3303Pathobiology of Neurologic Diseases CHAPTER 424

with mitochondrial fragmentation, and apoptosis enhanced by withdrawal of growth factor support. However, many of these phenotypes

were observed in pluripotent cells prior to neural differentiation and

in neural progenitors and a broad array of CNS neurons in contrast to

the cell type–specific features of the disease. Nonetheless, neurons that

assumed striatal fate appear to be more vulnerable to stress and apoptosis than other cell types. As with other iPSC models of nervous system

diseases, there have so far been few efforts to validate results in multiple

iPSC lines having different genetic backgrounds but with similar CAG

repeat lengths. An HD consortium has been formed to address this

problem by generating a series of iPSC lines from multiple patients. An

alternative strategy to validate disease phenotypes has been to use gene

editing to create isogenic iPSC lines that are corrected to produce wildtype control and HD iPSC lines against the same genetic background.

FUTURE PERSPECTIVES

Despite early successes, it may prove difficult to reconstitute neurodegenerative disease conditions in human cells in vitro over a short

course of time because the pathogenic changes of degenerative diseases

progress slowly and commence in the later stages of life. The differentiation and maturation of human neurons from stem cell lines occur

over a span of months, which may not be long enough to establish the

aged-brain conditions under which patients develop robust neurodegenerative pathology. Possible manipulation through gene editing or

by application of aging-associated stresses, such as DNA-damaging

agents or proteasome inhibitors, may accelerate the expression of

degenerative phenotypes in human iPSC-derived cellular models. Stem

cell–derived organoid models are also ideal platforms to apply methods for cellular-level visualization such as clarity and multi-electrode

recording techniques to better evaluate three-dimensional organoid

structures and explore early-forming circuits. These applications are

only just beginning.

Two-dimensional cell cultures are ideal for production and evaluation of large numbers of specific cells of a particular identity, but may

not provide the complex extracellular environment necessary to model

certain disease processes, such as extracellular protein aggregation.

These features can be best modeled using three-dimensional organoids,

but current methods do not reproduce all the relevant features of brain

tissue. Optimization will be needed to better reproduce the cellular

composition of brain, including endothelial cells, astrocytes, microglia,

and oligodendrocytes. It may also be necessary to combine different

brain regions generated separately, possibly by fusion of tissues such

as dorsal cortex, subpallium, thalamus, retina, and others. However,

currently there is a limited ability to recreate tissues or neurons with

regional brain identity, such as hippocampus, thalamus, or cerebellum.

More faithful organoid models could also emerge through the application of bioengineered scaffolds, matrices, or perfusion systems that

might allow the growth of larger structures. Of course, not all aspects of

mature brain architecture and function will be modeled by these tissue

structures, particularly as they represent fetal stages of development,

but perhaps the most precocious events in disease etiology can be captured and investigated and these may share mechanistic pathways with

disease features that manifest at later stages.

The current excitement surrounding human stem cells has more to

do with their promise to improve on animal models of disease than

their potential as a source for cell-based therapies. Even without new

insights into disease pathogenesis, there is promise that iPSC models

such as brain organoids will act as drug-screening platforms for discovery of novel therapeutics and for detection of off-target and toxic

effects. The failure of many neurotherapeutic approaches to translate

from animal models to clinical practice underscores the need for better

predictive models, and stem cell models and brain organoids based on

human cells may be ideally suited to bridge this divide.

A CURRENT PERSPECTIVE ON NEURAL

STEM CELLS IN THE CLINIC

The prospect of stem cell therapies to treat diseases or injuries of the

nervous system has captured the attention of researchers, clinicians,

and the public. The pace of research is usually slow and deliberate, but

in the stem cell arena there has been enormous pressure to accelerate

the pace of progress in order to bring cell-based therapies to the clinic.

Expectations have been raised, and clinics have already begun offering

unproven or dangerous treatments to a public that is ill-informed and

vulnerable to exploitation. Nonetheless, there is cautious optimism that

stem cells will eventually realize the promise of regenerative therapy

for at least some currently untreatable or incurable nervous system

diseases.

Pursuit of a cell-based therapy for PD has been ongoing for many

decades. Following anecdotal success in a handful of patients who

appeared to improve following striatal grafts of fetal midbrain dopaminergic cells, two National Institutes of Health funded, double-blind

control studies were launched in the 1990s. However, only a small

number of younger patients showed some benefit, and several patients

developed spontaneous dyskinetic movements related to the therapy.

These efforts constituted a failed trial as the treated patients who did

not experience side effects failed to improve significantly. However,

techniques to extract dopaminergic cells from fetal tissue have been

improved, and on the basis of encouraging results in individual transplanted patients, some of whom have managed to go off their Parkinson’s medication, a new trial of fetal cell transplantation for PD has

started in Europe. This is a very consequential trial, as a poor clinical

outcome could dampen enthusiasm for the planned follow-up stem cell

trials in PD and possibly in other disorders as well.

Meanwhile, the dyskinesias that curtailed the NIH trials in the 1990s

were eventually ascribed to an abundance of serotonergic neurons

that were inadvertently included in some of the cell grafts. Protocols

for deriving dopaminergic neurons from stem cells could potentially

avoid this complication by providing a more purified cell population,

and several groups around the world have been aggressively pursuing

a stem cell–based approach to PD. In 2018, researchers from Kyoto

University in Japan started a phase 1/2 clinical trial to treat PD using

stem cells. The investigators chose to use iPSCs derived from a healthy

person who had the most common HLA haplotype in Japan. The iPSCs

were used to make dopamine-secreting neurons. Seven patients will

have the reprogrammed stem cells surgically delivered into the brain

and be followed for 2 years postinjection to assess safety and possible efficacy. The U.S. Food and Drug Administration (FDA) recently

approved the first clinical trial of a stem cell–derived dopamine neuron

for the treatment of PD in the United States. These cells, derived from

an embryonic stem cell line, will be delivered to 10 patients in a phase

1 clinical trial to assess safety, tolerability, and preliminary efficacy. A

European trial led by scientists in Sweden and the UK is expected to

begin soon and will also use dopamine-secreting midbrain-like neurons derived from embryonic stem cells.

One of the first cell-based clinical trials for a neurologic disease targeted patients suffering from an untreatable childhood disorder, Batten

disease. Batten disease is an autosomal recessive metabolic disorder

resulting from an inability to synthesize a lysosomal enzyme critical

to brain function. The phase 1 trial involved six patients with infantile

and late-infantile forms of the disease who received neural stem cells

rather than any specific postmitotic cell type. Neural stem cells derived

from donated fetal tissue were expanded in vitro prior to surgical grafting into the brain. This approach was not without risk, as the neural

stem cells were proliferating and could potentially form an abnormal

growth. The rationale was that the cells would be capable of synthesizing and secreting the missing lysosomal enzyme and would therefore

serve as a delivery device. Animal studies using a transgenic mouse

model of Batten disease demonstrated rescue, and this promising result

led to a small phase 1 trial. The phase 1 study was considered a success

as no adverse events were reported and the cells appeared to be safe,

though there was no clinical improvement and no clear evidence of

whether the cells had dispersed, transformed into neurons or glia, or

indeed survived at all. Despite clearing the phase 1 trial, the company

did not pursue further trials for Batten disease, but instead initiated

clinical trials using the same cell product for several other indications, including an inherited fatal dysmyelination syndrome known

as Pelizaeus-Merzbacher disease (PMD). The human neural stem cells

have both neurogenic and gliogenic potential, and when delivered to

3304 PART 13 Neurologic Disorders

white matter regions in experimental animals, most persisting cells had

become oligodendrocytes. This supported use of the cells to promote

myelin formation in conditions such as PMD. The company also initiated trials in spinal cord injury. However, the spinal cord trial failed to

achieve sufficient benefit in phase 2 and the company ceased its work

on stem cell therapies.

Spinal cord injury is an attractive target for novel therapies because

there are more than 1 million patients suffering from spinal cord

injuries worldwide, with no effective treatment options. Not surprisingly, there has been intense interest in achieving a stem cell treatment

for this condition and dozens of early-stage clinical trials, and anecdotal treatment results have been reported by investigators around the

globe. The vast majority have not been blinded controlled trials, but

rather individual reports treating a handful of patients and somewhat

surprisingly, most are using mesenchymal (MSC) or hematopoetic

stem cells that normally generate either bone, cartilage, fat, or blood

cells. As described below, the rationale for the use of MSCs for neurologic conditions is based on vague and poorly understood mechanisms

of action.

A series of stem cell trials designed to treat subacute spinal cord

injury is underway in the United States and Europe that are using

neural stem cells or their derivatives as potential therapeutic agents.

The first to enter clinical trials in the United States was based on a

protocol designed to generate oligodendrocytes from pluripotent

embryonic stem cells. Evidence of efficacy was obtained in animal

models following surgical grafting of cells to sites of spinal cord injury.

However, evidence of myelination of host axons was minimal, and

other mechanisms were invoked for improvement in gait, including

trophic support and immune modulation. Regulatory permission for

a phase 1 trial for subacute midthoracic injury was initially stalled by

concern over abnormal growths at sites of cell deposit in some animals,

but this was satisfactorily addressed and patient trials commenced.

However, following a change in leadership, the stem cell program was

terminated. The program was acquired by another company that has

resumed the spinal cord injury trial and received regulatory approval

to advance to include cervical-level injuries. The current phase 1/2a

multicenter clinical trial is an open-label, single-arm trial testing three

sequential escalating doses administered 21–42 days postinjury in 25

patients with subacute severe cervical spinal cord injuries. No adverse

events have been reported for 21 patients at 2 years posttreatment. A

later stage comparative clinical trial is now planned to probe for possible efficacy.

A team from Yale University working with Japanese scientists

treated 13 patients with intravenous infusions of stem cells extracted

from the patients’ own bone marrow. The patients were treated around

40 days after their injury. They reported no adverse events and some

improvement in sensation and movement. The paper reporting these

results was published in 2021, but in 2018, on the basis of the results,

unpublished at the time, Japan’s health ministry gave conditional

approval for the treatment, called Stemirac. This became the first stem

cell therapy for spinal cord injury to receive government approval

for sale to patients. But the approval of a therapy that may carry risk

following a small, unblinded, and uncontrolled study without actual

proof of efficacy raised considerable concern among scientists in the

stem cell community. Charging patients for such an unproven therapy

raises even more ethical concerns. Patients can now be charged for

their treatment while trials to test efficacy are proceeding.

The possibility of treating ALS by replacing dying motor neurons

with stem cell–derived substitutes has excited interest, but this prospect seems very remote. Even if new neurons are able to integrate

into spinal cord circuits and become properly innervated, they would

have to grow long axons that would take many months to years to

project to appropriate targets and attract myelinating Schwann cells.

Furthermore, cells would need to be grafted at multiple spinal cord

and brainstem levels, and the upper motor neuron deficit would need

to be treated by replacing projecting neurons in the motor cortex. An

additional complication is the recent finding that spinal motor neurons

have unique segmental identity, and replacement cells might need to

be generated with a range of molecular identities in order to integrate

at multiple spinal levels. This would still leave unaddressed the toxic

effects recently shown to be produced in ALS by diseased astrocytes

and microglia that could attack the replacement cells. A more tractable

near-term solution would be to graft support cells that could rescue

or protect endogenous motor neurons from damage. This approach

was tried in a mouse model of ALS. Human stem cell–derived neural

progenitor cells engineered to express GDNF, a growth factor known

to provide trophic support for neurons, were grafted to the spinal cord

of young ALS mice. The cells dispersed and were able to rescue motor

neurons, a very promising result, but disappointingly, the animals

became weak and died at the same rate as untreated control animals.

However, ALS is a deadly disease with no known treatment. In the

hope that patients will respond differently from mice, a phase 1/2a

clinical trial based on this approach was approved by the FDA in 2016

and completed in 2019.

Among the many MSC-based clinical trials for ALS, two are particularly notable. Corestem, a stem cell company in South Korea,

launched a phase 1 open-label study demonstrating the safety and

feasibility of intrathecal injections of autologous bone marrow–derived

MSCs in seven patients with ALS. This was followed by a phase 2 trial

that demonstrated safety and efficacy for slowing disease progression.

On the basis of these results, Corestem received conditional approval

in South Korea in 2014 to market the first stem cell therapy for ALS.

By 2021, more than 300 patients had received this cell treatment.

However, full approval is contingent on the results of a randomized,

double-blind, placebo-controlled, multicenter phase 3 study, which

has yet to occur. The importance of conducting proper phase 3 clinical

trials to determine therapeutic efficacy in ALS is underscored by the

recent experience of BrainStorm Cell Therapeutics. In 2016, the company reported preliminary positive results for its bone marrow MSC

cell therapy in an uncontrolled study of nearly 50 ALS patients. Based

on those results, the company launched a multicenter, placebo-controlled, randomized, double-blind trial of 189 ALS patients. In a press

release on November 27, 2020, the company reported that there was no

significant clinical improvement in the treatment group. Interestingly,

despite the failed clinical trial, a public campaign led by ALS patients

and advocates called on the FDA to approve the stem cell treatment.

The social media response prompted the FDA to take the unusual step

of releasing a public statement underscoring the lack of efficacy.

Following Shinya Yamanaka’s discovery of iPSCs, the Japanese

government has invested in bringing iPSC-derived cell therapy to the

clinic. Banks of iPSC lines selected to capture the diversity of HLA

haplotypes found in the Japanese population are being produced in the

hope that these will allow cell therapies to be matched to individual

patient haplotypes in order to avoid immune rejection. While these

stem cell banks were still being produced, the first Japanese study to

use stem cells was approved in August, 2013, and involved patients

who were to receive customized therapy using cells derived from their

own skin fibroblasts. The targeted disease was age-related macular

degeneration, a common cause of blindness in the elderly that results

from loss of retinal pigment epithelial (RPE) cells. RPE cells are relatively easy to generate from pluripotent stem cells, making replacement

therapy an attractive target in this condition. A challenge is to coax the

replacement cells to recreate an epithelium in the subretinal space. The

Japanese approach involves surgical insertion of a biofilm seeded with

RPE cells into the retina. One patient was treated with his/her own

stem cell–derived RPE cells, but prior to treating 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.

By far the largest number of human trials have been performed

using MSCs sourced from a variety of sites including bone marrow,

peripheral blood, adipose tissue, umbilical cord, etc. Interest in the

potential utility of MSCs for regenerative therapy began with the

optimistic report that bone marrow stem cells were pluripotent and

3305 Seizures and Epilepsy CHAPTER 425

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 almost every degenerative disease

and injury model. But when it became clear that the MSCs were not

transforming into or generating new neurons or cardiac myocytes,

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 framework 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 therapies 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.

■ FURTHER READING

Ayers JI et al: Expanding spectrum of prion diseases. Emerg Top Life

Sci 4:155, 2020.

Bhaduri A et al: Are organoids ready for prime time? Cell Stem Cell

27:361, 2020.

Duncan GJ et al: Neuron-oligodendrocyte interactions in the structure and integrity of axons. Front Cell Dev Biol 9:653101, 2021.

Hickman S et al: Microglia in neurodegeneration. Nat Neurosci

21:1359, 2018.

Hong S et al: Complement and microglia mediate early synapse loss in

Alzheimer mouse models. Science 352:712, 2016.

Kandel ER et al (eds): Principles of Neural Science, 6th ed. McGraw

Hill, New York, 2021.

Li Q, Barres BA: Microglia and macrophages in brain homeostasis

and disease. Nat Rev Immunol 18:225, 2018.

Lubetzki C et al: Remyelination in multiple sclerosis: From basic science to clinical translation. Lancet Neurol 19:678, 2020.

Morais LH et al: The gut microbiota-brain axis in behaviour and brain

disorders. Nat Rev Microbiol 19:241, 2021.

Nikolakopoulou P et al: Recent progress in translational engineered

in vitro models of the central nervous system. Brain 143:3181, 2020.

Pease-Raissi SE, Chan JR: Building a (w)rapport between neurons

and oligodendroglia: Reciprocal interactions underlying adaptive

myelination. Neuron 109:1258, 2021.

Prusiner SB et al: Evidence for α-synuclein prions causing multiple

system atrophy in humans with parkinsonism. Proc Natl Acad Sci

USA 112:E5308, 2015.

Sipp D et al: Clear up this stem-cell mess. Nature 561:455, 2018.

Turner L: The US Direct-to-Consumer Marketplace for Autologous

Stem Cell Interventions. Perspect Biol Med 61:7, 2018.

Yamanaka S: Pluripotent stem cell-based cell therapy-promise and

challenges. Cell Stem Cell 27:523, 2020.

A seizure (from the Latin sacire, “to take possession of ”) is a transient

occurrence of signs or symptoms due to abnormal excessive or synchronous neuronal activity in the brain. Depending on the distribution

of discharges, this abnormal brain activity can have various manifestations, ranging from dramatic convulsive activity to experiential phenomena 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 necessarily 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 seizures, the incidence of epilepsy is ~0.3–0.5% in different populations

throughout the world, and the prevalence of epilepsy has been estimated 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 classification of seizures in 2017 (Table 425-1). This system is based on the

clinical features of seizures and associated electroencephalographic

findings. Other potentially distinctive features such as etiology or cellular 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 generalized. Focal seizures originate within networks limited to one brain

region (note that the term partial seizures is no longer used). Generalized seizures arise within and rapidly engage networks distributed

Section 2 Diseases of the Central Nervous

System

425 Seizures and Epilepsy

Vikram R. Rao, Daniel H. Lowenstein

TABLE 425-1 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

a. Motor, nonmotor, or unclassified

a

Based 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.)

3306 PART 13 Neurologic Disorders

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 abnormalities

that have a more widespread distribution. There are clear 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 subcategories of “simple focal seizures” and “complex focal seizures” have been

eliminated. Instead, the classification emphasizes the effect on awareness (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 detected using surgically placed intracranial electrodes.

Focal Seizures with Intact Awareness Focal seizures can have

motor manifestations (such as tonic, clonic, or myoclonic movements)

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 note the onset

of 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 discharges in a very limited region over

the appropriate area of cerebral cortex if the seizure focus involves the

cerebral convexity.

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 “Jacksonian march,” represents the spread of seizure activity over a progressively 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 seizure may continue for hours or days. This condition, termed epilepsia

partialis continua, is often refractory to medical therapy.

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 temporal or frontal cortex may also cause alterations in hearing, olfaction,

or emotional state. This includes the sensation of unusual, intense

odors (e.g., burning rubber or kerosene) or sounds (crude or highly

complex sounds), or an epigastric sensation that rises from the stomach or chest to the head. Some patients describe odd, internal feelings

such as fear, a sense of impending change, detachment, depersonalization, déjá vu, or illusions that objects are growing smaller (micropsia)

or larger (macropsia). These subjective, “internal” 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 ability 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

is usually accompanied by automatisms, which are involuntary, automatic behaviors that have a wide range of manifestations. Automatisms

may consist of very basic behaviors, such as chewing, lip smacking,

swallowing, or “picking” movements of the hands, or more elaborate

behaviors, such as a display of emotion or running. The patient is

typically confused following the seizure, and the transition to full

recovery of consciousness may range from seconds up to an hour or

longer. Examination immediately following the seizure may show an

anterograde amnesia or transient neurologic deficits (such as aphasia,

hemi-neglect, or visual loss) caused by postictal 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 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, distinguishing between these two entities is extremely important, because

there may be 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 characterized 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 discharge, absence seizures

are usually accompanied by subtle, bilateral motor signs such as rapid

blinking of the eyelids, chewing movements, or small-amplitude, clonic

movements of the hands.

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 unexplained

“daydreaming” and a decline in school performance recognized 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 were

3307 Seizures and Epilepsy CHAPTER 425

suspected clinically. Hyperventilation tends to provoke these electrographic discharges and even the seizures themselves and is routinely

used when recording the EEG.

Atypical Absence Seizures Atypical absence seizures have features that deviate both clinically and electrophysiologically from typical absence seizures. For example, the lapse of consciousness is usually

of longer duration 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 per second, 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 mental retardation. 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 a number of the 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 develops. 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 flaccidity, 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 nervous system (CNS) diseases such as alcoholic cerebral atrophy.

The EEG during the tonic phase of the seizure shows a progressive

increase in generalized low-voltage fast activity, followed by generalized 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, then slowing that

gradually recovers as the patient awakens.

There are a number of 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 seizure 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. Similar to

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

commonly seen in association with metabolic disorders, degenerative

CNS diseases, or anoxic brain injury (Chap. 307). Although the distinction from other forms of myoclonus is imprecise, myoclonic seizures are considered to be true epileptic events because they are caused

by cortical (vs subcortical 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,

which consist of diffuse, giant slow waves with a chaotic background of

irregular, multifocal spikes and sharp waves. During the clinical spasm,

there is a marked suppression of the EEG background (the “electrodecremental response”). The electromyogram (EMG) also reveals a

characteristic 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; additional examples with a known genetic basis are shown in Table 425-2.

■ 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. Consciousness is preserved unless the myoclonus

is especially severe. Many patients also experience generalized tonicclonic seizures, and up to one-third have absence seizures. Although

complete remission is uncommon, the seizures usually respond well to

appropriate anticonvulsant 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 generalized tonic-clonic, atonic, and atypical absence seizures); (2) an EEG

showing slow (<3 Hz) spike-and-wave discharges and a variety of

other abnormalities; and (3) impaired cognitive function in most but

not all cases. 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 disease and the physical

and psychosocial consequences of severe, poorly controlled epilepsy.

■ 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 425-3). High-resolution magnetic

resonance imaging (MRI) can detect the characteristic hippocampal

3308 PART 13 Neurologic Disorders

sclerosis that appears to be essential in the pathophysiology of MTLE

for many patients (Fig. 425-1). Recognition of this syndrome is especially 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

different 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 seizures or epilepsy in a given patient.

1. The normal brain is capable of having a seizure under the appropriate

circumstances, and there are differences between individuals in the

susceptibility or threshold for seizures. For example, seizures may be

induced by high fevers 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

TABLE 425-2 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

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

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%

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

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

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

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

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

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

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

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

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

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) (UnverrichtLundborg disease); autosomal recessive inheritance;

age of onset between 6 and 15 years, myoclonic

seizures, ataxia, and progressive cognitive decline;

brain shows neuronal degeneration

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

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

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

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

Relatively rare but of uncertain incidence; recent

increased ascertainment due to improved imaging

techniques; relationship between migration defect

and seizure phenotype unknown

a

The first five syndromes listed in the table (SHE, benign familial neonatal convulsions, GEFS+, ADEAF, and FFEVF) 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.

Abbreviations: GABA, γ-aminobutyric acid; PME, progressive myoclonus epilepsy.

3309 Seizures and Epilepsy CHAPTER 425

2. There are a variety of conditions that have an extremely high likelihood of resulting in a chronic seizure disorder. One of the best examples 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, infections, and abnormalities

of CNS development. Likewise, the genetic abnormalities associated

with epilepsy likely involve processes that trigger the appearance of

specific sets of epileptogenic factors.

3. Seizures are episodic. Seizures occur intermittently, and, depending

on the underlying cause, people with epilepsy may feel completely

normal for months or even 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. Precipitants 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.

These observations emphasize the concept that the many causes of

seizures and epilepsy result from a dynamic interplay between endogenous 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 prophylactic use of anticonvulsant drugs. An emerging concept holds that underlying seizure risk itself fluctuates cyclically, potentially explaining why the same precipitating factor (e.g., a missed dose

of antiseizure medication) 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 425-4). 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 seizures early after delivery. Seizures due to inborn errors of

metabolism usually present once regular feeding begins, typically 2–3

days after birth. Pyridoxine (vitamin B6

) deficiency, an important cause

of neonatal seizures, can be effectively treated with pyridoxine replacement. The idiopathic or inherited forms of benign neonatal seizures are

also seen during this time period.

The most common seizures arising in late infancy and early childhood 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 425-3 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 intracranial 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.

FIGURE 425-1 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.

of children. This implies there are various underlying endogenous

factors that influence the threshold for having a seizure. Some of

these factors are genetic, as a family history of epilepsy has a clear

influence on the likelihood of seizures occurring in otherwise normal individuals. Normal development also plays an important role,

because the brain appears to have different seizure thresholds at

different maturational stages.

3310 PART 13 Neurologic Disorders

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

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 an increase in the 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 the relatively late manifestation of a

developmental disorder, an acquired lesion such as head trauma, CNS

infection (especially viral encephalitis), or very rarely, 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 predominate. 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 population), including patients without an identifiable cancer. This etiology should be suspected when a previously normal individual presents

with a particularly aggressive seizure pattern developing over weeks

to months and characterized by increasingly frequent and prolonged

seizures, especially when combined with psychiatric symptoms and

changes in cognitive function (Chap. 94).

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 posttraumatic 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 associated with

only a slightly increased likelihood of epilepsy. Nonetheless, most epileptologists know of patients who have 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 chronic

epilepsy resulting from mild head injury.

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 seizures (i.e., occurring

at the time of the stroke) are seen more often with embolic rather than

hemorrhagic or thrombotic stroke. 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, vasculitides, and many other systemic diseases may cause seizures over a

broad age range. A wide variety of medications and abused substances

are known to precipitate seizures as well (Table 425-5).

BASIC MECHANISMS

■ MECHANISMS OF SEIZURE INITIATION

AND PROPAGATION

Focal seizure activity can begin in a very 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 a large number of local excitatory neurons, resulting in an apparent hypersynchronization of the excitatory

bursts across a relatively large cortical region. The bursting activity in

individual neurons (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 voltage-dependent 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 a sufficient number of neurons result in

summation of field potentials producing a so-called 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 extracellular K+, which blunts hyperpolarization and depolarizes

TABLE 425-4 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

Adolescents (12–18 years) Trauma

Genetic disorders

Infection

Illicit drug use

Brain tumor

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.