It is estimated that 20% to 40% of children
presenting with epilepsy have an identifiable etiology that would
place them in the symptomatic category.2 Nonetheless, the
consideration of a possible underlying etiology dominates the initial
evaluation of a child presenting with epilepsy. Many of the causes
listed below are identifiable using magnetic resonance imaging (MRI).
When MRI does not reveal an etiology for the epilepsy, further evaluation
of potential genetic and metabolic causes should be undertaken. Table 558-1 lists some of the major diagnostic
considerations that will motivate a thorough evaluation.
Many of the individual conditions are discussed in other chapters.
Symptomatic epilepsy should be suspected in a child with epilepsy
in the following conditions: (1) any child with new onset of localization-related
(focal) epilepsy; (2) any child presenting with epilepsy with other neurological
symptoms, such as developmental delay, or signs, such as hemiparesis;
and (3) any child with a history or examination that leads to the
suspicion of a specific etiology. Uncovering a specific etiology
does not necessarily lead to a specific treatment based on the mechanisms
of epileptogenesis of each condition, but this may provide prognostic
information and allow the treating physician and family to focus
on the treatment rather than on the cause of the epilepsy.
Acquired Neurological Conditions
Leading to Symptomatic Epilepsy
Some of the causes of symptomatic epilepsy are neurological insults
that may occur at any time in otherwise neurologically normal children.
These etiologies include hypoxic-ischemic injury, head trauma, intracerebral hemorrhage,
ischemic or thrombotic stroke, brain tumor, and central nervous
system infection. Any of these conditions, particularly hypoxic-ischemic
injury and infection, may arise prenatally or perinatally as well.
In many cases, the history of the antecedent neurological condition
is known at the time of presentation of unprovoked seizures. Acute
symptomatic seizures may have been part of the initial presentation,
but the epilepsy (defined as recurrent unprovoked seizures) typically
occurs months or years later. On the other hand, the same condition
may initially present with epilepsy, with neuroimaging performed
as part of the evaluation for new onset epilepsy revealing a remote etiology.
One such example is the previously asymptomatic in utero or
Careful consideration of historical factors predisposing a child
to such neurological conditions, as well as clues on the general
and neurological examinations, may help elucidate a remote etiology.
For example, perinatal depression would suggest neonatal hypoxic-ischemic encephalopathy,
and congenital heart disease would raise the suspicion of stroke.
Microcephaly might suggest a history of congenital infection.
An important cause of symptomatic epilepsy is congenital malformations
of cortical development.4 These include small focal regions
of cortical dysplasia, large hemispheric abnormalities, such as
hemimegalencephaly, and widespread abnormalities, such as lissencephaly,
subcortical band heterotopia, polymicrogyria, and periventricular
heterotopia. These malformations are usually identifiable on 1.5
or 3 Tesla MRI. The age of presentation of seizures and the extent
of cognitive and other neurological problems associated with these
malformations are widely variable. They comprise about 40% of
patients with medically intractable epilepsy.5
Neurocutaneous syndromes are frequently associated with epilepsy,
and it may be the epilepsy that brings children with such conditions
to medical evaluation and diagnosis. Notably, in tuberous sclerosis
complex (TSC), up to 80% to 90% of affected individuals
are reported to have epilepsy. Although there are a number of central
nervous system manifestations of TSC, the cortical tubers have been
shown to give rise to seizures.6 Neurofibromatosis type
1 is another neurocutaneous syndrome that predisposes to epilepsy,
and macrocephaly, ocular findings, and dermatological findings may suggest
this diagnosis. These and the other syndromes listed in Table 558-1 are included in Chapter 198.
Many genetic syndromes include seizures and epilepsy as part
of their phenotype, but a few bear specific mention in the setting
of symptomatic epilepsy. Wolf-Hirschorn (4p monosomy) syndrome and
ring chromosome 20 are both conditions that might be suggested by dysmorphic
features and systemic abnormalities and can be diagnosed by karyotype.
Fragile X syndrome, Angelman syndrome, and Rett syndrome also have
specific features accompanying epilepsy and are discussed elsewhere
in this text. Fragile X can sometimes be ascertained by karyotype,
but if there is high suspicion for this condition, molecular testing
must be performed. Specific molecular genetic testing is required
to diagnose Angelman and Rett syndromes.
Another group of genetic disorders giving rise to symptomatic
epilepsy are the progressive myoclonus epilepsies (PMEs). They present with
the constellation of myoclonic and tonic-clonic seizures, myoclonus,
ataxia, and progressive neurological decline. The prototypical PMEs
include Unverricht-Lundborg disease, Lafora disease, sialidosis
types I and II, neuronal ceroid lipofuscinosis, dentatorubral pallidoluysian
atrophy, and myoclonic epilepsy with ragged red fibers. Unlike the
symptomatic epilepsies mentioned thus far, these disorders are usually
associated with generalized epileptiform abnormalities on EEG.
A wide range of inborn errors of metabolism can be associated
with epilepsy, and examples are listed in Table
Evaluation of the
Patient with Suspected Symptomatic Epilepsy
The epilepsy associated with the symptomatic etiologies is most
often localization-related or arising from focal areas of cortex.
Electroencephalography (EEG) will often show focal abnormalities,
including epileptiform spikes or focal slowing, though it may be
normal. A notable exception occurs with generalized abnormalities
seen with the PMEs. It is important to try to record the EEG in
both the awake and asleep states because sleep may potentiate epileptiform
Especially if the history, physical examination, or EEG suggests
a structural etiology for epilepsy, MRI should be performed first
and as soon as is practical. If the MRI is normal, both a complete
genetic as well as metabolic evaluation must be performed in a patient
thought to have symptomatic epilepsy. If the examination suggests
a specific genetic syndrome or if there are multiple dysmorphic
features, evaluation with a karyotype and testing for specific conditions should
be performed. If these evaluations are unrevealing of a diagnosis,
chromosomal microarray analysis or other genome-wide screens for deletions
and duplications may be indicated, and the clinician should consider
consultation with a geneticist if there is continued strong suspicion of
a genetic etiology. In the absence of a structural or genetic diagnosis
and in the presence of symptoms suspicious for metabolic disorders (eg,
history of developmental regression, history of unexplained coma),
a screening metabolic evaluation should be performed.