizures within hours or days of a mild 
head injury and subsequently develop chronic seizures of the same 
type; such cases may represent rare examples of epilepsy resulting from 
mild head injury.
PART 13
Neurologic Disorders
The causes of seizures in older adults include cerebrovascular 
disease, trauma (including subdural hematoma), CNS tumors, and 
degenerative diseases. Cerebrovascular disease may account for ~50% 
of new cases of epilepsy in patients >65 years. Acute poststroke seizures 
(i.e., occurring within the first 24 h after acute stroke) are more com­
mon after hemorrhagic strokes compared to ischemic strokes. Chronic 
seizures typically appear months to years after the initial event and are 
associated with all forms of stroke.
Metabolic disturbances such as electrolyte imbalance, hypo- or 
hyperglycemia, renal failure, and hepatic failure may cause seizures 
at any age. Similarly, endocrine disorders, hematologic disorders, vas­
culitides, and many other systemic diseases may cause seizures over a 
broad age range. Many medications and abused substances can precipi­
tate seizures as well (Table 436-5).
BASIC MECHANISMS
■
■MECHANISMS OF SEIZURE INITIATION AND 
PROPAGATION
Focal seizure activity can begin in a discrete region of cortex and 
then slowly invade the surrounding regions. The hallmark of an 
established seizure is typically an electrographic “spike” due to intense 
near-simultaneous firing of many local excitatory neurons, resulting 
in an apparent hypersynchronization of the excitatory bursts across a 
relatively large cortical region. The bursting activity in individual neu­
rons (the “paroxysmal depolarization shift”) is caused by a relatively 
long-lasting depolarization of the neuronal membrane due to influx 
of extracellular calcium (Ca2+), which leads to the opening of voltagedependent sodium (Na+) channels, influx of Na+, and generation of 
repetitive action potentials. This is followed by a hyperpolarizing 
afterpotential mediated by γ-aminobutyric acid (GABA) receptors or 
potassium (K+) channels, depending on the cell type. The synchronized 
bursts from enough neurons result in summation of field potentials 
producing a spike discharge on the EEG.
The spreading seizure wavefront is thought to slow and ultimately 
halt by intact hyperpolarization and a “surround” inhibition created by 
feedforward activation of inhibitory neurons. With sufficient activation, 
there is a recruitment of surrounding neurons via a number of synaptic 
and nonsynaptic mechanisms, including (1) an increase in extracel­
lular K+, which blunts hyperpolarization and depolarizes neighboring 
neurons; (2) accumulation of Ca2+ in presynaptic terminals, leading to 
enhanced neurotransmitter release; (3) depolarization-induced activa­
tion of the N-methyl-d-aspartate (NMDA) subtype of the excitatory 
amino acid receptor, which causes additional Ca2+ influx and neuronal 
activation; and (4) ephaptic interactions related to changes in tissue 
osmolarity and cell swelling. The recruitment of a sufficient number of 
neurons leads to the propagation of excitatory currents into contiguous 
areas via local cortical connections and to more distant areas via long 
commissural pathways such as the corpus callosum.
Many factors control neuronal excitability, and thus, there are 
many potential mechanisms for altering a neuron’s propensity to have 

TABLE 436-5  Drugs and Other Substances That Can Cause Seizures
Alkylating agents (e.g., busulfan, chlorambucil)
Antimalarials (chloroquine, mefloquine)
Antimicrobials/antivirals
  β-Lactam and related compounds
  Quinolones
  Acyclovir
  Isoniazid
  Ganciclovir
Anesthetics and analgesics
  Meperidine
  Fentanyl
  Tramadol
  Local anesthetics
Dietary supplements
  Ephedra (ma huang)
  Gingko
Immunomodulatory drugs
  Cyclosporine
  OKT3 (monoclonal antibodies to T cells)
  Tacrolimus
  Interferons
Psychotropics
  Antidepressants (e.g., bupropion)
  Antipsychotics (e.g., clozapine)
  Lithium
Radiographic contrast agents
Drug withdrawal
  Alcohol
  Baclofen
  Barbiturates (short-acting)
  Benzodiazepines (short-acting)
  Zolpidem
Drugs of abuse
  Amphetamine
  Cocaine
  Phencyclidine
  Methylphenidate
Flumazenila
aIn benzodiazepine-dependent patients.
bursting activity. Mechanisms intrinsic to the neuron include changes 
in the conductance of ion channels, response characteristics of mem­
brane receptors, cytoplasmic buffering, second-messenger systems, 
and protein expression as determined by gene transcription, transla­
tion, and posttranslational modification. Mechanisms extrinsic to the 
neuron include changes in the amount or type of neurotransmitters 
present at the synapse, modulation of receptors by extracellular ions 
and other molecules, and temporal and spatial properties of synaptic 
and nonsynaptic input. Glial cells, such as astrocytes and oligodendro­
cytes, have an important role in many of these mechanisms as well.
Certain recognized causes of seizures are explained by these mecha­
nisms. For example, accidental ingestion of domoic acid, an analogue 
of glutamate (the principal excitatory neurotransmitter in the brain) 
produced by naturally occurring microscopic algae, causes profound 
seizures via direct activation of excitatory amino acid receptors 
throughout the CNS. Penicillin, which can lower the seizure threshold 
in humans and is a potent convulsant in experimental models, reduces 
inhibition by antagonizing the effects of GABA at its receptor. The basic 
mechanisms of other precipitating factors of seizures, such as sleep 
deprivation, fever, alcohol withdrawal, hypoxia, and infection, are not 
as well understood but presumably involve analogous perturbations in

neuronal excitability. Similarly, the endogenous factors that determine 
an individual’s seizure threshold may relate to these properties as well.
Knowledge of the mechanisms responsible for initiation and propa­
gation of most generalized seizures (including tonic-clonic, myoclonic, 
and atonic types) remains rudimentary and reflects the limited under­
standing of the connectivity of the brain at a systems level. Much 
more is understood about the origin of generalized spike-and-wave 
discharges in absence seizures. These appear to be related to oscilla­
tory rhythms normally generated during sleep by circuits connecting 
the thalamus and cortex. This oscillatory behavior involves an interac­
tion between GABAB receptors, T-type Ca2+ channels, and K+ channels 
located within the thalamus. Pharmacologic studies indicate that mod­
ulation of these receptors and channels can induce absence seizures, 
and there is good evidence that the genetic forms of absence epilepsy 
may be associated with mutations of components of this system.
■
■MECHANISMS OF EPILEPTOGENESIS
Epileptogenesis refers to the transformation of a normal neuronal 
network into one that is chronically hyperexcitable. There is often a 
delay of months to years between an initial CNS injury such as trauma, 
stroke, or infection and the first clinically evident seizure. The injury 
appears to initiate a process that gradually lowers the seizure threshold 
in the affected region until a spontaneous seizure occurs. In many 
genetic and idiopathic forms of epilepsy, epileptogenesis is presumably 
determined by developmentally regulated events.
Pathologic studies of the hippocampus from patients with temporal 
lobe epilepsy suggest that some forms of epileptogenesis are related to 
structural changes in neuronal networks. For example, many patients 
with MTLE have a highly selective loss of neurons that normally con­
tribute to inhibition of the main excitatory neurons within the dentate 
gyrus. There is also evidence that, in response to the loss of neurons, 
there is reorganization of surviving neurons in a way that affects the 
excitability of the network. Some of these changes can be seen in experi­
mental models of prolonged electrical seizures or traumatic brain injury. 
Thus, an initial injury such as head injury may lead to a focal region of 
structural change that causes local hyperexcitability. The local hyperex­
citability leads to further structural changes that evolve over time until 
the focal lesion produces clinically evident seizures. Similar models 
have provided strong evidence for long-term alterations in intrinsic, bio­
chemical properties of cells within the network such as chronic changes 
in glutamate or GABA receptor function. Induction of inflammatory 
cascades may be a critical factor in these processes as well.
■
■GENETIC CAUSES OF EPILEPSY
An area of ongoing progress in epilepsy research has been the iden­
tification of genetic mutations associated with a variety of epilepsy 
syndromes (Table 436-2). Although most of the mutations identified to 
date cause rare forms of epilepsy, their discovery has led to extremely 
important conceptual advances. For example, it appears that many 
of the inherited epilepsies are due to mutations affecting ion channel 
function. These syndromes are therefore part of the larger group of 
channelopathies causing paroxysmal disorders such as cardiac arrhyth­
mias, episodic ataxia, periodic weakness, and familial hemiplegic 
migraine. Other gene mutations are proving to be associated with path­
ways influencing CNS development, synaptic physiology, or neuronal 
homeostasis. De novo and somatic mutations may explain a significant 
proportion of these syndromes, especially those with onset in early 
childhood. A current challenge is to identify the multiple susceptibility 
genes that underlie the more common forms of idiopathic epilepsies. 
Ion channel mutations and copy number variants may be pathogenic 
in a subset of these patients.
■
■MECHANISMS OF ACTION OF ANTISEIZURE 
DRUGS
Antiseizure drugs appear to act primarily by blocking the initiation or 
spread of seizures. This occurs through a variety of mechanisms that 
modify the activity of ion channels or neurotransmitters, and in most 
cases, the drugs have pleiotropic effects. The mechanisms include inhi­
bition of Na+-dependent action potentials in a frequency-dependent 

manner (e.g., phenytoin, carbamazepine, lamotrigine, topiramate, 
zonisamide, lacosamide, rufinamide, cenobamate), inhibition of 
voltage-gated Ca2+ channels (phenytoin, gabapentin, pregabalin), facili­
tating the opening of potassium channels (ezogabine), attenuation of 
glutamate activity (lamotrigine, topiramate, felbamate, perampanel), 
potentiation of GABA receptor function (benzodiazepines, barbitu­
rates), increase in the availability of GABA (valproic acid, gabapentin, 
tiagabine), and modulation of release of synaptic vesicles (levetirace­
tam, brivaracetam). Two of the effective drugs for absence seizures, 
ethosuximide and valproic acid, probably act by inhibiting T-type Ca2+ 
channels in thalamic neurons. Cannabidiol (CBD), a derivative of can­
nabis plants, is effective for reducing seizures in children with Dravet 
syndrome, Lennox-Gastaut syndrome, and tuberous sclerosis but does 
not act through endogenous cannabinoid receptors. Rather, CBD has a 
multimodal mechanism of action involving modulation of intracellular 
calcium via G protein–coupled receptor 55, extracellular calcium influx 
via transient receptor potential vanilloid type 1 (TRPV1) channels, and 
adenosine-mediated signaling. Fenfluramine is an amphetamine deriv­
ative that probably exerts its antiseizure effect by inhibiting serotonin 
reuptake and increasing extracellular levels. Ganaxolone is a synthetic 
analogue of allopregnanolone and an allosteric modulator of GABAA 
receptors that reduces seizures associated with cyclin-dependent 
kinase-like 5 (CDKL-5) deficiency disorder.

CHAPTER 436
Seizures and Epilepsy
In contrast to the relatively large number of antiseizure drugs that 
can attenuate seizure activity, there are currently no drugs known to 
prevent the formation of a seizure focus following CNS injury. Eventual 
development of such “antiepileptogenic” drugs will provide means of 
preventing the emergence of epilepsy following injuries such as head 
trauma, stroke, and CNS infection.
APPROACH TO THE PATIENT
Seizure
When a patient presents shortly after a seizure, the first priorities 
are attention to vital signs, respiratory and cardiovascular support, 
and treatment of seizures if they resume (see “Treatment: Seizures 
and Epilepsy”). Life-threatening conditions such as CNS infection, 
metabolic derangement, or drug toxicity must be recognized and 
managed appropriately.
When the patient is not acutely ill, the evaluation will initially 
focus on whether there is a history of earlier seizures (Fig. 436-2). 
If this is the first seizure, then the emphasis will be to (1) establish 
whether the reported episode was a seizure rather than another 
paroxysmal event, (2) determine the cause of the seizure by identi­
fying risk factors and precipitating events, and (3) decide whether 
antiseizure drug therapy is required in addition to treatment for any 
underlying illness.
In the patient with prior seizures or a known history of epilepsy, 
the evaluation is directed toward (1) identification of the underly­
ing cause and precipitating factors, and (2) determination of the 
adequacy of the patient’s current therapy.
■
■HISTORY AND EXAMINATION
The first goal is to determine whether the event was truly a seizure. A 
detailed history is essential, because in many cases the diagnosis of a 
seizure is based solely on clinical grounds—the examination and labora­
tory studies are often normal. Questions should focus on the symptoms 
before, during, and after the episode to differentiate a seizure from 
other paroxysmal events (see “Differential Diagnosis of Seizures” 
below). Seizures frequently occur out-of-hospital, and the patient may 
be unaware of the ictal and immediate postictal phases; thus, witnesses 
to the event should be interviewed carefully.
The history should also focus on risk factors and predisposing 
events. Clues for a predisposition to seizures include a history of febrile 
seizures, a family history of seizures, and, of particular importance, 
earlier auras or brief seizures not recognized as such. Epileptogenic 
factors such as prior head trauma, stroke, tumor, or CNS infection 
should be identified. In children, a careful assessment of developmental

Adult Patient with a Seizure
History
Physical examination
Exclude
 
Syncope
 
Transient ischemic attack
 
Migraine
 
Acute psychosis
 
Other causes of episodic cerebral dysfunction
History of epilepsy; currently treated
with antiseizure drugs
PART 13
Neurologic Disorders
Assess: adequacy of antiseizure drug therapy
  Side effects
  Serum levels
Consider
 CBC
 Electrolytes, calcium, magnesium
 Serum glucose
 Liver and renal function tests
 Urinalysis
 Toxicology screen
Normal
Abnormal or change in
neurologic examination
  Treat identifiable
  metabolic abnormalities
Assess cause of
  neurologic change
Therapeutic
antiseizure
drug levels
Subtherapeutic
antiseizure
drug levels
Increase antiseizure drug
therapy to maximum
tolerated dose; consider
alternative antiepileptic
drugs
Appropriate
increase or
resumption
of dose
Yes
No
Consider: Mass lesion; stroke; CNS infection;
trauma; degenerative disease
Treat underlying disorder
Consider: Antiseizure drug therapy
FIGURE 436-2  Evaluation of the adult patient with a seizure. CBC, complete blood count; CNS, central nervous system; CT, computed tomography; EEG, electroencephalogram; 
MRI, magnetic resonance imaging.
milestones may provide evidence for underlying CNS disease. Precipi­
tating factors such as sleep deprivation, systemic diseases, electrolyte or 
metabolic derangements, acute infection, drugs that lower the seizure 
threshold (Table 436-5), or alcohol or illicit drug use should also be 
identified.
The general physical examination includes a search for signs of 
infection or systemic illness. Careful examination of the skin may 

No history of epilepsy
Laboratory studies
  CBC
  Electrolytes, calcium, magnesium
  Serum glucose
  Liver and renal function tests
  Urinalysis
  Toxicology screen
Negative
metabolic screen
Positive metabolic screen
or symptoms/signs
suggesting a metabolic
or infectious disorder
MRI scan
and EEG
Further workup
  Lumbar puncture
  Cultures
  Endocrine studies
  CT
  MRI if focal
   features present
Focal features of 
seizures
Focal abnormalities
on clinical or lab
examination
Other evidence of
neurologic
dysfunction
Treat underlying
metabolic abnormality
Consider: Antiseizure drug therapy
Idiopathic seizures
Consider: Antiseizure drug therapy
reveal signs of neurocutaneous disorders, such as tuberous sclerosis 
or neurofibromatosis, or chronic liver or renal disease. A finding of 
organomegaly may indicate a metabolic storage disease, and limb 
asymmetry may provide a clue to brain injury early in development. 
Signs of head trauma and use of alcohol or illicit drugs should be 
sought. Auscultation of the heart and carotid arteries may identify an 
abnormality that predisposes to cerebrovascular disease.

All patients require a complete neurologic examination, with par­
ticular emphasis on eliciting signs of cerebral hemispheric disease 
(Chap. 433). Careful assessment of mental status (including memory, 
language function, and abstract thinking) may suggest lesions in the 
anterior frontal, parietal, or temporal lobes. Testing of visual fields 
will help screen for lesions in the optic pathways and occipital lobes. 
Screening tests of motor function such as pronator drift, deep tendon 
reflexes, gait, and coordination may suggest lesions in motor (frontal) 
cortex, and cortical sensory testing (e.g., double simultaneous stimula­
tion) may detect lesions in the parietal cortex.
■
■LABORATORY STUDIES
Routine blood studies are indicated to identify the more common 
metabolic causes of seizures such as abnormalities in electrolytes, glu­
cose, calcium, or magnesium, and hepatic or renal disease. A screen for 
toxins in blood and urine should also be obtained from all patients in 
appropriate risk groups, especially when no clear precipitating factor 
has been identified. A lumbar puncture is indicated if there is any sus­
picion of meningitis or encephalitis, and it is mandatory in all patients 
infected with HIV, even in the absence of symptoms or signs suggesting 
infection. Testing for autoantibodies in the serum and cerebrospinal 
fluid (CSF) should be considered in patients presenting with fulminant 
onset of epilepsy associated with other abnormalities such as psychiat­
ric symptoms or cognitive disturbances (Chap. 99).
■
■ELECTROPHYSIOLOGIC STUDIES
The electrical activity of the brain (the EEG) is easily recorded from 
electrodes placed on the scalp. The potential difference between pairs 
of electrodes on the scalp (bipolar derivation) or between individual 
scalp electrodes and a relatively inactive common reference point (ref­
erential derivation) is amplified and displayed on a computer monitor. 
Digital systems allow the EEG to be displayed with any desired format 
and to be manipulated for more detailed analysis, and they also enable 
computational algorithms that can automatically detect certain abnor­
malities. The characteristics of the nor­
mal EEG depend on the patient’s age and 
level of arousal. The rhythmic activity 
normally recorded represents the post­
synaptic potentials of vertically oriented 
pyramidal cells of the cerebral cortex 
and is characterized by its frequency. In 
normal awake adults lying quietly with 
the eyes closed, an 8- to 13-Hz alpha 
rhythm is seen posteriorly in the EEG, 
intermixed with a variable amount of 
generalized faster (beta) activity (>13 
Hz); the alpha rhythm is attenuated when 
the eyes are opened (Fig. 436-3). During 
drowsiness and light sleep, slower activity 
in the theta (4–7 Hz) and delta (<4 Hz) 
ranges becomes more conspicuous.
Eyes open
Fp1-F3
F3-C3
C3-P3
P3-O1
Fp2-F4
F4-C4
C4-P4
P4-O2
A
B
F3-A1
C3-A1
All patients who have a possible sei­
zure disorder should be evaluated with 
an EEG as soon as possible. In the evalu­
ation of a patient with suspected epilepsy, 
the presence of electrographic seizure 
activity during the clinical event (i.e., 
abnormal, repetitive, rhythmic activity 
having a discrete onset and termination) 
clearly establishes the diagnosis. The 
EEG is always abnormal during general­
ized tonic-clonic seizures. The absence 
of electrographic seizure activity does 
not exclude a seizure disorder, however, 
because focal seizures may originate from 
a region of the cortex that cannot be 
detected by standard scalp electrodes. 
Because seizures are typically infrequent 
and unpredictable, it is often not possible 
P3-A1
O1-A1
F4-A2
C4-A2
P4-A2
O2-A2
C
D
FIGURE 436-3  Electroencephalograms. A. Normal electroencephalogram (EEG) showing a posteriorly situated 9-Hz 
alpha rhythm that attenuates with eye opening. B. Abnormal EEG showing irregular diffuse slow activity in an obtunded 
patient with encephalitis. C. Irregular slow activity in the right central region, on a diffusely slowed background, in a 
patient with a right parietal glioma. D. Periodic complexes occurring once every second in a patient with CreutzfeldtJakob disease. Horizontal calibration: 1 s; vertical calibration: 200 μV in A, 300 μV in other panels. In this and the 
following figure, electrode placements are indicated at the left of each panel and accord with the international 10–20 
system. A, earlobe; C, central; F, frontal; Fp, frontal polar; O, occipital; P, parietal; T, temporal. Right-sided placements 
are indicated by even numbers, left-sided placements by odd numbers, and midline placements by Z. (Reproduced with 
permission from MJ Aminoff: Aminoff’s Electrodiagnosis in Clinical Neurology, 6th ed. Oxford: Elsevier Saunders, 2012.)

to obtain the EEG during a clinical event. In such situations, activating 
procedures are generally undertaken to provoke abnormalities while 
the EEG is recorded. These procedures commonly include hyperven­
tilation, photic stimulation, sleep, and sleep deprivation on the night 
prior to the recording. Continuous monitoring for prolonged periods 
in video-EEG telemetry units for hospitalized patients or the use of 
portable equipment to record the EEG continuously for ≥24 h in ambu­
latory patients has made it easier to capture the electrophysiologic 
correlates of clinical events. Video-EEG telemetry is now a routine 
approach for the accurate diagnosis of epilepsy in patients with poorly 
characterized events or seizures that are difficult to control. A variety of 
technologies, including sub-scalp EEG devices, are being developed to 
enable ultra-long-term ambulatory recordings of brain activity, analo­
gous to implanted loop recorders used to capture infrequent cardiac 
arrhythmias.

The EEG may also be helpful in the interictal period by showing 
certain abnormalities that are highly supportive of the diagnosis of 
epilepsy. Such epileptiform activity consists of bursts of abnormal dis­
charges containing spikes or sharp waves. The presence of epileptiform 
activity is not entirely specific for epilepsy, but it has a much greater 
prevalence in patients with epilepsy than in other individuals. How­
ever, even in an individual who is known to have epilepsy, the initial 
routine interictal EEG may be normal 50–80% of the time. Thus, the 
EEG has limited sensitivity and cannot establish the diagnosis of epi­
lepsy in many cases.
CHAPTER 436
Seizures and Epilepsy
The EEG is also used for classifying seizure disorders and aiding 
in the selection of antiseizure medications (Fig. 436-4). For example, 
episodic generalized spike-wave activity is usually seen in patients 
with typical absence epilepsy and may be seen with other generalized 
epilepsy syndromes. Focal interictal epileptiform discharges would 
support the diagnosis of a focal seizure disorder such as temporal lobe 
epilepsy or frontal lobe seizures, depending on the location of the 
discharges.
F3-C3
C3-P3
P3-O1
F4-C4
C4-P4
P4-O2
T3-CZ
CZ-T4
Fp1-F3
F3-C3
C3-P3
P3-O1
Fp2-F4
F4-C4
C4-P4
P4-O2

F3-C3
C3-P3
P3-O1
F4-C4
C4-P4
P4-O2
T3-CZ
CZ-T4
A
Fp1-F7
F7-T3
PART 13
Neurologic Disorders
T3-T5
T5-O1
Fp2-F8
F8-T4
T4-T6
T6-O2
B
Fp1-A1
F7-A1
T3-A1
T5-A1
Fp2-A2
F8-A2
T4-A2
T6-A2
C
FIGURE 436-4  Electrographic seizures. A. Onset of a tonic seizure showing 
generalized repetitive sharp activity with synchronous onset over both 
hemispheres. B. Burst of repetitive spikes occurring with sudden onset in the right 
temporal region during a clinical spell characterized by transient impairment of 
awareness. C. Generalized 3-Hz spike-wave activity occurring synchronously over 
both hemispheres during an absence seizure. Horizontal calibration: 1 s; vertical 
calibration: 400 μV in A, 200 μV in B, and 750 μV in C. (Reproduced with permission 
from MJ Aminoff: Aminoff’s Electrodiagnosis in Clinical Neurology, 6th ed. Oxford: 
Elsevier Saunders, 2012.)
The routine scalp EEG may also be used to assess the prognosis of 
seizure disorders; in general, a normal EEG implies a better prognosis, 
whereas an abnormal background or frequent epileptiform activity 
suggests a worse outcome. Unfortunately, the EEG has not proved to be 
useful in predicting which patients with predisposing conditions such 
as head injury or brain tumor will go on to develop epilepsy, because 
in such circumstances, epileptiform activity is commonly encountered 
regardless of whether seizures occur.
High-density EEG provides higher resolution localization by utiliz­
ing up to 257 scalp electrodes, as opposed to the 21 electrodes used in 
a standard EEG recording. This makes use of scalp voltage field data to 
determine dipole location, orientation, and propagation. EEG source 
imaging (ESI) permits visualization of these dipoles by mapping them 
onto a three-dimensional model that is co-registered on brain MRI.
Magnetoencephalography (MEG) provides another way of look­
ing noninvasively at cortical activity. Instead of measuring electrical 

activity of the brain, it measures the small magnetic fields that are gen­
erated by this activity. The epileptiform activity seen on MEG can be 
analyzed, and its source in the brain can be estimated using a variety of 
mathematical techniques. These source estimates can then be plotted 
on an anatomic image of the brain such as an MRI (discussed below) to 
generate a magnetic source image (MSI). MSI can be useful to localize 
potential seizure foci.
■
■BRAIN IMAGING
Almost all patients with new-onset seizures should have a brain imag­
ing study to determine whether there is an underlying structural 
abnormality that is responsible. The only potential exception to this 
rule is children who have an unambiguous history and examination 
suggestive of a benign, generalized seizure disorder such as absence 
epilepsy. MRI has been shown to be superior to computed tomography 
(CT) for the detection of cerebral lesions associated with epilepsy. In 
some cases, MRI will identify lesions such as tumors, vascular malfor­
mations, or other pathologies that need urgent therapy. The availability 
of newer MRI methods, such as three-dimensional structural imaging 
at submillimeter resolution, has increased the sensitivity for detection 
of abnormalities of cortical architecture, including hippocampal atro­
phy associated with mesial temporal sclerosis, as well as abnormalities 
of neuronal migration. In such cases, the findings provide an explana­
tion for the patient’s seizures and point to the need for chronic antisei­
zure drug therapy or possible surgical resection.
In the patient with a suspected CNS infection or mass lesion, CT 
scanning should be performed emergently when MRI is not immedi­
ately available. Otherwise, it is usually appropriate to obtain an MRI 
study within a few days of the initial evaluation. Functional imaging 
procedures such as positron emission tomography (PET) and singlephoton emission computed tomography (SPECT) are also used to eval­
uate certain patients with medically refractory seizures (Table 436-3).
■
■GENETIC TESTING
With the increasing recognition of specific gene mutations causing epi­
lepsy (Table 436-2), genetic testing is beginning to emerge as part of the 
diagnostic evaluation of patients with epilepsy. In addition to provid­
ing a definitive diagnosis (which may be of great benefit to the patient 
and family members and curtail the pursuit of additional, unrevealing 
laboratory testing), genetic testing may offer a guide for therapeutic 
options (see section “Selection of Antiseizure Drugs” below). Genetic 
testing is currently being done mainly in infants and children with 
epilepsy syndromes thought to have a genetic cause but should also be 
considered in older patients with a history suggesting an undiagnosed 
genetic epilepsy syndrome that began early in life.
DIFFERENTIAL DIAGNOSIS OF SEIZURES
Disorders that may mimic seizures are listed in Table 436-6. In most 
cases, seizures can be distinguished from other conditions by meticu­
lous attention to the history and relevant laboratory studies. On occa­
sion, additional studies such as video-EEG monitoring, sleep studies, 
tilt-table analysis, or cardiac electrophysiology may be required to 
reach a correct diagnosis. Two of the more common nonepileptic syn­
dromes in the differential diagnosis are discussed below.
■
■SYNCOPE
The diagnostic dilemma encountered most frequently is the distinc­
tion between a generalized seizure and syncope. Observations by the 
patient and bystanders that can help differentiate between the two are 
listed in Table 436-7. Characteristics of a seizure include the presence 
of an aura, cyanosis, unconsciousness, motor manifestations lasting 
>15 s, postictal disorientation, muscle soreness, and sleepiness. In 
contrast, a syncopal episode is more likely if the event was provoked 
by acute pain or emotional stress or occurred immediately after arising 
from the lying or sitting position. Patients with syncope often describe 
a stereotyped transition from consciousness to unconsciousness that 
includes tiredness, sweating, nausea, and tunneling of vision, and they 
experience a relatively brief loss of consciousness with rapid recov­
ery of normal mentation. Headache and incontinence are unreliable

TABLE 436-6  Differential Diagnosis of Seizures
Syncope
Vasovagal syncope
Cardiac arrhythmia
Valvular heart disease
Cardiac failure
Orthostatic hypotension
Psychological disorders
Psychogenic seizure
Hyperventilation
Panic attack
Metabolic disturbances
Alcoholic blackouts
Delirium tremens
Hypoglycemia
Hypoxia
Psychoactive drugs (e.g., 
hallucinogens)
Migraine
Confusional migraine
Basilar migraine
Transient ischemic attack (TIA)
Basilar artery TIA
Sleep disorders
Narcolepsy/cataplexy
Benign sleep myoclonus
Movement disorders
Tics
Nonepileptic myoclonus
Paroxysmal choreoathetosis
Special considerations in children
Breath-holding spells
Migraine with recurrent abdominal 
pain and cyclic vomiting
Benign paroxysmal vertigo
Apnea
Night terrors
Sleepwalking
features in differentiating between syncope and seizure. A brief period 
(i.e., 1–10 s) of convulsive motor activity is frequently seen immedi­
ately at the onset of a syncopal episode, especially if the patient remains 
in an upright posture after fainting (e.g., in a dentist’s chair) and there­
fore has a sustained decrease in cerebral perfusion. Rarely, a syncopal 
episode can induce a full tonic-clonic seizure. In such cases, the evalu­
ation must focus on both the cause of the syncopal event as well as 
the possibility that the patient has a propensity for recurrent seizures. 
Postictal symptoms can be helpful when differentiating convulsive syn­
cope from seizure, as confusion and disorientation are typically much 
less prominent following syncope.
■
■PSYCHOGENIC SEIZURES
Psychogenic seizures are nonepileptic behaviors that resemble seizures. 
They are often part of a conversion reaction precipitated by underlying 
psychological distress. Certain behaviors such as side-to-side turning 
of the head, ictal eye closure, asynchronous and large-amplitude shak­
ing movements of the limbs, twitching of all four extremities without 
TABLE 436-7  Features That Distinguish Generalized Tonic-Clonic 
Seizure from Syncope
FEATURES
SEIZURE
SYNCOPE
Immediate precipitating factors
Usually none
Emotional stress, 
Valsalva, orthostatic 
hypotension, cardiac 
etiologies
Premonitory symptoms
None or aura (e.g., 
odd odor)
Tiredness, nausea, 
diaphoresis, tunneling 
of vision
Posture at onset
Variable
Usually erect
Transition to unconsciousness
Often immediate
Gradual over secondsa
Duration of unconsciousness
Minutes
Seconds
Duration of tonic or clonic 
movements
30–60 s
Never >15 s
Facial appearance during event Cyanosis, frothing 
Pallor
at mouth
Disorientation and sleepiness 
after event
Many minutes to 
hours
<5 min
Aching of muscles after event
Often
Sometimes
Biting of tongue
Sometimes
Rarely
Incontinence
Sometimes
Sometimes
Headache
Sometimes
Rarely
aMay be sudden with certain cardiac arrhythmias.

loss of consciousness, and pelvic thrusting are more commonly asso­
ciated with psychogenic rather than epileptic seizures. Psychogenic 
seizures often last longer than epileptic seizures and may wax and wane 
over minutes to hours. However, the distinction is sometimes difficult 
on clinical grounds alone, and there are many examples of diagnostic 
errors made by experienced epileptologists. This is especially true for 
psychogenic seizures that resemble focal seizures, because the behav­
ioral manifestations of focal seizures (especially of frontal lobe origin) 
can be extremely unusual, and, in both cases, the routine surface EEG 
may be normal. Video-EEG monitoring is very useful when historic 
features are nondiagnostic. Generalized tonic-clonic seizures always 
produce marked EEG abnormalities during and after the seizure. For 
suspected focal seizures, the use of additional electrodes may help 
to localize a seizure focus. Most generalized seizures and some focal 
seizures are accompanied by a rise in serum prolactin during the 
immediate 30-min postictal period, whereas psychogenic seizures are 
not, though this is not always reliable because baseline prolactin levels 
are rarely available and certain medications can elevate prolactin levels. 
The diagnosis of psychogenic seizures also does not exclude a concur­
rent diagnosis of epilepsy, because the two often coexist.

CHAPTER 436
TREATMENT
Seizures and Epilepsy
Seizures and Epilepsy
Therapy for a patient with a seizure disorder is almost always 
multimodal and includes treatment of underlying conditions that 
cause or contribute to the seizures, avoidance of precipitating fac­
tors, suppression of recurrent seizures by prophylactic therapy with 
antiseizure medications or surgery, and addressing a variety of 
psychological and social issues. Treatment plans must be individu­
alized, given the many different types and causes of seizures as well 
as the differences in efficacy and toxicity of antiseizure medications 
for each patient. In almost all cases, a neurologist with experience 
in the treatment of epilepsy should design and oversee implementa­
tion of the treatment strategy. Furthermore, patients with refractory 
epilepsy or those who require polypharmacy with antiseizure drugs 
should remain under the regular care of a neurologist.
TREATMENT OF UNDERLYING CONDITIONS
If the sole cause of a seizure is a metabolic disturbance such as 
an abnormality of serum electrolytes or glucose, then treatment 
is aimed at reversing the metabolic problem and preventing its 
recurrence. Therapy with antiseizure drugs is usually unnecessary 
unless the metabolic disorder cannot be corrected promptly and the 
patient is at risk of having further seizures. If the apparent cause of 
a seizure was a medication (e.g., bupropion) or illicit drug use (e.g., 
cocaine), then appropriate therapy is avoidance of the drug; there 
is usually no need for antiseizure medications unless subsequent 
seizures occur in the absence of these precipitants.
Seizures caused by a structural CNS lesion such as a brain tumor, 
vascular malformation, or brain abscess may not recur after appro­
priate treatment of the underlying lesion. However, despite removal 
of the structural lesion, there is a risk that the seizure focus will 
remain in the surrounding tissue or develop de novo as a result of 
gliosis and other processes induced by surgery, radiation, or other 
therapies. Most patients are therefore maintained on an antiseizure 
medication for 6–12 months, and an attempt is made to withdraw 
medications only if the patient has been completely seizure free. If 
seizures are refractory to medication, the patient may benefit from 
surgical removal of the seizure-producing brain tissue (see below).
AVOIDANCE OF PRECIPITATING FACTORS
Unfortunately, little is known about the specific factors that deter­
mine precisely when a seizure will occur in a patient with epilepsy. 
An almost universal precipitating factor for seizures is sleep depri­
vation, so patients should do everything possible to optimize their 
sleep quality. Many patients can identify other avoidable situations 
that appear to lower their seizure threshold. For example, patients 
may note an association between alcohol intake and seizures, and

they should be encouraged to modify their drinking habits accord­
ingly. There are also relatively rare cases of patients with seizures 
that are induced by highly specific stimuli such as a video game 
monitor, music, startling sounds, or an individual’s voice (“reflex 
epilepsy”). Because there is often an association between stress 
and seizures, stress reduction techniques such as physical exercise, 
meditation, or counseling may be helpful.

ANTISEIZURE DRUG THERAPY
Antiseizure drug therapy is the mainstay of treatment for most 
people with epilepsy. The overall goal is to completely prevent sei­
zures without causing any untoward side effects, preferably with a 
single medication and a dosing schedule that is easy for the patient 
to follow. Seizure classification is an important element in designing 
the treatment plan, because some antiseizure drugs have different 
activities against various seizure types. However, there is consider­
able overlap between antiseizure drugs, and choice of therapy is 
often determined by anticipated side effects, drug-drug interac­
tions, medical comorbidities, dosing frequency, and cost.
PART 13
Neurologic Disorders
When to Initiate Antiseizure Drug Therapy  Antiseizure drug 
therapy should be started in any patient with recurrent seizures 
of unknown etiology or a known cause that cannot be reversed. 
Whether to initiate therapy in a patient with a single seizure is con­
troversial. Patients with a single seizure due to an identified lesion 
such as a CNS tumor, infection, or trauma, in which there is strong 
evidence that the lesion is epileptogenic, should be treated. The risk 
of seizure recurrence in a patient with an apparently unprovoked 
seizure is uncertain, with estimates ranging from 31 to 71% in the 
first 12 months after the initial seizure. This uncertainty arises from 
differences in the underlying seizure types and etiologies in various 
published epidemiologic studies. Generally accepted risk factors 
associated with recurrent seizures include the following: (1) prior 
brain insult such as a stroke or trauma, (2) an EEG with epilep­
tiform abnormalities, (3) a significant brain imaging abnormality, 
or (4) a nocturnal seizure. Most patients with one or more of these 
risk factors should be treated. Issues such as employment or driving 
may influence the decision regarding whether to start medications 
as well. For example, a patient with a single unprovoked seizure 
whose job depends on driving may prefer taking an antiseizure 
drug to reduce risk of seizure recurrence and the potential loss of 
driving privileges.
Selection of Antiseizure Drugs  Antiseizure drugs available in 
the United States are shown in Table 436-8, and the main phar­
macologic characteristics of commonly used drugs are listed in 
Table 436-9. Worldwide, older medications such as phenytoin, 
valproic acid, carbamazepine, phenobarbital, and ethosuximide 
are generally used as first-line therapy for most seizure disorders 
because, overall, they are as effective as more recent drugs and 
significantly less expensive overall. Most of the new drugs that have 
become available in the past decade are used as adjunctive therapy, 
although many are now also being used as first-line monotherapy.
In addition to efficacy, factors influencing the choice of an initial 
medication include the convenience of dosing (e.g., once daily vs 
three times daily) and potential side effects. In this regard, many of 
the newer drugs have the advantage of reduced drug-drug interac­
tions and easier dosing. Almost all the commonly used antiseizure 
drugs can cause similar, dose-related side effects such as sedation, 
ataxia, dizziness, and diplopia. Long-term use of some agents in 
adults, especially the elderly, can lead to osteoporosis. Close followup is required to ensure these side effects are promptly recognized 
and reversed. Most of the older drugs and some of the newer ones 
can also cause idiosyncratic toxicity such as rash, bone marrow 
suppression, or hepatotoxicity. Although rare, these side effects 
should be considered during drug selection, and patients must be 
instructed about symptoms or signs that should signal the need to 
alert their health care provider. For some drugs, laboratory tests 
(e.g., complete blood count and liver function tests) are recom­
mended prior to the institution of therapy (to establish baseline 

TABLE 436-8  Selection of Antiseizure Drugs
GENERALIZEDONSET 
TONIC-CLONIC
FOCAL
ATYPICAL ABSENCE, 
MYOCLONIC, 
ATONIC
TYPICAL 
ABSENCE
First-Line
Lamotrigine
Valproic acid
Lamotrigine
Carbamazepine
Oxcarbazepine
Eslicarbazepine
Phenytoin
Levetiracetam
Valproic acid
Ethosuximide
Lamotrigine
Valproic acid
Lamotrigine
Topiramate
Alternatives
Zonisamidea
Zonisamidea
Clonazepam
Zonisamide
Levetiracetam
Clonazepam
Felbamate
Clobazam
Rufinamide
Fenfluramine
Phenytoin
Levetiracetam
Carbamazepine
Oxcarbazepine
Topiramate
Phenobarbital
Primidone
Felbamate
Perampanel
Brivaracetam
Topiramate
Valproic acid
Tiagabinea
Gabapentina
Lacosamidea
Phenobarbital
Primidone
Felbamate
Perampanel
Cenobamatea
aAs adjunctive therapy.
values) and during initial dosing and titration of the agent. Moni­
toring serum concentrations of antiseizure medications can help 
determine when a therapeutic dose has been reached, though clini­
cal response is paramount (see below).
An important advance in the care of people with epilepsy has 
been the application of genetic testing to help guide the choice of 
therapy (as well as establishing the underlying cause of a patient’s 
syndrome; Table 436-2). For example, the identification of a muta­
tion in the SLC2A1 gene, which encodes the glucose type 1 trans­
porter (GLUT-1) and is a cause of GLUT-1 deficiency, should 
prompt immediate treatment with the ketogenic diet. Mutations 
of the ALDH7A1 gene, which encodes antiquitin, can cause altera­
tions in pyridoxine metabolism that are reversed by treatment with 
pyridoxine. There is also mounting evidence that certain gene 
mutations may indicate better or worse response to specific anti­
seizure drugs. For example, patients with mutations in the sodium 
channel subunit SCN1A should generally avoid taking phenytoin 
or lamotrigine, whereas patients with mutations in the SCN2A 
or SCN8A sodium channel subunits appear to respond favorably 
to high-dose phenytoin. Genetic testing may also help predict 
antiseizure drug toxicity. Studies have shown that individuals of 
Asian descent who carry the human leukocyte antigen (HLA) allele 
HLA-B*1502 are at particularly high risk of developing serious 
skin reactions from carbamazepine, phenytoin, oxcarbazepine, and 
lamotrigine. HLA-A*31:01 has also been found to be associated 
with carbamazepine-induced hypersensitivity reactions in patients 
of European or Japanese ancestry. 
Antiseizure Drug Selection for Focal Seizures 
Carbam­
azepine (or related drugs, oxcarbazepine and eslicarbazepine), 
lamotrigine, phenytoin, and levetiracetam are currently the drugs 
of choice approved for the initial treatment of focal seizures, 
including those that evolve into generalized seizures. Overall, they 
have very similar efficacy, but differences in pharmacokinetics and 
toxicity are the main determinants for use in a given patient. For 
example, an advantage of carbamazepine (which is also available in 
an extended-release form) is that its metabolism follows first-order 
pharmacokinetics, which allows for a linear relationship between 
drug dose, serum levels, and toxicity. Carbamazepine can cause leu­
kopenia, aplastic anemia, or hepatotoxicity and would therefore be

TABLE 436-9  Dosage and Adverse Effects of Commonly Used Antiepileptic Drugs
TRADE 
NAME
PRINCIPAL 
USES
TYPICAL DOSE; 
DOSE INTERVAL
HALF-LIFE
GENERIC NAME
Brivaracetam
Briviact
Focal onset
100–200 mg/d; bid
7–10 h
Not 
established
Cannabidiol
Epidiolex
Dravet and 
Lennox-Gastaut 
syndromes
10–20 mg/kg 

per d; bid
 
Tuberous 
sclerosis 
complexassociated 
seizures
Carbamazepine
Tegretolc
Tonic-clonic
Focal onset
600–1800 mg/d 
(15–35 mg/
kg, child); bid 
(capsules or 
tablets), tid-qid 
(oral suspension)
Cenobamate
Xcopri
Focal onset
100–400 mg/d; 
daily (tablets)
Clobazam
Onfi
Lennox-Gastaut 
syndrome
10–40 mg/d 

(5–20 mg/d for 
patients <30 kg 
body weight); bid
Clonazepam
Klonopin
Absence
Atypical 
absence
Myoclonic
1–12 mg/d; qd-tid
24–48 h
10–70 ng/mL
Ataxia
Sedation
Lethargy
Eslicarbazepine
Aptiom
Focal onset
400–1600 mg/d; qd
20–24 h
10–35 μg/mL (as 
oxcarbazepine 
mono-hydroxy 
derivative)
Ethosuximide
Zarontin
Absence
750–1250 mg/d 
(20–40 mg/kg); 
qd-bid
Felbamate
Felbatol
Focal onset
Lennox-Gastaut 
syndrome
Tonic-clonic
2400–3600 mg/d, 
tid-qid
Fenfluramine
Fintepla
Dravet and 
Lennox-Gastaut 
syndromes
0.1–0.35 mg/kg/
dose bid (oral 
solution); dosage 
depends on 
coadministration 
with stiripentol 
and/or clobazam

ADVERSE EFFECTS
DRUG 
INTERACTIONSa
NEUROLOGIC
SYSTEMIC
THERAPEUTIC 
RANGE
Fatigue
Dizziness
Weakness
Ataxia
Mood changes
Gastrointestinal 
irritation
May increase 
carbamazepineepoxide causing 
decreased 
tolerability
May increase 
phenytoin
18–32 h
Not 
established
Sedation
Elevated 
transaminases
Anorexia
Weight loss
Diarrhea
Increases 
clobazam causing 
somnolence
CHAPTER 436
10–17 h 
(variable due to 
autoinduction: 
complete 
3–5 wk after 
initiation)
4–12 μg/mL
Ataxia
Dizziness
Diplopia
Vertigo
Aplastic anemia
Leukopenia
Gastrointestinal 
irritation
Hepatotoxicity
Hyponatremia
Rash
Level decreased 
by enzymeinducing drugsb
Level increased 
by erythromycin, 
propoxyphene, 
isoniazid, 
cimetidine, 
fluoxetine
Seizures and Epilepsy
50–60 h
Not 
established
Cognitive 
dysfunction
Dizziness
Disequilibrium
Gait disturbance
Headache
 
Anorexia
Constipation
Diarrhea
Dyspepsia
Nausea
 
Major CYP3A4 
inducer; moderate 
CYP2C19 inhibitor
36–42 h 
(71–82 h for 
less active 
metabolite)
Not 
established
Fatigue
Sedation
Ataxia
Aggression
Insomnia
Constipation
Anorexia
Skin rash
Level increased 
by CYP2C19 
inhibitors
Anorexia
Level decreased 
by enzymeinducing drugsb
Sedation
Ataxia
Dizziness
Diplopia
Vertigo
See 
carbamazepine
Level decreased 
by enzymeinducing drugsb
60 h, adult
30 h, child
40–100 μg/mL
Ataxia
Lethargy
Headache
Gastrointestinal 
irritation
Skin rash
Bone marrow 
suppression
Level decreased 
by enzymeinducing drugsb
Level increased 
by valproic acid
16–22 h
30–60 μg/mL
Insomnia
Dizziness
Sedation
Headache
Aplastic anemia
Hepatic failure
Weight loss
Gastrointestinal 
irritation
Increases 
phenytoin, 
valproic 
acid, active 
carbamazepine 
metabolite
20 h
Not 
established
Ataxia
Behavioral 
disturbance
Headache
Somnolence
Anorexia
Constipation
Hypertension
Serotonin 
syndrome
Weight loss 
CYP1A2, CYP2B6, 
CYP2D6, CYPDA4 
substrate
(Continued)

TABLE 436-9  Dosage and Adverse Effects of Commonly Used Antiepileptic Drugs
TRADE 
NAME
PRINCIPAL 
USES
TYPICAL DOSE; 
DOSE INTERVAL
HALF-LIFE
GENERIC NAME
Gabapentin
Neurontin
Focal onset
900–2400 mg/d; 
tid-qid
5–9 h
2–20 μg/mL
Sedation
Dizziness
Ataxia
Fatigue
Ganaxolone
Ztalmy
CDKL-5 
deficiency 
disorder–
associated 
seizures
450–1800 mg/d; tid 
(oral suspension)
34 h
Not 
established
Lacosamide
Vimpat
Focal onset
200–400 mg/d; bid
13 h
Not 
established
PART 13
Neurologic Disorders
Lamotrigine
Lamictalc
Focal onset
Tonic-clonic
Atypical 
absence
Myoclonic
Lennox-Gastaut 
syndrome
150–500 mg/d; 
bid (immediate 
release), daily 
(extended release) 
(lower daily dose 
for regimens with 
valproic acid; 
higher daily dose 
for regimens 
with an enzyme 
inducer)
25 h
14 h (with 
enzyme 
inducers), 59 h 
(with valproic 
acid)
Levetiracetam
Keppra
Focal onset
1000–3000 mg/d; 
bid (immediate 
release), daily 
(extended release)
6–8 h
5–45 μg/mL
Sedation
Fatigue
Incoordination
Mood changes
Oxcarbazepinec
Trileptal
Focal onset
Tonic-clonic
900–2400 mg/d 
(30–45 mg/kg, 
child); bid
10–17 h 
(for active 
metabolite)
Perampanel
Fycompa
Focal onset
Tonic-clonic
4–12 mg; qd
105 h
Not 
established
Phenobarbital
Luminal
Tonic-clonic
Focal onset
60–180 mg/d; 
qd-tid
90 h
10–40 μg/mL
Sedation
Ataxia
Confusion
Dizziness
Decreased libido
Depression
Phenytoinc 
(diphenylhydantoin)
Dilantin
Tonic-clonic
Focal onset
300–400 mg/d 
(3–6 mg/kg, adult; 
4–8 mg/kg, child); 
qd-tid
24 h (wide 
variation, dosedependent)
Primidone
Mysoline
Tonic-clonic
Focal onset
750–1000 mg/d; 
bid-tid
Primidone, 
8–15 h
Phenobarbital, 
90 h

(Continued)
ADVERSE EFFECTS
DRUG 
INTERACTIONSa
NEUROLOGIC
SYSTEMIC
THERAPEUTIC 
RANGE
Gastrointestinal 
irritation
Weight gain
Edema
No known 
significant 
interactions
Gait disturbance
Somnolence
Bronchitis
Fever
Nasal congestion
CYP2B6, CYP2C19, 
CYP3A4 substrate
Dizziness
Ataxia
Diplopia
Vertigo
Gastrointestinal 
irritation
Cardiac 
conduction 
(PR interval 
prolongation)
Level decreased 
by enzymeinducing drugsb
2.5–20 μg/mL
Dizziness
Diplopia
Sedation
Ataxia
Headache
Skin rash
Stevens-Johnson 
syndrome
Level decreased 
by enzymeinducing 
drugsb and oral 
contraceptives
Level increased 
by valproic acid
Anemia
Leukopenia
No known 
significant 
interactions
10–35 μg/mL
Fatigue
Ataxia
Dizziness
Diplopia
Vertigo
Headache
See 
carbamazepine
Level decreased 
by enzymeinducing drugsb
May increase 
phenytoin
Dizziness
Somnolence
Aggression
Ataxia
Anxiety
Paranoia
Headache
Nausea
Level decreased 
by enzymeinducing drugsb
Skin rash
Level increased 
by valproic acid, 
phenytoin
10–20 μg/mL
Dizziness
Diplopia
Ataxia
Incoordination
Confusion
Gingival 
hyperplasia
Lymphadenopathy
Hirsutism
Osteomalacia
Facial coarsening
Skin rash
Level increased 
by isoniazid, 
sulfonamides, 
fluoxetine
Level decreased 
by enzymeinducing drugsb
Altered folate 
metabolism
Primidone, 
4–12 μg/mL
Phenobarbital, 
10–40 μg/mL
Same as 
phenobarbital
 
Level increased 
by valproic acid
Level decreased 
by phenytoin 
(increased 
conversion to 
phenobarbital)
(Continued)

TABLE 436-9  Dosage and Adverse Effects of Commonly Used Antiepileptic Drugs
TRADE 
NAME
PRINCIPAL 
USES
TYPICAL DOSE; 
DOSE INTERVAL
HALF-LIFE
GENERIC NAME
Rufinamide
Banzel
Lennox-Gastaut 
syndrome
3200 mg/d (45 mg/
kg, child); bid
Tiagabine
Gabitril
Focal onset
32–56 mg/d; bidqid (as adjunct to 
enzyme-inducing 
antiepileptic drug 
regimen)
Topiramatec
Topamax
Focal onset
Tonic-clonic
Lennox-Gastaut 
syndrome
200–400 mg/d; 
bid (immediate 
release), daily 
(extended release)
Valproic acid 
(valproate sodium, 
divalproex sodium)
Depakene
Depakote
Tonic-clonic
Absence
Atypical 
absence
Myoclonic
Focal onset
Atonic
750–2000 mg/d 
(20–60 mg/kg); bidqid (immediate and 
delayed release), 
daily (extended 
release)
Zonisamide
Zonegran
Focal onset
Tonic-clonic
200–400 mg/d; 
qd-bid
aExamples only; please refer to other sources for comprehensive listings of all potential drug-drug interactions. bPhenytoin, carbamazepine, phenobarbital. cExtendedrelease product available.
contraindicated in patients with predispositions to these problems. 
Oxcarbazepine has the advantage of being metabolized in a way that 
avoids an intermediate metabolite (“toxic epoxide”) associated with 
some of the side effects of carbamazepine. Oxcarbazepine also has 
fewer drug interactions than carbamazepine. Eslicarbazepine has a 
long serum half-life and is dosed once daily.
Lamotrigine tends to be well tolerated in terms of side effects and 
has mood-stabilizing properties that can be beneficial. However, 
patients need to be particularly vigilant about the possibility of a 
skin rash during the initiation of therapy. This can be extremely 
severe and lead to Stevens-Johnson syndrome if unrecognized and 
if the medication is not discontinued immediately. This risk can be 
reduced by using low initial doses and slow titration. Lamotrigine 
must be started at even lower initial doses when used as add-on 
therapy with valproic acid, because valproic acid inhibits lamotrig­
ine metabolism and substantially prolongs its half-life.
Phenytoin has a relatively long half-life and offers the advantage 
of once- or twice-daily dosing compared to twice- or thrice-daily 
dosing for many of the other drugs. However, phenytoin shows 
properties of nonlinear kinetics, such that small increases in phe­
nytoin doses above a standard maintenance dose can precipitate 
marked side effects. This is one of the main causes of acute phe­
nytoin toxicity (dizziness, diplopia, ataxia). Long-term use of phe­
nytoin is associated with untoward cosmetic effects (e.g., hirsutism, 

(Continued)
ADVERSE EFFECTS
DRUG 
INTERACTIONSa
NEUROLOGIC
SYSTEMIC
THERAPEUTIC 
RANGE
6–10 h
Not 
established
Sedation
Fatigue
Dizziness
Ataxia
Headache
Diplopia
Gastrointestinal 
irritation
Leukopenia
Cardiac 
conduction 
(QT interval 
shortening)
Level decreased 
by enzymeinducing drugsb
Level increased 
by valproic acid
May increase 
phenytoin
2–5 h (with 
enzyme 
inducer), 

7–9 h (without 
enzyme 
inducer)
Not 
established
Confusion
Sedation
Depression
Dizziness
Speech or 
language 
problems
Paresthesias
Psychosis
Gastrointestinal 
irritation
Level decreased 
by enzymeinducing drugsb
CHAPTER 436
20 h 
(immediate 
release), 

30 h (extended 
release)
2–20 μg/mL
Psychomotor 
slowing
Sedation
Speech or 
language 
problems
Fatigue
Paresthesias
Renal stones 
(avoid use with 
other carbonic 
anhydrase 
inhibitors)
Glaucoma
Weight loss
Hypohidrosis
Level decreased 
by enzymeinducing drugsb
Seizures and Epilepsy
15 h
50–125 μg/mL
Ataxia
Sedation
Tremor
Hepatotoxicity
Thrombocytopenia
Gastrointestinal 
irritation
Weight gain
Transient alopecia
Hyperammonemia
Level decreased 
by enzymeinducing drugsb
50–68 h
10–40 μg/mL
Sedation
Dizziness
Confusion
Headache
Psychosis
Anorexia
Renal stones
Hypohidrosis
Level decreased 
by enzymeinducing drugsb
coarsening of facial features, gingival hypertrophy) and osteoporo­
sis. Due to these side effects, phenytoin is often avoided in young 
patients who are likely to require the drug for many years.
Levetiracetam has the advantage of having no known clinically 
relevant drug-drug interactions, making it especially useful in the 
elderly and patients on other medications. However, a significant 
number of patients taking levetiracetam complain of irritability, 
anxiety, and other psychiatric symptoms.
Topiramate can be used for both focal and generalized seizures. 
Like some of the other antiseizure drugs, topiramate can cause sig­
nificant psychomotor slowing and other cognitive problems. Addi­
tionally, it should not be used in patients at risk for renal stones.
Valproic acid is an effective alternative for some patients with 
focal seizures, especially when the seizures generalize. Gastro­
intestinal side effects are fewer when using the delayed-release 
formulation. Laboratory testing is required to monitor toxicity 
because valproic acid can rarely cause reversible bone marrow 
suppression and hepatotoxicity. This drug should generally be 
avoided in patients with preexisting bone marrow or liver disease. 
Valproic acid also has relatively high risks of unacceptable adverse 
effects for women of childbearing age, including hyperandrogen­
ism, that may affect fertility and teratogenesis (e.g., neural tube 
defects) in offspring. Irreversible, fatal hepatic failure appearing as 
an idiosyncratic rather than dose-related side effect is a relatively

rare complication; its risk is highest in children <2 years old, espe­
cially those taking other antiseizure drugs or with inborn errors of 
metabolism.

Zonisamide, brivaracetam, tiagabine, gabapentin, perampanel, 
and lacosamide are additional drugs currently used for the treat­
ment of focal seizures with or without evolution into generalized 
seizures. Phenobarbital and other barbiturate compounds were 
commonly used in the past as first-line therapy for many forms 
of epilepsy. However, the barbiturates frequently cause sedation in 
adults, hyperactivity in children, and other more subtle cognitive 
changes; thus, their use should be limited to situations in which no 
other suitable treatment alternatives exist. Cenobamate is a recently 
approved antiseizure drug that has been shown to significantly 
improve seizure control in patients with focal epilepsy who were not 
adequately treated with up to three medications. 
Antiseizure Drug Selection for Generalized Seizures  

Lamotrigine, valproic acid, and levetiracetam are currently consid­
ered the best initial choice for the treatment of primary generalized, 
tonic-clonic seizures. Topiramate, zonisamide, perampanel, phe­
nytoin, carbamazepine, and oxcarbazepine are suitable alternatives, 
although carbamazepine, oxcarbazepine, and phenytoin can worsen 
certain types of generalized seizures. Valproic acid is particularly 
effective in absence, myoclonic, and atonic seizures. It is therefore 
commonly used in patients with generalized epilepsy syndromes 
having mixed seizure types. However, levetiracetam, rather than 
valproic acid, is increasingly considered the initial drug of choice 
for women with epilepsies having mixed seizure types given the 
adverse effects of valproic acid for women of childbearing age 
(discussed below). Lamotrigine is also an alternative to valproate, 
especially for absence epilepsies. Ethosuximide is a particularly 
effective drug for the treatment of absence seizures, but it is not 
useful for tonic-clonic or focal seizures. Periodic monitoring of 
blood cell counts is required since ethosuximide rarely causes bone 
marrow suppression.
INITIATION AND MONITORING OF THERAPY
Because the response to any antiseizure drug is unpredictable, 
patients should be carefully educated about the approach to ther­
apy. The goal is to prevent seizures and minimize the side effects 
of treatment; determination of the optimal medication and the 
optimal dose typically involves trial and error. This process may 
take months or longer if the baseline seizure frequency is low. Most 
antiseizure drugs need to be introduced relatively slowly to mini­
mize side effects. Patients should expect that minor side effects 
such as mild sedation, slight changes in cognition, or imbalance 
will typically resolve within a few days. Starting doses are usually 
the lowest value listed under the dosage column in Table 436-9. 
Subsequent increases should be made only after achieving a steady 
state with the previous dose (i.e., after an interval of five or more 
half-lives).
PART 13
Neurologic Disorders
Monitoring of serum antiseizure drug levels can be very useful 
for establishing the initial dosing schedule. However, the pub­
lished therapeutic ranges of serum drug concentrations are only 
an approximate guide for determining the proper dose for a given 
patient. The key determinants are the clinical measures of seizure 
frequency and presence of side effects, not the laboratory values. 
Conventional assays of serum drug levels measure the total drug 
(i.e., both free and protein bound). However, it is the concentra­
tion of free drug that reflects extracellular levels in the brain and 
correlates best with efficacy. Thus, patients with decreased levels 
of serum proteins (e.g., decreased serum albumin due to impaired 
liver or renal function) may have an increased ratio of free to bound 
drug, yet the concentration of free drug may be adequate for seizure 
control. These patients may have a “subtherapeutic” drug level, but 
the dose should be changed only if seizures remain uncontrolled, 
not just to achieve a “therapeutic” level. It is also useful to moni­
tor free drug levels in such patients. In practice, other than during 
the initiation or modification of therapy, monitoring of antiseizure 
drug levels is most useful for documenting adherence, assessing 

clinical suspicion of toxicity, or establishing baseline serum con­
centrations prior to pregnancy, when clearance of many antiseizure 
drugs increases significantly.
If seizures continue despite gradual increases to the maximum 
tolerated dose and documented compliance, then it becomes neces­
sary to switch to another antiseizure drug. This is usually done by 
maintaining the patient on the first drug while a second drug is 
added. The dose of the second drug should be adjusted to decrease 
seizure frequency without causing toxicity. Once this is achieved, 
the first drug can be gradually withdrawn (usually over weeks 
unless there is significant toxicity). The dose of the second drug is 
then further optimized based on seizure response and side effects. 
Monotherapy should be the goal whenever possible.
WHEN TO DISCONTINUE THERAPY
Some patients who have their seizures completely controlled with 
antiseizure drugs can eventually discontinue therapy. The following 
patient profile yields the greatest chance of remaining seizure free 
after drug withdrawal: (1) complete medical control of seizures for 
1–5 years; (2) single seizure type, with generalized seizures having a 
better prognosis than focal seizures; (3) normal neurologic exami­
nation, including intelligence; (4) no family history of epilepsy; and 
(5) normal EEG. The appropriate seizure-free interval is unknown 
and depends on the form of epilepsy and whether or not the causal 
factor is still present (e.g., resection of a brain tumor causing 
seizures). However, it seems reasonable to attempt withdrawal of 
therapy after 2 years in a patient who meets all the above criteria, is 
motivated to discontinue the medication, and clearly understands 
the potential risks and benefits. In most cases, it is preferable to 
reduce the dose of the drug gradually over 2–3 months. Most recur­
rences occur in the first 3 months after discontinuing therapy, and 
patients should be advised to avoid potentially dangerous situations 
such as driving or swimming during this period. Rarely, seizure-free 
patients who discontinue antiseizure medications but then have a 
recurrent seizure may not regain full control when these medica­
tions are resumed.
TREATMENT OF REFRACTORY EPILEPSY
Approximately half of people with epilepsy do not respond to treat­
ment with the first antiseizure drug, and it becomes necessary to try 
additional drugs alone or in combination. Patients who have focal 
epilepsy related to an underlying structural lesion or those with 
multiple seizure types and developmental delay are particularly 
likely to require multiple drugs. There are currently no clear guide­
lines for rational polypharmacy, although in theory, a combination 
of drugs with different mechanisms of action may be most useful. 
In most cases, the initial combination therapy combines first-line 
drugs (i.e., carbamazepine, oxcarbazepine, lamotrigine, valproic 
acid, levetiracetam, and phenytoin). If these drugs are unsuccessful, 
then the addition of other drugs such as cenobamate, zonisamide, 
brivaracetam, topiramate, or lacosamide is indicated. Patients with 
myoclonic seizures resistant to valproic acid may benefit from the 
addition of levetiracetam, zonisamide, clonazepam, or clobazam, 
and those with absence seizures may respond to a combination of 
valproic acid and ethosuximide. The same principles concerning 
the monitoring of therapeutic response, toxicity, and serum levels 
for monotherapy apply to polypharmacy, and potential drug inter­
actions need to be recognized. If there is no improvement, a third 
drug can be added while the first two are maintained. If there is 
a response, the less effective or less well tolerated of the first two 
drugs should be gradually withdrawn.
SURGICAL TREATMENT OF REFRACTORY EPILEPSY
Approximately 30% of patients with epilepsy continue to have 
seizures despite efforts to find an effective combination of anti­
seizure drugs. For some patients with focal epilepsy, surgery can 
be extremely effective in substantially reducing seizure frequency 
and even providing complete seizure control. Understanding the 
potential value of surgery is especially important when a patient’s 
seizures are not controlled with initial treatment, as such patients

often do not respond to subsequent medication trials. Rather than 
submitting the patient to years of unsuccessful medical therapy and 
the psychosocial trauma and increased mortality associated with 
ongoing seizures, the patient should have an efficient but relatively 
brief attempt at medical therapy and then be referred for surgical 
evaluation.
The most common surgical procedure for patients with temporal 
lobe epilepsy involves resection of the anteromedial temporal lobe 
(temporal lobectomy) or a more limited removal of the underlying 
hippocampus and amygdala (amygdalohippocampectomy). Focal 
seizures arising from extratemporal regions may be abolished by 
a focal neocortical resection with precise removal of an identified 
lesion (lesionectomy). Localized neocortical resection without a 
clear lesion identified on MRI is also possible when other tests (e.g., 
MEG, PET, SPECT) implicate a focal cortical region as a seizure 
onset zone. When the cortical region cannot be removed, multiple 
subpial transection, which disrupts intracortical connections, is 
sometimes used to prevent seizure spread. Hemispherectomy or 
multilobar resection is useful for some patients with severe seizures 
due to hemispheric abnormalities such as hemimegalencephaly or 
other dysplastic abnormalities, and corpus callosotomy has been 
shown to be effective for disabling tonic or atonic seizures, usually 
when they are part of a mixed-seizure syndrome (e.g., LennoxGastaut syndrome).
Presurgical evaluation is designed to identify the functional and 
structural basis of the patient’s seizure disorder. Inpatient videoEEG monitoring is used to localize the seizure focus and to cor­
relate the abnormal electrophysiologic activity with neuroimaging 
and behavioral manifestations of the seizure. Routine scalp EEG 
recordings and a high-resolution MRI scan are often sufficient for 
localization of the epileptogenic focus, especially when the findings 
are concordant. Functional imaging studies such as SPECT, PET, 
and MEG are adjunctive tests that may help to reveal or verify the 
localization of an apparent epileptogenic region. Once the pre­
sumed location of the seizure onset is identified, additional studies, 
including neuropsychological testing, the intracarotid amobarbital 
(Wada) test, and functional MRI may be used to assess language 
and memory localization and to determine the possible functional 
consequences of surgical removal of the epileptogenic region. In 
some cases, standard noninvasive evaluation is not sufficient to 
localize the seizure onset zone, and invasive electrophysiologic 
monitoring is required for more definitive localization. Tradition­
ally, this required open craniotomy and subdural electrode place­
ment. Robot-assisted stereotactic EEG (stereo-EEG) has surged in 
use as a less invasive surgical option that involves placing depth 
electrodes through burr holes in the skull and into the brain paren­
chyma to record from regions suspected of generating seizures. 
Although subdural electrodes provide extensive cortical sampling, 
they are unable to record from deep structures; depth electrodes 
permit sampling of both cortical and subcortical tissue, albeit with 
more restricted spatial resolution. Stereo-EEG studies are typically 
associated with shorter hospital stays and lower complication rates 
than subdural electrode studies.
The exact extent of the resection to be undertaken can also be 
determined by performing cortical mapping at the time of the sur­
gical procedure, allowing for a tailored resection. This involves elec­
trocorticographic recordings made with electrodes on the surface of 
the brain to identify the extent of epileptiform disturbances. If the 
region to be resected is within or near brain regions suspected of 
having sensorimotor or language function, electrical cortical stimu­
lation mapping is performed on the awake patient to determine the 
function of cortical regions in question to avoid resection of socalled eloquent cortex and thereby minimize postsurgical deficits.
Advances in presurgical evaluation and microsurgical techniques 
have led to a steady increase in the success of epilepsy surgery. 
Clinically significant complications of surgery are <5%, and the 
use of functional mapping procedures has markedly reduced the 
neurologic sequelae due to removal or sectioning of brain tissue. 
For example, ~70% of well-selected patients treated with temporal 

lobectomy will become seizure free, and another 15–25% will have 
at least a 90% reduction in seizure frequency. Marked improvement 
is also usually seen in patients treated with hemispherectomy for 
catastrophic seizure disorders due to large hemispheric abnormali­
ties. Postoperatively, patients generally need to remain on antisei­
zure drug therapy, but the marked reduction of seizures following 
resective surgery can have a very beneficial effect on quality of life. 
Recently, catheter-based stereotactic laser thermal ablation has been 
developed as a less invasive means for destroying the seizure focus 
in select patients.

Not all medically refractory patients are suitable candidates for 
resective surgery or laser ablation. For example, some patients have 
seizures arising from more than one brain region or from a single 
“eloquent” region that mediates a critical function (e.g., vision, 
movement, language), such that the potential harm from removal 
is unacceptably high. In these patients, implanted neurostimula­
tion devices that deliver electrical energy to the brain to reduce 
seizures represent palliative treatment options. Vagus nerve stimu­
lation (VNS) involves an extracranial device that works through 
scheduled intermittent (“open loop”) stimulation of the left vagus 
nerve. Efficacy of VNS is limited, and side effects related to recur­
rent laryngeal nerve activation (e.g., hoarseness, throat pain, dys­
pnea) can be significant and dose-limiting. By contrast, responsive 
neurostimulation (RNS) involves an implanted device connected 
to two lead wires that are placed intracranially at the site(s) from 
where seizures arise. The neurostimulator detects the onset of a 
seizure (often before the seizure becomes clinically apparent) and 
delivers electrical stimulation—typically imperceptible—directly 
to the brain to reduce seizures over time, a form of “closed loop” 
neurostimulation. RNS is the only device that provides chronic 
EEG, which has a growing number of clinical applications, such as 
quantifying the lateralization of seizures arising from both sides of 
the brain, characterizing clinical spells, assessing effects of medica­
tions and other therapeutic interventions, and revealing cyclical 
patterns of epileptic brain activity that may help anticipate future 
events. A third modality, thalamic deep brain stimulation (DBS), 
involves open loop stimulation of deep, bilateral cerebral structures, 
the anterior thalamic nuclei, which are key nodes in limbic circuits 
mediating certain types of seizures. Whereas precise seizure local­
ization is necessary for RNS, it is not required for VNS or DBS. 
Stimulation of thalamic nuclei, which project broadly to different 
cortical regions, with RNS or DBS is an appealing approach to treat­
ing poorly localized, spatially extensive, or multifocal seizure foci.
CHAPTER 436
Seizures and Epilepsy
Long-term clinical trials of all three neurostimulation devices 
demonstrate significant reductions in frequency with outcomes 
improving over time, but only a minority of patients treated with 
these devices achieve seizure freedom (e.g., ~15% with RNS). Fur­
thermore, no head-to-head device trials exist to establish relative 
superiority, so choice of a device is guided by patient-specific fac­
tors and by the strengths and limitations of each technology.
■
■STATUS EPILEPTICUS
Status epilepticus refers to continuous seizures or repetitive, discrete 
seizures with impaired consciousness in the interictal period. Status 
epilepticus has numerous subtypes, including generalized convulsive 
status epilepticus (GCSE) (e.g., persistent, generalized electrographic 
seizures, coma, and tonic-clonic movements) and nonconvulsive status 
epilepticus (NCSE; e.g., persistent absence seizures or focal seizures 
with confusion or partially impaired consciousness, and minimal 
motor abnormalities). The duration of seizure activity sufficient to 
meet the definition of status epilepticus has traditionally been specified 
as 15–30 min. However, a more practical definition is to consider status 
epilepticus as a situation in which the duration of seizures prompts the 
acute use of anticonvulsant therapy. For GCSE, this is typically when 
seizures last beyond 5 min.
GCSE is an emergency and must be treated immediately, because 
cardiorespiratory dysfunction, hyperthermia, and metabolic derange­
ments can develop as a consequence of prolonged seizures, and these

can lead to irreversible CNS injury. Furthermore, CNS injury can occur 
even when the patient is paralyzed with neuromuscular blockade but 
continues to have electrographic seizures. The most common causes 
of GCSE are anticonvulsant withdrawal or noncompliance, metabolic 
disturbances, drug toxicity, CNS infection, CNS tumors, refractory 
epilepsy, and head trauma.

GCSE is obvious when the patient is having overt seizures. How­
ever, after 30–45 min of uninterrupted seizures, the signs may become 
increasingly subtle. Patients may have mild clonic movements of only 
the fingers or fine, rapid movements of the eyes. There may be parox­
ysmal episodes of tachycardia, hypertension, and pupillary dilation. 
In such cases, the EEG may be the only method of establishing the 
diagnosis. Thus, if the patient stops having overt seizures, yet remains 
comatose, an EEG should be performed to rule out ongoing status 
epilepticus. This is obviously also essential when a patient with GCSE 
has been paralyzed with neuromuscular blockade in the process of 
protecting the airway.
The first steps in the management of a patient in GCSE are to attend 
to any acute cardiorespiratory problems or hyperthermia, perform a 
brief medical and neurologic examination, establish venous access, and 
send samples for laboratory studies to identify metabolic abnormalities. 
Anticonvulsant therapy should then begin without delay (Fig. 436-5).
PART 13
Neurologic Disorders
The treatment of NCSE is thought to be less urgent than GCSE, 
because the ongoing seizures are not accompanied by the severe 
metabolic disturbances seen with GCSE. However, evidence suggests 
that NCSE, especially that caused by ongoing, focal seizure activity, is 
associated with cellular injury in the region of the seizure focus; there­
fore, this condition should be treated as promptly as possible using the 
general approach described for GCSE. Portable headband devices that 
provide a limited form of EEG can be rapidly applied without skilled 
technicians to help rule out NCSE in acute care settings.
Impending and early SE
(5–30 min)
Generalized
convulsive or
“subtle” SE
Established and
early refractory SE
(30 min to 48 h)
IV MDZ 0.2 mg/kg → 0.2–0.6 mg/kg/h
and/or
IV PRO 2 mg/kg → 2–10 mg/kg/h 
Late refractory SE
(>48 h)
Other medications
Lidocaine, verapamil,
magnesium, ketogenic diet,
immunomodulation
FIGURE 436-5  Pharmacologic treatment of generalized tonic-clonic status epilepticus (SE) in adults. CLZ, clonazepam; ECT, electroconvulsive therapy; LCM, lacosamide; 
LEV, levetiracetam; LZP, lorazepam; MDZ, midazolam; PGB, pregabalin; PHT, phenytoin or fosphenytoin; PRO, propofol; PTB, pentobarbital; RNS, responsive neurostimulation; 
rTMS, repetitive transcranial magnetic stimulation; THP, thiopental; TPM, topiramate; VNS, vagus nerve stimulation; VPA, valproic acid. (Data from AO Rossetti, DH 
Lowenstein: Management of refractory status epilepticus in adults: still more questions than answers. Lancet Neurol 10:922, 2011.)

BEYOND SEIZURES: OTHER MANAGEMENT 
ISSUES
■
■EPILEPSY COMORBIDITIES
The adverse effects of epilepsy often go beyond clinical seizures. Many 
people with epilepsy feel completely normal between seizures and live 
highly successful and productive lives. However, a significant propor­
tion of patients suffer from varying degrees of cognitive dysfunction, 
including psychiatric disease, and it has become increasingly clear 
that the network dysfunction underlying epilepsy can have effects well 
beyond the occurrence of seizures. For example, patients with seizures 
secondary to developmental abnormalities or acquired brain injury 
may have impaired cognitive function and other neurologic deficits 
due to abnormal brain structure. Frequent interictal EEG abnormali­
ties are associated with subtle dysfunction of memory and attention. 
Patients with many seizures, especially those emanating from the tem­
poral lobe, often note an impairment of short-term memory that may 
progress over time.
The psychiatric problems associated with epilepsy include depres­
sion, anxiety, and psychosis. This risk varies considerably depending 
on many factors, including the etiology, frequency, and severity of 
seizures and the patient’s age and previous personal or family history 
of psychiatric disorder. Depression occurs in ~20–30% of patients, and 
the incidence of suicide is higher in people with epilepsy than in the 
general population. Depression should be treated through counsel­
ing and/or medication. The selective serotonin reuptake inhibitors 
(SSRIs) typically have minimal effect on seizures, whereas tricyclic 
antidepressants may lower the seizure threshold. Anxiety can be a 
seizure symptom, and anxious or psychotic behavior can occur dur­
ing a postictal delirium. Postictal psychosis is a rare phenomenon that 
typically occurs after a period of increased seizure frequency. There is 
IV benzodiazepine
LZP 0.1 mg/kg, or MDZ 0.2 mg/kg,
or
CLZ 0.015 mg/kg
IV antiseizure drug
PHT 20 mg/kg, or VPA 20–30 mg/kg,
or
LEV 20–30 mg/kg
Focal-complex,
myoclonic or
absence SE
Further IV/PO antiseizure drug
VPA, LEV, LCM, TPM, PGB, or other
PTB (THP)
5 mg/kg (1 mg/kg) → 1–5 mg/kg/h
Other approaches
Surgery, VNS, RNS, rTMS,
ECT, hypothermia
Other anesthetics
Isoflurane, desflurane,
ketamine

usually a brief lucid interval lasting up to a week, followed by days to 
weeks of agitated, psychotic behavior. The psychosis usually resolves 
spontaneously but frequently will require short-term treatment with 
antipsychotic or anxiolytic medications.
■
■MORTALITY OF EPILEPSY
People with epilepsy have a risk of death that is roughly two to three 
times greater than expected in a matched population without epilepsy. 
Most of the increased mortality is due to the underlying etiology of 
epilepsy (e.g., tumors or strokes in older adults). However, a signifi­
cant number of patients die from accidents, status epilepticus, and a 
syndrome known as sudden unexpected death in epilepsy (SUDEP), 
which usually affects young people with convulsive seizures and tends 
to occur at night. The cause of SUDEP is unknown; it may result from 
brainstem-mediated effects of seizures on pulmonary, cardiac, and 
arousal functions. Genetic mutations may be the cause of both epilepsy 
and a cardiac conduction defect that gives rise to sudden death.
■
■PSYCHOSOCIAL ISSUES
There continues to be a cultural stigma about epilepsy, although it is 
slowly declining in societies with effective health education programs. 
Many people with epilepsy harbor fear of progressive cognitive decline 
or dying during a seizure. These issues need to be carefully addressed 
by educating the patient about epilepsy and by ensuring that family 
members, teachers, fellow employees, and other associates are equally 
well informed. A useful source of educational material is the website 
www.epilepsy.com.
■
■EMPLOYMENT, DRIVING, AND OTHER ACTIVITIES
Many patients with epilepsy face difficulty in obtaining or maintaining 
employment, even when their seizures are well controlled. Federal and 
state legislation is designed to prevent employers from discriminating 
against people with epilepsy, and patients should be encouraged to 
understand and claim their legal rights. Patients in these circumstances 
also benefit greatly from the assistance of health providers who act as 
strong patient advocates.
Loss of driving privileges is one of the most disruptive social con­
sequences of epilepsy. Physicians should be very clear about local 
regulations concerning driving and epilepsy because the laws vary con­
siderably among states and countries. In all cases, it is the physician’s 
responsibility to warn patients of the danger imposed on themselves 
and others while driving if their seizures are uncontrolled (unless the 
seizures are not associated with impairment of consciousness or motor 
control). In general, most states in the United States allow patients to 
drive after a seizure-free interval (on or off medications) of 3–18 months.
Patients with incompletely controlled seizures must also contend 
with the risk of being in other situations where an impairment of con­
sciousness or loss of motor control could lead to major injury or death. 
Thus, depending on the type and frequency of seizures, many patients 
need to be instructed to avoid working at heights or with machinery or 
to have someone close by for activities such as bathing and swimming.
The importance of quantifying seizures in people living with epi­
lepsy has catalyzed a burgeoning industry of wearable sensors, such as 
wristwatches, that can detect seizures through noninvasive measure­
ment of physiologic variables. Generally, non-EEG devices either have 
low sensitivity or high false alarm rate, but reliability is highest for 
detection of tonic-clonic seizures.
SPECIAL ISSUES RELATED TO WOMEN 

AND EPILEPSY
■
■CATAMENIAL EPILEPSY
Some women experience a marked increase in seizure frequency 
around the time of menses. This is believed to be mediated by either 
the effects of estrogen and progesterone on neuronal excitability or 
changes in antiseizure drug levels due to altered protein binding or 
metabolism. Vulnerability to seizures is typically highest just before 
and during menses and during ovulation due to relatively high estrogen 
and low progesterone levels. Some women with epilepsy may benefit 
from increases in antiseizure drug dosages during menses. Natural 

progestins or intramuscular medroxyprogesterone may be of benefit to 
a subset of women.

■
■PREGNANCY
Most women with epilepsy who become pregnant will have an uncom­
plicated gestation and deliver a normal baby. However, epilepsy poses 
some important risks to a pregnancy. Seizure frequency during preg­
nancy will remain unchanged in ~50% of women, increase in ~30%, 
and decrease in ~20%. Changes in seizure frequency are attributed to 
endocrine effects on the CNS, variations in antiseizure drug pharma­
cokinetics (such as acceleration of hepatic drug metabolism, increased 
renal blood flow, increased volume of distribution, or effects on plasma 
protein binding), or decreased antiseizure medication absorption due 
to nausea and vomiting. It is useful to see patients at frequent intervals 
during pregnancy and monitor serum antiseizure drug levels monthly; 
the risk of seizure exacerbation increases when serum levels decrease 
>35% from prepregnancy levels. Measurement of the unbound drug 
concentrations may be useful if there is an increase in seizure fre­
quency or worsening of side effects of antiseizure drugs.
CHAPTER 436
The overall incidence of fetal abnormalities in children born to 
mothers with epilepsy is 5–6%, compared to 2–3% in healthy women. 
Part of the higher incidence is due to teratogenic effects of antiseizure 
drugs, and the risk increases with the number of medications used 
(e.g., 10–20% risk of malformations with three drugs) and possibly 
with higher doses. A meta-analysis of published pregnancy registries 
and cohorts found that the most common malformations were defects 
in the cardiovascular and musculoskeletal system (1.4–1.8%). Valproic 
acid is strongly associated with an increased risk of adverse fetal out­
comes (7–20%). Findings from a large pregnancy registry suggest that 
the newer antiseizure drugs are far safer than valproic acid.
Seizures and Epilepsy
Because the potential harm of uncontrolled convulsive seizures on 
the mother and fetus is considered greater than the teratogenic effects 
of antiseizure drugs, it is currently recommended that pregnant women 
be maintained on effective drug therapy. When possible, it seems 
prudent to have the patient on monotherapy at the lowest effective 
dose, especially during the first trimester. For some women, however, 
the type and frequency of their seizures may allow for them to safely 
wean off antiseizure drugs prior to conception. Patients should also 
take folate (1–4 mg/d), because the antifolate effects of anticonvulsants 
are thought to play a role in the development of neural tube defects, 
although the benefits of this treatment remain unproven in this setting.
Enzyme-inducing drugs such as phenytoin, carbamazepine, oxcar­
bazepine, topiramate, phenobarbital, and primidone cause a transient 
and reversible deficiency of vitamin K–dependent clotting factors in 
~50% of newborn infants. Although neonatal hemorrhage is uncom­
mon, the mother should be treated with oral vitamin K (20 mg/d, 
phylloquinone) in the last 2 weeks of pregnancy, and the infant should 
receive intramuscular vitamin K (1 mg) at birth.
■
■CONTRACEPTION
Special care should be taken when prescribing antiseizure medications 
for women who are taking oral contraceptive agents. Drugs such as 
carbamazepine, phenytoin, phenobarbital, and topiramate can signifi­
cantly decrease the efficacy of oral contraceptives via enzyme induc­
tion and other mechanisms. Patients should be advised to consider 
alternative forms of contraception, including intrauterine devices and 
other long-acting reversible contraceptives, or their oral contraceptive 
medications should be modified to offset the effects of the antiseizure 
medications. Estrogen-containing oral contraceptive agents induce 
glucuronidation of lamotrigine and can decrease lamotrigine serum 
levels by >50%.
■
■BREAST-FEEDING
Antiseizure medications are excreted into breast milk, and the ratio of 
drug concentration in breast milk relative to serum ranges from ~5% 
(valproic acid) to 300% (levetiracetam). Given the overall benefits 
of breast-feeding and the lack of evidence for long-term harm to the 
infant by being exposed to antiseizure drugs, mothers with epilepsy 
should be encouraged to breast-feed unless there is evidence of drug 
effects on the infant, such as lethargy or poor feeding.