Seizure 49 (2017) 83–89

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Seizure
journal homepage: www.elsevier.com/locate/yseiz

Review

Epilepsy and cognition – A bidirectional relationship?

Christoph Helmstaedter* , Juri-Alexander Witt
Department of Epileptology, University of Bonn, Bonn, Germany

A R T I C L E I N F O A B S T R A C T

Article history:
Received 8 June 2016 Cognitive comorbidities are very common in epilepsy and often seen as secondary to epilepsy or caused
Received in revised form 9 December 2016 by epilepsy. The implicit and sometimes explicit assumption is that epilepsy (i.e. having seizures)
Accepted 28 February 2017 damages the brain and thus leads to functional deterioration and behavioral alterations. This article
highlights the historical background surrounding this viewpoint which is characterized by old reports on
Keywords: ‘epileptic dementia’ and the fact that most cognitive research in chronic epilepsies is done
Epilepsy retrospectively. The central question of the present article is whether there is a bidirectional relationship
Cognition between epilepsy and cognition. In this regard it is essential to disentangle what is the disease and what
Comorbidity
is the symptom. Cognitive problems often exist from the onset of epilepsy, if not before, and the impact of
Causal relationship
epilepsy on cognition cannot be discerned without also considering the underlying brain pathology and
its dynamics. Unraveling the etiologies of epilepsy increasingly reveals conditions wherein epilepsy,
cognitive and behavioral problems are all symptoms of a common underlying pathological condition.
Functional reserve capacities determine the outcome of epilepsy and its treatment. A functional
interrelationship exists between epilepsy and behavior, since epileptic activity can affect behavior and
behavior can alter epileptic activity. In conclusion, an epilepsy-centric unidirectional view of the
behavioral problems being caused by epilepsy is obsolete. Such a view may even prevent the search for
and treatment of the underlying etiological factors. Instead a practical clinical approach is favored
according to which the comorbidities of epilepsy must be diagnosed at the onset of the disease, and
according to which comorbidities may require separate treatment approaches.
© 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

1. Introduction epileptology leans towards a relatively epilepsy-centric view in

Cognitive impairments, as well as mood and behavioral
problems, represent very common comorbidities of epilepsy. In
chronic epilepsies, cognitive deficits are observed in about 70-80%
of patients, and a depressed mood can be seen in up to 60% [1,2]. It
is generally accepted that cognition in epilepsy is multifactorially
determined by structural brain lesions, the active epilepsy, its
treatment, and individual reserve capacities [3,4]. Whereas ictal
and postictal cognitive dysfunction is reversible [5], a commonly
held position is that with the accumulation of lifetime seizures a
progressive mental decline is present in chronic and uncontrolled
epilepsy. However, an index disease such as epilepsy and its
comorbid conditions (e.g. depressed mood, memory deficits) can
but must not be interrelated [6]. The term comorbidity neither
implies nor excludes a causal association. Nevertheless,
* Corresponding author at: Department of Epileptology, University of Bonn,
Sigmund Freud Str. 25 53105 Bonn, Germany.
E-mail address: C.Helmstaedter@uni-bonn.de (C. Helmstaedter).
which the active epilepsy with recurrent seizures is either
implicitly or overtly understood as the major origin of the mental
and behavioral problems seen with epilepsy. This suggests that the
problems should be resolved when the seizures are successfully
treated. The epilepsy-centric view, however, has recently been
challenged by observations that: a) comorbidities determine the
outcomes of epilepsies [7]; b) comorbidities often precede the
onset of epilepsy; and c) conditions exist wherein both epilepsy
and the accompanying behavioral comorbidities must be consid-
ered as symptoms or expressions of a common underlying
pathology [8].
Historically, the idea that epilepsy causes progressive cognitive
decline dates back to the term “epileptic dementia” which was
coined at the turn of the 19th century. The German psychiatrist
Emil W. G. M. Kraepelin [9] and subsequently the German
psychiatrist and neurologist Oswald Bumke [10] wrote about
epileptic dementia and the epileptic character. Kraepelin stated
that a pronounced, strange sort of dementia appears in more than
50% of the patients with epilepsy which is characterized by
generalized slowness and clumsiness of all psychic capabilities

http://dx.doi.org/10.1016/j.seizure.2017.02.017
1059-1311/© 2017 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
84 C. Helmstaedter, J.-A. Witt / Seizure 49 (2017) 83–89
(“In mehr als der Hälfte der Fälle, die dem Irrenarzt zu Gesicht
kommen, findet sich ein mehr oder weniger ausgeprägter,
eigenartiger Schwachsinn”1 p. 456, [9]). Interestingly, it was
suggested that the prevalence would even be higher after
excluding all the “simple” symptomatic cases and those cases
with so-called residual epilepsy. For example, it was a commonly
held belief that tumors were an insufficient cause for explaining
the characteristic dementia in epilepsy. The same assumption was
held for what has been called the epileptic personality which was
characterized by irritability, viciousness, hopelessness, religious
ideation, subservience, and stilted courtesy. Thus, the neuro-
psychiatrists of that time suggested that a “pure” or “genuine
epilepsy” causes mental decline and personality change. Although
the negative behavioral side-effects of the drug bromide were well
known (sleepiness, drowsiness, memory problems), and although
transient and reversible postictal impairments were well recog-
nized, it was also noted that frequent seizures can cause
permanent intellectual deficits [10]. However, the question
remains as to whether these problems occur together or whether
one phenomenon depends upon the other.
Another source of the assumed unidirectional determination of
cognitive impairments caused by epilepsy can be seen in a research
bias. The vast majority of neuropsychological studies on epilepsy
concern long-standing chronic epilepsies. This is because neuro-
psychology and the related research are predominantly performed
within the context of epilepsy surgery and pharmacological trials
(mostly add-on studies). In long-standing epilepsies, it is hardly
possible to retrospectively discern the origin, development and
determinants of actual cognitive deficits, thus leaving one with
retrospective speculations rather than prospective evidence. A
common finding of retrospective studies in chronic patients with
epilepsy is that the longer the duration of epilepsy, the worse the
cognition [11].
Finally, animal models of epilepsy have contributed to the
presumption that seizures damage the brain. In this area, there is
clear evidence highlighting the negative effect of epilepsy and
seizures on brain structure and behavior [12], but the question
remains as to whether this can easily be transferred to man [13].
Thus, the notion of recurrent seizures as the leading cause of
behavioral change and mental decline in epilepsy is a commonly
held notion throughout the world, but the question is whether this
position really holds true when closely examining the scientific
literature. The causal relationship between epilepsy and its
behavioral comorbidities was first challenged in epidemiological
studies showing that psychiatric comorbidities may well precede
the onset of epilepsy [14,15] and that they may even be viewed as a
biomarker for developing epilepsy. However, it should be noted
that similar considerations can be found with regard to dementia
and its comorbidities as it is understood that depression, mild
cognitive impairment and even subjective memory impairment
are biomarkers or first hints of who is at risk for developing
dementia [16,17].
This article also seeks to address the etiologies of cognitive and
behavioral problems in epilepsy and the sequence of their
occurrence during the course of the disease. We will question
the notion of a causal relationship between epilepsy and cognitive
impairment and discuss the conditions under which epilepsy (i.e.
having seizures) must be perceived as a symptom rather than as a
disease. Finally, we will address the impact of epileptic activity and
seizures on cognition and, conversely, the impact of cognition on
epileptic activity and seizures.
1
Translation: “In more than half of the cases, which are seen by the mad-doctor,
there is a more or less pronounced, peculiar feeblemindedness.”
2. Untangling the etiologies of cognitive and behavioral
problems in epilepsy
Cognitive and behavioral problems in epilepsy must be seen
within a multifactorial and neurodevelopmental model which,
apart from demographic patient characteristics and the type of
epilepsy, takes into account the structural morphological aspects,
seizures, interictal epileptic activity, treatments, psychiatric
comorbidites, and individual reserve capacities. Thus, cognitive
problems in epilepsy can have multiple causes which, when
viewed individually or in combination, determine the course of
cognitive development and, when taken as symptoms, are not
disease-specific [3].
The same holds true for behavioral problems. Depression can be
caused by different factors: a) it may be primarily reactive due to
conflicts or problems that might be related to having epilepsy; b) it
may be induced by antiepileptic medication; c) it could be due to
structural damage or epileptic disturbances in networks subserv-
ing emotional processing; or d) it may be the result of a common
underlying pathology or the combination of one or more of these
factors [18,19]. Different from cognitive problems, depression,
however, is usually considered a disease. In epilepsy, it may also be
seen as a symptom.
For patients with longstanding epilepsy, untangling the source
of an observed cognitive dysfunction can be challenging. If a
patient with focal cortical dysplasia and chronic frontal lobe
epilepsy, who is also depressed, is treated with a combination of
three antiepileptic drugs, including one which is known to affect
executive functions, and if the neuropsychological evaluation
reveals a low IQ and impaired executive functions, several factors
converge which may explain the impairments. The executive
deficit may be caused a number of factors: a) the underlying lesion
and/or its neuro-developmental effects; b) the active epilepsy (i.e.
seizures and interictal epileptic activity); c) the total drug load; d)
drug-drug interactions; e) any specific pharmacological agent; or f)
the lack of drive and motivation due to depression. On an
individual level, the relative contribution of the various etiological
factors can be evaluated only longitudinally with repeated
standardized assessments along with a reduction of the drug
load, exchange of the individual drugs, achievement of seizure
freedom, or after the successful treatment of the depressive
symptomatology.
On a group level, with well-defined and matched control
groups, one can easily differentiate and quantify the differential
impact of the active epilepsy, the total drug load and the
antiepileptic treatment with an individual substance on cognition
[20].
Within a multifactorial model of cognitive and behavioral
problems in epilepsy, it is also important to consider the potential
beneficial effects of the antiepileptic therapy on cognition via drug
inherent effects, positive effects on mood, and seizure control [21–
23], as well as neurodevelopmental aspects such as neuronal
plasticity and mental reserve capacities [4].
3. The impact of chronic epilepsy on cognition
As already stated, the idea that epilepsy damages the brain and
thus leads to a progressive mental decline is mostly supported by
cross-sectional studies focusing on the relation between cognition
and the duration of epilepsy. The respective finding is that the
longer the duration of epilepsy, the poorer the cognitive status.
This has been demonstrated in particular with regard to the
intelligence of patients with temporal lobe epilepsy and was
interpreted as being caused by an accumulation of noxae and
damages along with the uncontrolled epilepsy. However, the
suggested decline appears slow with a change of more than one
 C. Helmstaedter, J.-A. Witt / Seizure 49 (2017) 83–89
standard deviation over a time period of about 30 years [11]. Cross-
sectional studies generally disclose the methodological problem
which states that in chronic epilepsy, a long duration of epilepsy is
highly confounded with an earlier onset and/or an older age. Thus,
the low IQ score in a patient with a long-standing epilepsy can be
due to: a) the chronic epilepsy and the negative cumulative effect
of seizures; b) an initial impairment and its negative effects on
mental development; or c) an initial impairment interacting with
normal ageing. Again, a condition in which combinations of these
aspects contribute to the observed clinical picture at a certain time
point must also be considered. An interesting observation
concerning the lower IQ score with a longer epilepsy duration is
that the same relationship applies to education (i.e. the longer the
epilepsy, the less educated the patients). While intelligence may be
lost over time, a loss in education and degrees is not possible [24].
Therefore, this finding would imply that interference of early onset
epilepsy is associated with developmental cognitive problems
hindering acquisition of knowledge and skills rather than with a
mental decline in terms of a loss of previously acquired functions.
Another way to infer the impact of chronic epilepsy on
cognition with a cross-sectional study design is to compare age-
related regressions of cognition in patients against age-related
regressions observed in healthy controls. The comparison of
patients and healthy subjects at any given age should reveal the
time points of different mental trajectories. Interestingly, such a
procedure does not support the assumption of accelerated mental
decline with a longer duration of epilepsy, but rather shows that
impairments are established early on, that they hinder mental
development, and that their course over time is quite stable,
running parallel to, but at a significant lower level than, cognitive
ageing in healthy people [25,26].
Apart from cross-sectional studies, there is also information on
cognitive development from several longitudinal studies in
medically and surgically treated patients with epilepsy. Whereas
the age range of cross-sectional studies can cover a lifetime, the
observational periods of longitudinal studies mostly span 10 years
at best [27–31]. The longest longitudinal evaluation of a single
patient had a follow-up period of 56 years after surgical treatment
of a left temporal lobe epilepsy [32]. In this patient, a cognitive
decline from early postsurgical assessments to the long-term
follow-up at 82 years of age was restricted to functions associated
with the resection site (i.e. verbal memory and language functions)
without any debilitating effect on daily functioning. The longest
follow-up (50 years) in a cohort of children with idiopathic
symptomatic and cryptogenic epilepsies has been published by
Sillanpää et al. in 2015 [33], but this study did not take cognition
into account. However, the fact that many patients (61%) were in
terminal remission and in remission being off medications (43%)
contradicts the often assumed detrimental effects of chronic
epilepsies. Whether there is cognitive recovery with remission and
tempering of drug treatment would be of major interest.
Even when taking into account the restriction of limited
observation intervals, longitudinal group studies still provide
evidence of at least some decline. Deterioration, however, does not
appear to be the rule. Determinants of a negative trend are active
seizures and generalized tonic-clonic seizures in particular,
traumatic brain injury, structural epilepsy, as well as drug therapy
and a poorer baseline performance [27–30,34,35]. These factors
are markers for more severe epilepsies as well as for reduced
mental reserve capacities for compensation. The observations with
regard to cognitive trajectories are consistent with cross-sectional
and longitudinal MRI studies which address the question of
structural alterations over time, with some studies revealing a
volume loss while others do not display any change [36].
Postoperative studies which permit the study of the cognition
course in controlled epilepsies show that after initial losses due to
85
surgery, the long-term follow-up indicates a rather stable course, if
not an improvement due to seizure control and the reduced
antiepileptic drug load [30,37–40].
Up to this point, epilepsies having a clear negative dynamic
with progression of the epilepsy and cognitive decline have not yet
been addressed. For these so-called epileptic encephalopathies, an
effect of the epilepsy on cognition beyond the underlying
pathology is often proposed, however no common seizure-
dependent mechanism for epilepsy progression or intellectual
deterioration can be discerned [41]. Of special interest is the effect
of status epilepticus on cognition. It is the worst seizure scenario
and thus a kind of proof-of-principle. Studies which have evaluated
cognitive change over time in patients who experienced a status
within the observation interval (versus those who have not)
interestingly found either no changes or only minor changes
[5,16,42,43]. One major finding was that patients with a status
showed poorer cognition already at baseline. This would be
consistent with the cross-sectional observation in patients with
convulsive or non-convulsive status epilepticus; these groups had
a lower IQ and less education when compared to those patients
without a status in their history. This indicates that it is more likely
that a more severely damaged brain develops a status than the
theory stating that a status damages the brain [44]. This does not
imply that no clinical conditions exist whereby the underlying
pathology, of which the status is an expression, can lead to mental
deterioration and permanent damage [44]. Also, secondary
damage due to hypoxia or traumatic brain injuries due to severe
falls may cause irreversible cognitive deterioration. One can also
argue that excitotoxicity due to excitatory over-activation during
status epilepticus can cause irreversible neuronal cell loss [45].
However, lack of a clear-cut neuropsychological deterioration after
an epileptic status solely due to the ictal epileptic discharges puts
the clinical relevance of the epileptic activity into perspective.
Other than the underlying pathology, no clear evidence
currently exists which states that epileptic activity and seizure
occurrence alone can cause a significant mental decline or a
permanent irreversible cognitive impairment in chronic epilepsies.
It seems more likely that the time prior to and around epilepsy
onset is of much greater importance with regard to the origin of the
cognitive impairment than previously assumed. Accordingly, it is
essential to examine cognition at the time of epilepsy onset in
order to understand when the problems occur and what effects the
course of the disease and its treatment will have on cognition.
4. Cognition in new-onset epilepsy
Thanks to the existence of routine neuro- and social-pediatric
services, the close observation of children in kindergarten and
school, and parental concerns and efforts, most children with new-
onset epilepsy are closely monitored with regard to their mental
status and brain development. When taking all of this into account,
it is difficult to comprehend why it took so many years for
neuropsychologists to direct their focus to the onset of epilepsy in
adults. Possible reasons (i.e. research bias) have already been
mentioned. Another explanation is that neuropsychology in new-
onset epilepsies for the adult population is not as yet considered a
routine assessment and not paid for. Finally, there seems to be
scarce and insufficient communication between adults and
pediatric neurologists, which is mostly due to a lack of transition
from children to adult patient care [46]. No one would doubt that
cognitive and behavioral problems in children very often exist from
the beginning of epilepsy and that the trajectories of cognition
afterwards depend on the pathology, disease dynamics, positive/
negative treatment effects, and seizure control [47,48].
A recent review on cognition at the time of adult and late onset
epilepsies revealed what one would expect [49]. Cognitive
86 C. Helmstaedter, J.-A. Witt / Seizure 49 (2017) 83–89
impairment is very often already present at the time of epilepsy
onset. The review summarized 11 studies on untreated adult,
newly diagnosed or new-onset epilepsies. Up to 70% of the more
than 500 patients with new-onset and not yet treated epilepsies,
assessed in three of the included studies, displayed some cognitive
deficit when formally tested with psychometric tests on attention,
executive functions, and memory [49–51]. Predictors of the
presence and severity of impairment include education (protec-
tive), etiology of the epilepsy, and the presence of generalized
tonic-clonic seizures. Consequently, cognitive screening in new-
onset epilepsies should become a routine assessment, also for the
adult population [51,52]. Information concerning the patient’s
cognitive status at the onset of epilepsy and prior to the initial
treatment enables the physician to monitor the course of the
disease and to attribute the potential changes which may occur to
either the treatment’s success or failure, AED side effects, and the
dynamics of the underlying pathology. The inclusion of multiple
epilepsy centers with large cohorts of patients would permit
identification of epilepsy subgroups, responders vs. non-respond-
ers and the ability to identify suitable candidates for surgical or
other non-pharmacological treatments early in the course of the
disease [8].
Follow-up evaluations of newly diagnosed or new-onset and
first treated epilepsies provide divergent findings. Two follow-up
studies of newly diagnosed patients which were part of the SANAD
(Standard and New Antiepileptic Drug) study provided evidence of
a principally stable course, but of worsened functions as well
[53,54]. A closer look at the variables which changed reveals that
after correcting for multiple testing, the most robust changes were
seen with regard to attention, psychomotor speed and executive
functions. These functions, however, belong to those most
sensitive to drug treatment and seizure control [55,56], and there
is additional evidence from a large monotherapy study in patients
with new-onset epilepsy that the cognitive outcome can as well
vary as a function of the administered antiepileptic drug [21].
Thus, deficits are often present when epilepsy begins, and their
temporal progress seems to depend on the etiology, positive/
negative treatment effects, and treatment success.
5. Is cognitive dysfunction a risk factor for developing epilepsy?
Prior to the epilepsy onset (e.g. the first unprovoked seizure(s)),
acquired, congenital, or developmental cerebral lesions, covert
epileptic dysfunction, and behavioral/psychiatric problems can
have a negative impact on cognition [49]. Accordingly, just on the
basis of theoretical considerations, one can expect cognitive
problems to already be present before epilepsy onset. Depending
on their etiology, cognitive deficits can be permanent. They may
also increase due to developmental hindrance or progress of the
underlying pathology or they may be reversible, if the treatment of
the underlying disease or seizures is successful. The fact that
cognitive impairment often is already present when an epilepsy
starts, however, does not answer the question as to whether
cognitive dysfunction is a risk factor for the developing epilepsy.
We are not aware of any studies that explicitly address this issue
but once again, this question can be approached theoretically. Both
cognitive impairments and seizures represent symptoms of altered
brain function, and it is not surprising that the probability of
seizure occurrence is increased in the presence of a pathology
which also causes cognitive problems. This does not mean that
cognitive dysfunction is a necessary or sufficient criterion for
developing epilepsy.
One can, however, argue that poorer cognitive functions are an
indicator of less cognitive differentiation, and thus less inhibitory
capacities, leading to an increased probability of seizure occur-
rence and spread. Better cognition is generally understood as a
marker of greater reserve capacity to cope with any harming
condition, be it transitory or permanent. Better cognition, as
expressed by IQ for example, has repeatedly been demonstrated as
an indicator for treatment success [57–61].
Epileptic dysfunction and cognition are in part strongly
connected to each other; they may occur together due to a
common underlying pathological process, but they may also be
related in a bidirectional way. Cognition can be negatively affected
by epileptic activity as it is discussed with the concept of TCI
(transient cognitive impairment) when cognition is corrupted
during the presence of epileptic EEG activity (i.e. single or groups of
spikes or spike waves, or longer phases of epileptic activity in terms
of nonconvulsive seizures) [62–65]. The occurrence of seizures not
only depends on the activity of the epileptic focus but also on the
activity of distant non-pathological brain areas [66]. Consequently,
if non-focal brain areas are under intentional use cognitive
activation can hinder seizure evolution, because it becomes
difficult for epilepsy to overtake/recruit the brain areas which
are already functionally occupied. Techniques of behavioral seizure
control techniques are mostly based on this principle [67–69].
Unfortunately this relation is not one-way and linear, i.e. cognition
opposes epilepsy. It rather seems to follow a U-shaped function in
terms of an optimal network favoring seizure generation and
spread. In fact sometimes cognitive activation of epilepsy-related
networks can trigger seizures [70] as it is observed particularly in
reflex epilepsies [71].
6. When seizures as well as cognitive and mood problems
represent symptoms
As described in the introduction section, epileptology tends to
have an epilepsy-centric view regarding epilepsy as the implicit
causal factor of cognitive and behavioral comorbidities. Physicians
from different disciplines could well argue that epilepsy represents
a secondary condition induced by head trauma, tumor, depression,
etc. as dependent on which medical condition is taken as the index
disease. Here, it is argued that the term comorbidity of epilepsy, as
long as any causal direction is implicated, is problematic, since it
prevents the unbiased view of the disease and may even prevent
the search for causal factors. The decisive question is when and
under which conditions epilepsy (i.e. having seizures) is a disease
or a symptom, thus leading back to the initial discussion of the
beginnings of epileptology, wherein about 82% of the cases of pure
or genuine epilepsy was assumed to represent the majority of
epilepsies [9,10,72]. This would be viewed in a totally different
manner today. In the 1990s, about 30% of the epilepsies of the
Icelandic population had an identifiable etiology [73]. From studies
in patients with temporal lobe epilepsy, we know that with
improved neuroimaging and with subsequent evaluations by
experts and quantitative analyses, the number of non-lesional
cases is fading away [74,75]. Thus, our knowledge is increasing
with regard to the etiologies of epilepsies, which finds its
expression in ever-changing terminology and classification sys-
tems. These tend to move away from a symptom- and syndrome-
based description of epilepsies and seizures, and towards the
inclusion of etiologies which also includes genetic causes [76]. The
most recent insights into the relation of epilepsy and its behavioral
“comorbidities” come from the recognition of an increasing
number of late-onset temporal lobe epilepsies on the basis of
autoimmunological inflammatory processes. In an epileptological
context, autoimmune encephalitis often presents with seizures of a
mesio-temporal origin, corresponding MRI changes (hippocampal
and/or amygdala swelling and FLAIR hyperintensity), as well as
cognitive and psychiatric symptoms which can be acute, but are
more often subacute and waxing and waning [77–79]. Subgroups
of limbic encephalitis can be discerned with auto-antibodies
 C. Helmstaedter, J.-A. Witt / Seizure 49 (2017) 83–89
directed against neuronal cell surface antigens, or intracellular
neuronal antigens as well as auto-antibody negative patients who
are thought to suffer from limbic encephalitis as they share clinical
features with antibody positive patients. Three aspects of limbic
encephalitis are relevant for the purpose of this paper. First, limbic
encephalitis can lead to temporal lobe epilepsy with hippocampal
atrophy and sclerosis. As seen in patients with antibodies against
the voltage-gated potassium channel (VGKC), the antibodies,
seizures, MRI abnormalities, cognition, and psychiatric symptoms
can co-vary during the course of the disease and with treatment
success. If treated successfully with immunomodulatory therapy,
the seizures disappear and both cognition and mood improve
[80–83]. Residual problems are possibly dependent on the affected
molecular target [80] and how early treatment is initiated (i.e.
whether permanent structural damage could be prevented).
Therefore, one obtains insight into the evolution of mesial
temporal lobe epilepsy with hippocampal sclerosis, and what is
more important, one can clearly state that in this condition,
seizures, cognitive problems, and psychiatric problems are
symptoms of the common underlying autoimmune disease.
Second, in antibody-negative patients and in glutamic acid
decarboxylase (GAD) antibody- related limbic encephalitis, seiz-
ures, structural brain alterations, cognition, and psychiatric
symptoms show variations over time which seem quite indepen-
dent of each other [81,84]. Here, seizures, morphological changes,
cognition and psychiatric problems again represent symptoms of
some underlying disease, which should be followed-up indepen-
dently with a multimodal diagnostic approach.
Third, in an epileptological context, patients with limbic
encephalitis are seen because they present with acute and often
late-onset temporal lobe epilepsy. Temporal lobe seizures are not a
required criterion for the diagnosis of limbic encephalitis, and
there is an unknown number of patients with limbic encephalitis
who do not have seizures and will not consult an epilepsy center.
Nevertheless, we had the chance to observe a patient prior to
developing seizures and prior to the diagnosis of a GAD antibody
related limbic encephalitis. This patient visited the clinic because
of two amnestic episodes months before. The patient complained
about anterograde as well as retrograde episodic memory
problems (loss of autonoetic awareness of recent biographical
memories and accelerated long-term forgetting). Over several
months, the patient searched for a doctor and was diagnosed as
suffering from burn-out and depression [85]. Here, the cognitive
and behavioral problems preceded the epilepsy. This is consistent
with the fact that the first epileptic seizure may mark the onset of
epilepsy with overt seizures, but not the onset of the underlying
pathological condition.
7. Conclusion
As outlined in the present article, there is indeed a certain
bidirectional relationship between epilepsy and cognition. On the
one hand seizures can have a time-limited and reversible negative
impact on cognition (i.e. ictal and postictal cognitive dysfunction),
and also interictal epileptic discharges may affect cognitive
performance. On the other hand there are cases in which certain
cognitive or behavioral activities can either elicit or prevent,
suppress or abort a seizure, providing the basis for behavioral
seizure control techniques.
However, seizures and cognitive deficits may also represent
distinct symptoms of a common underlying brain pathology as in
limbic encephalitis.
As it stands there is no convincing evidence in man that
recurrent seizures or the accumulation of lifetime seizures, taken
alone, lead to a progressive and irreversible decline of (previously
developed) cognitive functions. The idea of a “pure” epilepsy
87
without an underlying pathology which causes mental decline is
insupportable when taking into account that even with genetic
epilepsies, some kind of pathology must be present to cause
seizures. In those cases in which the etiology of epilepsy is clear-
cut, having seizures seems to be much more symptomatic than an
actual disease, and if seizures are considered symptomatic, then a
search for the underlying cause must be undertaken.
Thus, we suggest a very pragmatic approach in response to the
question raised in this article. A neuropsychological assessment
should be conducted in order to determine: 1) to which degree
cognitive and behavioral problems result from the active epilepsy
or its treatment; 2) whether impairments are consistent with early
vs. late acquired brain pathology; 3) whether the problems reflect
developmental hindrance or accelerated mental decline with
reference to the baseline conditions. If cognition or behavior are
impaired or show a negative dynamic, then this, like the first
seizure or the exacerbation of seizures, should alert the physician
to initiate a search for the underlying cause.
For depression as one of the major comorbidities of epilepsy it
has been demanded since long that it needs to be diagnosed and
treated. The same should be demanded in regard to the cognitive
impairments in epilepsy. For patients with epilepsy who display
cognitive and behavioral problems, additional education, training,
occupational therapy and/or psychotherapy should be provided.
Taking the suggested bidirectional relation of epilepsy and
cognition into account, we would even not exclude that training
up the brain may have beneficial effects in regard to seizure
control.
As long as we believe that seizures are causing all of the
problems seen in epilepsy, then all of the treatment efforts will be
directed towards the seizures. This assumes that all of the patient’s
problems would be resolved if the seizures were controlled.
However, this is not the case, and just focusing on the seizures may
prevent the search for any underlying, active or past disease
process which, when treated, may improve the patient’s overall
condition, including cognitive and behavioral problems. For many
years, we have speculated as to how adult patients with early-
onset temporal lobe epilepsy developed hippocampal sclerosis and
an association with febrile seizures was discovered. Limbic
encephalitis may provide additional answers. Seizures are the
prominent problem in epilepsy, but the other symptoms can pose a
severe burden as well. These symptoms must also be treated,
particularly if the seizures cannot be fully controlled.
Conflict of interest
Neither C.H. nor J.-A. Witt have any conflict of interest in regard
to the submitted work on the bidirectional relationship of
cognition and epilepsy.
Acknowledgement
We would like to thank Karen Wörmann for proof-reading the
manuscript.
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