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Epilepsia. 2011 January ; 52(Suppl 1): 7–12. doi:10.1111/j.1528-1167.2010.02905.x.

Epilepsy, Cognition, and Behavior: The clinical picture

Anne T. Berg, Ph.D.

Epilepsy Center, Northwestern Children’s Memorial Hospital, Chicago, IL, And Northern Illinois
University, DeKalb, IL, Fax: 815-653-0461
Anne T. Berg: Atberg@niu.edu

Abstract
Although epilepsy is defined by the occurrence of spontaneous epileptic seizures, a large body of
evidence indicates that epilepsy is linked to a spectrum behavioral, psychiatric, and cognitive
disorders as well as to sudden death. Explanations for these associations include: (1) The effects of
structural lesions which may impair the functions subserved by the regions of the brain involved in
the lesion. (2) The effects of seizure activity which may begin well before a clinical seizure occurs
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and may persist long after it is over raising questions about what truly constitutes “interictal.” In
addition, encephalopathic effects of epilepsy in infancy during critical periods in development
may be particularly severe and potentially irreversible. (3) Shared mechanisms underlying seizures
as well as these other disorders in the absence of structural lesions or separate diseases of the CNS.
Epidemiological and clinical studies demonstrate the elevated risk of cognitive, psychiatric, and
behavioral disorders not just during but also prior to the onset of epilepsy (seizures) itself. These
may outlast the active phase of epilepsy as well. The mounting evidence argues strongly for the
recognition of epilepsy as part of a spectrum of disorders and against the notion that even
uncomplicated epilepsy can a priori be considered benign.

Keywords
brain lesions; development; co-morbidity; encephalopathy; interictal discharge; progressive
effects; seizures

Epilepsy is defined by its quintessential and obligatory symptom, spontaneous epileptic

seizures. Most of the focus of clinical care including AED and surgical therapy is directed at
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controlling these seizures. A large literature repeatedly highlights the observation that there
are many other disorders that co-segregate with epilepsy and occur in people with epilepsy
at rates much higher than what would be expected in the general population. People,
especially those with childhood onset epilepsy, do not do as well as expected with respect to
school completion, employment, marriage, and parenthood (Camfield et al. 1993, Gaitatzis
et al. 2004, Shackleton et al. 2003, Strine et al. 2005, Tellez-Zenteno et al. 2007). They are
more likely than others to report symptoms of depression, sleep disturbances, and pain
syndromes. Approximately a quarter of all children in the population with epilepsy have
impaired intellectual function consistent with the designation “mental retardation.” (Berg et
al. 2004, Camfield et al. 2002). Death rates are higher from all causes(Lhatoo et al. 2001)but
of particular concern are sudden death and suicide. Sudden death may account for 10–20%
of the mortality seen in epilepsy, may occur at any age, and is particularly of concern in
patients with uncontrolled tonic-clonic seizures (Walczak et al. 2001, Nashef et al.

Disclosure: I confirm that I have read the Journal’s position on issues involved in ethical publication and affirm that this report is
consistent with those guidelines. I have no conflict of interest to disclose.
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2007)although asytole, a potential mechanism for SUDEP, can be seen with nonconvulsive
seizures as well (Rocamora et al. 2003, Zijlmans et al. 2002). Suicide risk is also increased
by up to five-fold following the diagnosis of epilepsy (Christensen et al. 2007). Finally,
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there is a strong association between autism and epilepsy in childhood (Tuchman et al.
1991).

There are many explanations for these findings. This review focuses on (1) the impact of the
underlying structural lesions and other conditions that cause epilepsy, (2) the effects of
seizures and inter-ictal discharges on brain function, and (3) potential shared mechanisms
that may produce epilepsy and independently cause some of the other disorders seen so
frequently in people with epilepsy.

Structural lesions
Approximately a quarter of all childhood epilepsy occurs in association with identifiable
structural brain lesions, presumed early insults as evidenced by cerebral palsy, or other
metabolic-genetic encephalopathies. Pre-and perinatal hypoxic-ischemic insults and stroke
as well as malformations of cortical development are the most common structural lesions
seen in childhood onset epilepsy (Berg, et al. 2009). In adults, one would expect to see a
different spectrum of causes with stroke, tumor, and trauma being most common. Most of
our information regarding underlying causes is from developed countries with relatively low
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infant mortality rates and long life-expectancies. Ultimately, the causes of epilepsy reflect
the epidemiology of neurological morbidity and can be expected to vary from one age group
to another and from one region of the world to another. To the extent that the integrity of
brain function is dependent on the integrity of brain structure, it is not surprising that people
whose epilepsy is attributable to a structural or metabolic cause have high rates of a variety
of difficulties. In one study, 64.5% children with abnormal brain imaging had intellectual
impairments (IQ<80), and 9.4% died. By comparison, in those without structural-metabolic
causes, 15.2% were intellectually impaired and <1% died (both p-values <0.0001) (Berg et
al., 2009).

Effects of seizures and interictal discharges

Seizures and interictal activity may also contribute to cognitive and behavioral disturbances.
These effects may be loosely partitioned into three types although the boundaries between
these categories are increasingly blurred.

1. Episodic transient effects

In addition to the obvious disruptions due to seizures themselves, some evidence indicates
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that interictal discharges, brief enough not to produce overt, recognizable clinical seizures,
may still have subtle but important effects on the quality of ongoing cognitive activity
(Kasteleijn-Nolst Trenité et al. 1987). A recent review suggested that much of what was
being called “interictal” epileptiform activity was in fact ictal activity associated with subtle
seizures (Aldenkamp and Arends 2004). We are beginning to understand that there is likely
a continuum in the manifestations and impacts of epileptiform discharges. This raises
questions about where exactly to draw the line between ictal versus interictal and seizure
versus non-seizure.

Post-ictal disruption of behavior and function is a well-documented phenomenon. Abundant

clinical anecdote and now some evidence from both humans and animal models suggests
that the postictal effects of some seizures may persist in subtle form for far longer than
previously appreciated. In a study of patients with newly-presenting motor seizures, Badawy
et al. demonstrated that 24 hours prior to a seizures, there were discernable increases in

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motor cortex excitability as measured by transcranial magnetic stimulation. During the 24

hours after, there was a detectable decease (depression) in excitability in the same areas
(Badawy et al. 2009). These were motor seizures; however, potentially similar patterns may
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occur in association with virtually any type of seizure leaving the question of the impact of
this subtle postictal suppressionon subtle cognitive functions. In adult rats, Lin demonstrated
seizure-related declines in a spatial hidden goal task. Rats that had been trained in this task
increasing lost proficiency over 11 days day during which a seizure was induced each day.
During the 9-day post-seizure recovery period, experimental rats eventually returned to
baseline levels of performance, similar to control rats (Lin et al. 2009). These types of
studies extend the notion of postictal and point to prolonged subclinical postictal effects.
Further, if these findings accurately reflect what happensin uncontrolled human epilepsy, it
raises that possibility that patients with daily seizures may never have periods in which they
are truly interictal but are always to some degree in an ictal or peri-ictal state.

2. Progressive effects
In adults, and particularly in the case of mesial temporal lobe epilepsy, there is good reason
to believe that the structural hippocampal damage is progressive (Briellmann et al. 2002).
Damage may extend beyond the hippocampus and surrounding limbic structures. A small
but potentially important thinning of the neocortex has been documented to occur over time
in patients with ongoing MTLE (Bernhardt et al. 2009). These changes may explain the
progressive decline in cognitive function, particularly memory functions, seen in these
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patients. In one series, substantial proportions (25–55%) of patients with MTLE incurred
significant losses on tests of memory, confrontational naming, and also fine motor function
over the course of four years(Hermann et al. 2006). Fewer than 5% of controls (as expected
by chance) experienced such losses.

3. Encephalopathic effects
The concept of epileptic encephalopathy is not new and is often used to refer to a group of
very severe epilepsy syndromes with onset typically in infancy though early childhood
(Dulac 2001). The recent report from the ILAE Commission on Classification and
Terminology (Berg et al. 2010)formally defined the concept as meaning that “ The epileptic
activity itself may contribute to severe cognitive and behavioral impairments above and
beyond that expected from the underlying pathology alone (e.g. cortical malformation).”
Evidence from laboratory models of long-term potentiation, the cellular basis of learning
provides a plausible basis for seizure activity to disrupt learning, memory and other
functions (Lamprecht and LeDoux 2004). A critical departure from other work in this area
was the proposition that the encephalopathic effects of seizures might occur in any form of
epilepsy and at any age. In fact, given the evidence of prolonged transient effects of
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individual seizures (e.g. (Badawy et al., 2009, Lin et al., 2009), some of the encephalopathic
effects could represent sub-clinical postictal phenomenon which, if seizures are frequent,
could be virtually continuous.

The work of Lin et al. cited above was in adult rats. The effects were reversible. The reason
for the concept of epileptic encephalopathy having developed in childhood epilepsy first is
because of the dramatic deficits seen in children with syndromes such as West, Dravet, and
Lennox-Gastaut. Approximately three quarters of children with these syndromes have
mental retardation or are developmentally devastated (Berg et al. 2008a). The risk of autism
or autistic features is also high, particularly in West syndrome (Saemundsen et al.
2007)suggesting the epilepsy, mental retardation, and autism form a triangle of
encephalopathy. In these and other syndromes, there is a strong impression that the epileptic
activity itself interferes with normal processes of brain development during critical times in

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development. In essence, the seizures create an epileptic cacophony which derails the initial
efforts to establish functional connections and networks.
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The process underlying epileptic encephalopathy need not be limited to those electro-clinical
syndromes traditionally identified as such but should apply to virtually any form of epilepsy.
Young age at onset, however, should still confer a high vulnerability, and all evidence so far
indicates that it does. For example, in a series of children referred for surgical evaluation,
Vasconcellos studied the association of age at onset, seizure frequency, and underlying
cause with cognitive test scores (Vasconcellos, et al. 2001). Their results demonstrated a
clear strong correlation between younger age at onset and lower IQ (r=0.36, p<0.001). The
combined impact of seizure frequency and young age at onset was striking. Of children with
age at onset >2 years and with seizures occurring monthly to weekly, 3% had mental
retardation. In that same age group, 17% of those with daily seizures had mental retardation.
In children <2 years at onset, the comparable figures were, respectively, 22% and 65%.
Specific underlying cause did not explain these findings. Thus two factors, young age at
onset and daily seizures accounted for a nearly 22-fold difference in the proportion with
mental retardation. Other studies have highlighted the relatively poor cognitive outcomes
seen in association with younger age at onset. In a separate surgical referral series of
children with intractable temporal lobe epilepsy, full-scale IQ was again strongly correlated
with age at onset (r=0.39, p=0.001) although not with duration of epilepsy (r=−0.06, p=0.64)
(Cormack et al. 2007). Of children with onset during the first year of life, 82% were
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intellectually disabled (including not assessable) compared to 32% of those with older age at
onset (p<0.001). In a study of adults with chronic temporal lobe epilepsy, patients with
younger age at onset (<7 years, reflecting the median of the case group) had lower cognitive
scores than did cases with older age at onset (Hermann et al. 2002). Older onset cases were
closer to healthy controls than they were to younger-onset cases. Finally, in a community
based study of all forms of epilepsy, children with younger age at onset (<5 years) were
more likely to have evidence of intellectual impairment compared to those with older onset
regardless of the type of epilepsy and regardless of whether the epilepsy was
pharmacoresistant or not (Berg et al., 2008a). In all, these studies converge on the
conclusion that young age at onset is associated with greater cognitive consequences. The
hypothesis of epileptic encephalopathy may explain at least part of this repeated finding.

The hypothesis of epileptic encephalopathy also comes with the prediction that effective
intervention may reverse some of the cognitive losses and in the case of developmental
encephalopathic effects, rescue development from what might otherwise be irreversible
effects. This is very hard to study in the human situation; however, repeated observations,
largely from the surgical literature provide some support for this notion. Two surgical
studies of children with very young age at onset (average 1–2 years) found striking
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correlations between duration of epilepsy prior to surgery and post-surgical developmental

quotients (DQ); the longer the delay to surgery, the lower the DQ (Freitag and Tuxhorn, I
2005, Jonas et al. 2004). Generally, improvements were confined to children who became
seizure free after surgery. Although the preference is for early intervention, it is possible that
even delayed intervention may still be of some benefit. In a series of children with Lennox-
Gastaut syndrome who underwent resective surgery to treat their epilepsy, a 9-point gain in
pre-to postsurgical DQ was found in those children who became completely seizure-free
even though many of them had substantial delays prior to surgery (Lee, et al. 2010).
Although additional evidence is needed, the current evidence is compelling enough and
strongly supports a recent recommendation from the ILAE Subcommission on Pediatric
Epilepsy Surgery that any child whose seizures have failed to come under complete control
after the use of two or three AEDs should be evaluated at a comprehensive epilepsy center
(Cross, et al. 2006).

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Essential Co-morbidity
In addition to the obvious effects of demonstrable brain lesions and other disorders and apart
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from the effects of the seizures themselves, there is a growing body of literature
demonstrating that various cognitive and psychiatric co-morbidities may precede the onset
of epilepsy, that is these disorders appear to identify individuals at increased risk of
developing epilepsy. This pattern of findings suggests the possibility that some of these
various co-morbidities may share common mechanisms with epilepsy, the hypothesis of
“essential co-morbidity.” This is of particular interest in the case of epilepsy in people with
no identifiable structural lesion or metabolic disorder underlying their epilepsy who are
sometimes referred to as having “just epilepsy.”

In the recent SANAD study (Taylor et al. 2009), patients with newly diagnosed but not yet
treated epilepsy as well as healthy controls participated in a battery of neurocognitive tests.
Even prior to initiating treatment, cases scored relatively worse compared to controls on 11
of 14 tests, in some cases substantially so. These findings suggest that subtle cognitive
impairments likely preceded the onset of epilepsy as these patients had only had a few
seizures at the time of testing.

In a population-based, prospective incident case-control study, children with newly

diagnosed epilepsy were compared to age and sex-matched controls from the population. A
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standardized psychiatric interview was used. Cases were two to three times as likely as
controls already to have met criteria for attention deficit disorder. This was true for boys and
girls separately and particularly true for the inattentive type of the disorder.

Within that same study and extending the age range into adulthood, the authors found that
cases were more likely than matched controls to have, in the past, suffered significant
symptoms of depression. They were approximately five times as likely to have attempted
suicide. Thus, the association goes both ways: people with epilepsy are at increased risk of
committing suicide (Christensen et al., 2007)and people who are depressed or who have
attempted suicide are more likely to develop epilepsy (Hesdorffer et al. 2006). In this
context, it is worth noting that there is an increased risk of cardiac events (including sudden
death) associated with both depression (Frasure and Lespérance, 2008)and with epilepsy
(Nashef et al. 2007). Reviews by Dr. Kanner and by Dr. Richerson in this issue explore
some of the mechanisms linking these three disorders.

Co-morbid conditions after epilepsy is resolved

Epilepsy often lasts for only a few years. At this point in time, we have very little
information about whether the cognitive, behavioral, and psychiatric disorders seen in
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epilepsy resolve with the epilepsy itself or whether they persist. Certainly in the case of
disorders directly attributable to an underlying lesion, we would not expect the disorder to
resolve. In the case of developmental encephalopathic effects, we would also not expect a
full recovery. In the case of shared mechanisms “essential co-morbidity,” it is less clear.
Some studies have found poor educational and social outcomes in people with childhood
onset epilepsy (Camfield et al., 1993, Shackleton et al., 2003)however, those studies do not
entirely address the issue. In one prospective study of childhood onset epilepsy, cases with
epilepsy of genetic or unknown cause were compared to their sibling controls (Berg et al.
2008b). Only cases and controls with full scales IQ ≥60 were included. Cases were more
likely than their sibling controls to have IQ scores in the borderline to very mild MR
range(60–79) (13% vs 5%, p=0.005). Cases had lower scores than their sibling controls on
almost all cognitive and achievement measures. When comparisons were limited to only
pairs in which both case and control had FSIQ≥80, a residual effect was still seen in
processing speed. Adjustment for the case’s remission and drug status did not influence the

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findings. This could represent a subtle but potentially important form of residual cognitive
difficulty. In light of studies reviewed above that demonstrate that depression, suicidality,
attention deficit disorder, and subtle cognitive impairments preceded the onset of seizures,
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we are left with the question whether these co-morbidities of epilepsy may persist long after
the seizures themselves have been controlled or, as in the case of some pediatric syndromes,
completely resolved. Is there a post-clinical phase to otherwise seemingly uncomplicated
epilepsy, and if so, how is it to be addressed?

Conclusions
Epilepsy is a complex set of brain disorders with epileptic seizures being the quintessential
defining element. Abundant evidence makes it clear that there is a spectrum of cognitive,
behavioral, and psychiatric disorders that appear to be part and parcel of many forms of
epilepsy. Investigations in so many areas of the neurosciences, as discussed by others in this
supplement, are beginning to elucidate the basis for these associations, and these discoveries
may contribute to the development of therapies and management techniques that will better
enable physicians to treat the full spectrum of disorders that epilepsy entails. In this context,
it is worth noting that the ILAE recently recommended that the term “benign” no longer be
used to describe epilepsy precisely because of the large number of disorders often seen in
association with even relatively uncomplicated epilepsy (Berg et al., 2010). For the
practicing clinician, perhaps the most important message to remember is that there is no
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such thing as “just epilepsy.” Any patient with epilepsy should be viewed as someone who
is at risk of encountering a variety of consequences including cognitive difficulties,
behavioral disorders, depression, suicide, and also sudden death. There is absolutely no
reason to re-stigmatize epilepsy, but there is every reason to make sure physicians, patients,
families, as well as educators and others are adequately prepared to recognize any such
difficulties and to manage them appropriately as they arise.

Acknowledgments
The Author receives funding from the National Institute of Neurological Disorders and Stroke, grant # R37-
NS31146.

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