Seizure 26 (2015) 65–68

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Seizure
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Review

Cognition in the early stages of adult epilepsy§

Juri-Alexander Witt, Christoph Helmstaedter *
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: Purpose: The impact of duration of epilepsy on cognition has been discussed for a long time. More
Received 28 November 2014 recently, it has been recognized that cognitive deficits are often already present at the onset of epilepsy
Received in revised form 30 January 2015 or even before. From an etiological point of view it is now understood that it is not really the question
Accepted 31 January 2015
what comes first, epilepsy or cognitive comorbidity. Instead the evidence suggests that both problems
rather originate from a common underlying pathology.
Keywords: Methods: We selected studies addressing cognition in adult new-onset or newly diagnosed epilepsies
Epilepsy
before treatment initiation. Potential factors are outlined that affect cognition prior to, around or after
Adults
epilepsy onset.
Neuropsychology
Cognition Results: Most studies investigated newly diagnosed patients, but many included individuals who
Newly diagnosed already had a long history of seizures at the time of diagnosis. Fewer studies focused on new-onset
New onset epilepsies. Overall, cognitive problems in the early stages of adult onset epilepsy were found to be
common. The occurrence of seizures may initially cause greater concern and lead to an underreporting of
cognitive problems prior to or around the time of diagnosis.
Conclusion: The high prevalence of objective cognitive impairments present at epilepsy onset calls for
early neuropsychological assessments soon after the diagnosis of epilepsy, and at best before medical
treatment is initiated. Without such baseline assessments subsequent neuropsychological testing during
follow-up is difficult to interpret in regard to the effects of treatment success or the course of underlying
disease processes. Beyond that, the baseline assessment may also guide treatment choices and serve as
an early indicator of the need for support or rehabilitation. In this way neuropsychological monitoring
can improve individual medical care, and increase tolerability, adherence, and treatment retention from
the point of diagnosis.
ß 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.

Cognitive deficits in epilepsy are frequent and can have
negative effects on daily functioning. The etiology of cognitive
deficits is often multi-factorial, since static and dynamic factors
can synergistically affect cognition [1,2]. Static factors primarily
refer to the presence of developmental or acquired cerebral lesions
causing both, epilepsy and cognitive impairment. Dynamic factors
contributing to cognitive impairment are (1) active epilepsy, i.e.
seizures and interictal epileptic discharges, (2) antiepileptic drug
treatment (AEDs), and (3) psychiatric comorbidities. However,
these factors are not necessarily independent of each other. Age at
§
One of the authors of this paper is a member of the current editorial team of
Seizure. The supervision of the independent peer review process was undertaken
and the decision about the publication of this manuscript were made by other
members of the editorial team.
* Corresponding author at: Department of Epileptology, University of Bonn,
Sigmund-Freud-Str. 25, 53105 Bonn, Germany.
Tel.: +49 228 287 16108; fax: +49 228 287 90 16108.
E-mail address: C.Helmstaedter@uni-bonn.de (C. Helmstaedter).
first hit or onset of epilepsy must be considered as an important
moderator variable, since early epilepsy and underlying patholo-
gies can negatively affect brain maturation and development
[3,4]. Additionally, individual reserve capacities and age- and sex-
dependent neural plasticity need to be considered [5].
Against the background of this etiological model of cognitive
deficits in epilepsy, the situation apparently becomes more and
more complex with an increasing duration of epilepsy (see Table 1
for an overview of the potential factors that may affect cognition in
the course of time). In the later stages of chronic epilepsy, and
without repeated standardized assessment, it is hardly possible to
retrospectively attribute cognitive deficits to particular factors
which may be involved (cf. [6] for an attempt on a group level). This
emphasizes the need for neuropsychological assessments at an
early stage of epilepsy to be able to disentangle the complex
interactions of the factors contributing to cognitive problems [7].
Ideally, cognition should be assessed shortly after the onset of
epilepsy and, at the latest, before treatment initiation. Such a
baseline assessment is required for a subsequent monitoring of

http://dx.doi.org/10.1016/j.seizure.2015.01.018
1059-1311/ß 2015 British Epilepsy Association. Published by Elsevier Ltd. All rights reserved.
66 J.-A. Witt, C. Helmstaedter / Seizure 26 (2015) 65–68
Table 1
Potential factors affecting cognition before and at epilepsy onset, and thereafter. Gray boxes indicate a potential impact.
Prior to At Controlled epilepsy
epilepsy epilepsy (100% seizure
onset onset control)
Cerebral
lesions
Covert epileptic
dysfunction
Overt epileptic
seizures
Antiepileptic
treatment
Behavioral/
psychiatric
problems
treatment success and the course of the disease. Furthermore,
information on the cognitive status can also indicate the need for
rehabilitative procedures, or it can direct treatment choices. By
means of cognitive monitoring, neuropsychology allows for quality
and outcome control of medical interventions striving for an
improved individual medical care [2].
Since the mutual relationship between pathology, epilepsy, and
cognition has become increasingly recognized, cognition in people
with new-onset epilepsy has been studied more intensively. In
2011, this issue was identified as a theme of major importance for
neuropsychological research in the field of epilepsy [8]. Beforehand
it is important to point out that a careful distinction needs to be
made between research relating to children and adults. In children,
neuropediatric services and parents are concerned with brain and
mental development as soon as a patient is diagnosed with
epilepsy. For a review focusing on cognition in pediatric patients
with new-onset seizures please see Hermann et al. [9]. In children
it has been demonstrated how early assessment allows for the
monitoring of the subsequent course of epilepsy [10,11]. This may
well serve as a model for adult epileptology. However, in adults it is
still common practice at the stage of diagnosis to explore the
etiology of seizures and focus on rapid seizure control but not to
take account of comorbidities such as cognitive difficulties.
For this review we performed a literature search (medline) for
original articles investigating cognition in ‘‘untreated’’ ‘‘adult
patients’’ with ‘‘new-onset epilepsy’’ or ‘‘newly-diagnosed epilep-
sy’’. Only studies with an objective cognitive assessment were
considered. A total of 11 studies met these criteria. Most of them
addressed at least attention and memory and reported respective
impairments in these domains [12–22] (for overview see Table 2).
However, the studies differed considerably in regard to patient
selection, sample sizes, etiologies, assessment tools, the question
of any pretreatment, and most importantly in regard to the
duration of untreated epilepsy. A point of major importance is that
most studies investigated newly diagnosed patients and not
patients with new-onset epilepsies, emphasizing the need for a
clear terminology [23]. Indeed the mean duration of epilepsy in the
different patient cohorts ranged from 92 days to 7 years. Even the
newly diagnosed patients of the SANAD study presented with a
mean epilepsy duration of 5 years [18]. The same is true for an early
study performed at our center comparing the cognitive effects of
first treatment on lesional versus non-lesional patients [22]. This
means that the neuropsychological findings from such studies
cannot tell us much about new-onset epilepsy. Another factor
Cured Chronic
epilepsy refractory
(seizure free, epilepsy
AEDs
withdrawn)
which needs to be considered is age at the onset of epilepsy, which
ranges on average between 27 and 71 years. The age at the onset
of epilepsy is strongly connected to its etiology. Therefore the
results obtained in early versus late onset epilepsies can hardly be
compared without taking pathology and the interaction of
pathology with the maturing versus aging brain into consideration.
In the light of the increasing incidence of epilepsy with older age, a
recent study investigated elderly patients with new-onset epilepsy
aged between 60 and 95 years. As expected elderly patients
showed greater impairments than the younger sample [20].
Some studies analyzed patients without evidence of brain
pathology in order to disclose the sole effect of active epilepsy on
cognition [12,14,18]. One study considered epilepsy syndromes
and compared the neuropsychological results between idiopathic,
symptomatic and cryptogenic epilepsies [19]: Among these
subtypes, symptomatic epilepsies presented with the worst
performance in executive function. Finally, most studies simply
compared the cognitive performance of patients with newly
diagnosed epilepsy and healthy controls on a group level. Only five
of the 11 studies assessed more than 100 patients, a minority had
larger reference groups of healthy subjects, and only six studies
provide prevalences/frequencies of cognitive deficits on an
individual level according to normative data or healthy controls
[18–20]. Taylor et al. report impaired performance in 1–18% of all
measures of the employed test battery [18]. Fifty-four percent of
the patients versus 21% of the healthy controls were impaired in at
least one test score. A study in 247 middle-aged patients with new-
onset epilepsy found impairments in attention and memory in 48–
49% of the sample [19]. Less than one third was unimpaired in both
domains. Subjective deficits in the respective domains were
complained by 25–29% of the patients only. This indicates an
underreporting of cognitive deficits at this early stage of epilepsy.
Comparable underreporting was evident in 257 elderly patients
with new-onset epilepsy [20]: The prevalence of objective deficits
in executive function was 58%, whereas subjective deficits
were reported in only up to 27% of the patients. The independent
observation in two studies that cognitive problems were
underreported when compared to objective assessment may be
interpreted in a way that in the patients’ view and at that early
stage of the disease the diagnosis of seizures and their expected
consequences are of pressing relevance. In chronic epilepsies
cognitive complaints are much more frequent [24,25].
The finding that cognitive-behavioral deficits may precede
seizure onset [26], raises the question of whether there is a
 J.-A. Witt, C. Helmstaedter / Seizure 26 (2015) 65–68 67

Table 2
Neuropsychological studies in untreated patients with new-onset or newly diagnosed epilepsy.

First author Year Investigated sample N Age [M (SD)] Duration of Reference Evaluated cognitive domains Pre-treatment
epilepsy group impairment
[M (SD)]

Kälviäinen 1992 Cryptogenic epilepsies 74 32 (12) n.a.a 39 healthy Attention, memory, language, 26–39%
intelligence
Helmstaedter 1993 Symptomatic (75%), idiopathic 16 27.2 (9.0) 6.7 years 19 healthy Attention, language, memory 3/10 measures
(25%) epilepsies
Äikiä 1995 Cryptogenic epilepsies 56 34.2 (14.4) n.a. 48 healthy Verbal memory, intelligence 14–75%
Prevey 1998 Symptomatic epilepsies 201 45.7 (15.7) 7.3 years 45 healthy Attention and executive 17/18 measures
functions, memory, motor
functions, intelligence
Ogunrin 2000 Focal or generalized seizures 60 31.6 (17.4) n.a. 60 healthy Attention, memory 7/8 measures
Pulliainen 2000 Focal or generalized seizures 52 30.2 (12.6) 1 year (54%), 26 healthy Attention, memory, motor 5/20 measures
>1 year (46%)b functions
Äikiä 2001 Left temporal lobe epilepsies 39 35.3 (15.4) 3.5 (5.5) years 46 healthy Verbal memory, verbal 44–92%
(62% cryptogenic) 16 treated intelligence
patient with
epilepsy
Wesnes 2009 Focal or generalized seizures 570 29.5 (median) n.a. Test norms Attention and executive Present, but not
functions, memory, motor specified
functions, fluid intelligence
Taylor 2010 Non-lesional with focal or 155 35.0 (14.4) 5.1 years 87 healthy Attention and executive 1–18%; 6/14
generalized seizures functions, memory measures
Witt 2012 Symptomatic (48%), 247 47.0 (18.8) 92.4 (94.4) 220–359 Attention and executive 48–49%, no
cryptogenic (27%), idiopathic days healthy functions, verbal memory impairment
(25%) epilepsies at all in 28%
Witt 2014 Symptomatic (88%), 257 71.5 (7.2) <6 months 689 healthy Attention and executive 58%
cryptogenic (12%) epilepsies functions

M, mean; SD, standard deviation; n.a., not available.

a
A median of 1 generalized and 0 complex-partial seizures before inclusion.
b
In 15% first manifestation before >10 years.

bidirectional relationship between the cognitive deficits and
epilepsy. It is clear that people with epilepsy have a higher risk
of cognitive deficits. But do people with cognitive impairment also
have a higher risk of developing epilepsy? Although this is rather
an epidemiological question, one may pursue a more theoretical
approach to answer this question. First of all, epilepsy is a
dysfunction of the brain associated with hyperexcitability leading
to recurrent seizures. In symptomatic epilepsies, the dysfunction is
caused by an epileptogenic lesion. Depending on its etiology and
pathology, such a lesion may exist for a long time before the
occurrence of the first seizure (cf. latent period in temporal lobe
epilepsy with hippocampal sclerosis). Since the lesion itself can
cause cognitive impairments, it would be not surprising that
patients with new-onset symptomatic epilepsy exhibit a cognitive
deficit consistent with the localization, lateralization and extent of
the lesion (cave: very early brain damage may additionally affect
development on a more global level thus causing intellectual
disability). Moreover, one cannot rule out that covert epileptic
dysfunction affects cognition even before the first overt seizure, as
may be observed with transitory cognitive impairment due to
interictal epileptic discharges [27]. Last but not least, psychiatric
disturbances that negatively affect cognition may also precede or
even promote epilepsy. For instance, there are studies indicating a
bidirectional relationship between depression and epilepsy
[28,29]. In addition, it needs to be considered that the new
diagnosis of epilepsy may have adverse effects on the patient’s
mood and due to this also on cognitive performance. However, one
study in new-onset epilepsies found no correlation between the
self-rated impact of the diagnosis on psychic well-being and
objective cognitive performance [19].
In summary, the current evidence from studies in newly
diagnosed and new-onset epilepsies show that cognitive deficits
are already very common at epilepsy onset. An important and
unanswered question is whether the cognitive impairment
resulting from acquired or developmental cerebral lesions is a
marker for the risk of future epilepsy (or epileptogenesis). Table 1
summarizes the potential factors that affect cognition prior to
and at epilepsy onset as well as in the time after the development
of seizures. It demonstrates, how difficult it is to isolate the
impact of an individual factor on cognition. The most discrimina-
tive information can be provided by intraindividual follow-up
examinations taking account of treatment changes and variations
in seizure control [30].
In new-onset symptomatic/structural epilepsy, the cognitive
profile at epilepsy onset is primarily determined by the char-
acteristics of the underlying brain lesion (time of damage/onset,
extent, site, and side), eventual interictal epileptic discharges, and
psychiatric problems. Individual patient characteristics and
related differences in reserve capacities and neural plasticity need
to be considered as well.
In idiopathic generalized epilepsies, genetically mediated
alterations of nerve cell proteins (e.g. subunits of ion channels)
are assumed to enhance neuronal excitability. Gross structural–
morphological brain abnormalities are usually not present. Here,
cognitive problems are primarily caused by dynamic epileptic
dysfunction, and also by secondary behavioral and psychiatric
problems. Such problems may precede the first seizure, leading to
dynamic and variable cognitive deficits as compared to the more
stable lesion-related impairments. Nevertheless, they may have,
even if reversible, a negative impact on cognitive development in
general.
The high prevalence of objective cognitive deficits, even at the
onset of epilepsy, the underreporting of cognitive problems by the
patient, and the increasing number of factors contributing to
cognitive dysfunction with more chronic epilepsy and its treatment
call for routine neuropsychological baseline assessments soon
after the onset/diagnosis, at least before treatment is initiated.
As outlined above, such a baseline assessment is a prerequisite
for valid repeat evaluations undertaken to reflect the course of
the disease and treatment success. Moreover, the baseline assess-
ment may direct drug choice and can be taken as an early
indicator of the need of supportive or rehabilitative care.
68 J.-A. Witt, C. Helmstaedter / Seizure 26 (2015) 65–68
However, it is still very uncommon for epilepsy services to
offer baseline cognitive assessments at the time of the diagnosis
nor subsequent cognitive monitoring as a matter of routine.
Cognitive assessment is often not reflected in the cost structure of
health care providers, and it is, at present, mostly limited to tertiary
epilepsy centers. Unfortunately, most patients with new-onset
seizures will in first instance see a general practitioner, resident
neurologist or an acute care hospital without any or only
limited and non-specialized neuropsychological service. One possi-
ble solution would be to establish clinics specializing in new-
onset epilepsies which offer sufficient neuropsychological expertise
to provide baseline and early follow-up assessments (for example
as an extension of tertiary epilepsy centers). An alternative
would be to improve the conditions of ambulatory neuropsycho-
logical services. The actual situation, at least in Germany, is quite
disappointing, both in terms of financing and with regard to
professional policy [31].
Neuropsychology can provide valid and reliable tools for quality
and outcome control of medical interventions. This has been
demonstrated particularly in the context of epilepsy surgery but
also in the context of medical treatment and pharmaceutical drug
trials. Disseminating this potential across institutions and coun-
tries remains a major challenge. European initiatives such as E-
Brain (www.ebrainjnc.com), or European networks like E-PILEPSY
(www.e-pilepsy.eu/) which aim at a harmonization of diagnostic
procedures and a common web-based platform for European
epilepsy centers may represent a first important step towards a
more routine use of neuropsychological assessment.
Conflict of interest statement
None of the authors has any conflict of interest in regard to the
topic and the contents of this article.
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